23 - Urology

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

> Table of Contents > 26 - Endocrinology

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26

Endocrinology

Paul A. Fitzgerald MD

Hormones exert their effects by interacting with receptors on the cell surface (catecholamines and peptide hormones) or in the cytoplasm and nucleus (thyroid and steroid hormones). Endocrine disorders result from an excess or deficiency of hormonal effects.

Common Presentations in Endocrinology

Unintended Weight Loss

Uncontrolled diabetes mellitus may be associated with weight loss, polyphagia, polydipsia, and polyuria. Anorexia and nausea may be seen with diabetic ketoacidosis and with adrenal insufficiency (due either to pituitary adrenocorticotropic hormone [ACTH] deficiency or to Addison's disease). Patients with severe diabetes insipidus may also lose weight. Patients with hyperthyroidism typically lose weight despite increased appetite; some patients with hypothyroidism lose weight because of diminished appetite. About 15% of patients with pheochromocytoma lose over 10% of their basal weight. Some patients with Cushing's syndrome lose weight as a result of muscle wasting.

A great variety of nonendocrine conditions enter into the differential diagnosis of unintended weight loss (see Chapter 2). Anorexia is frequently a side effect of medications or radiation therapy and is also seen with azotemia, AIDS, and many gastrointestinal conditions. Malignancies typically produce diminished appetite and cachexia. Tuberculosis may cause weight loss even when occult. Chronic respiratory insufficiency is often associated with weight loss. Psychiatric illnesses producing diminished appetite include depressed or agitated affective disorder, catatonia, and anorexia nervosa.

Abnormal Skin Pigmentation

Increased skin pigmentation can be caused by excessive ACTH secretion in Addison's disease and can occur after bilateral adrenalectomy for Cushing's disease (Nelson's syndrome). Pigmentation can be generalized or may be localized to palmar creases, extensor joint surfaces, tongue, nails, belt or bra lines, freckles, or new scars.

Pigmentation of the upper lip, forehead, or malar eminences, known as chloasma, can be caused by pregnancy (“mask of pregnancy”), oral contraceptives, or estrogen replacement therapy.

Acanthosis nigricans presents as velvety brown thickened skin of the neck and axillae. It may be associated with syndromes of severe insulin resistance type A (ovarian dysfunction and hirsutism) or type B (autoimmune). It may also be familial or associated with obesity, acromegaly, or thyroid disease. Acanthosis presenting after age 35 years is often a sign of an underlying malignancy, such as hepatocellular carcinoma.

Pretibial areas of pigmentation are common in diabetes (“diabetic shin spots”) as a result of minor trauma or following necrobiosis lipoidica diabeticorum.

Prominent lentigines can be a sign of Carney's complex, an autosomal dominant condition associated with atrial myxomas, schwannomas, and endocrine overactivity (eg, tumors of the thyroid, gonads, or pigmented adrenal nodular hyperplasia). Similar skin pigmentation is seen in Peutz-Jeghers syndrome with an increased risk of intestinal polyposis, adenocarcinoma, breast cancer, and tumors of the gonads and thyroid.

Diffuse hyperpigmentation is seen in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome; adrenal insufficiency, hypoparathyroidism, diabetes, osteosclerotic bone lesions, or thiamine deficiency may occur.

Gray-brown (“bronze”) hyperpigmentation is caused by hemochromatosis, which can cause endocrine deficiencies such as diabetes mellitus. An orange skin discoloration is characteristic of jaundice and carotenodermia (caused by ingestion of large amounts of carotene in vegetables, seaweed, or vitamin preparations).

Patchy hypopigmentation can be due to vitiligo, a condition sometimes associated with Addison's disease and with other endocrine deficiencies as part of the polyglandular autoimmune syndrome. Hypopigmentation can also be a manifestation of cobalamin deficiency, trisomy 13, and various dermatologic conditions.

Patients undergoing chronic hemodialysis frequently become hyperpigmented, and hypopigmentation has also been reported. Other causes of hyperpigmentation include sprue, malnutrition, HIV infection, and porphyria. Hyperpigmentation may be caused by certain drugs: amiodarone, arsenic, bleomycin, busulfan, clofazimine, hydroxychloroquine, chlorpromazine, doxorubicin (nail beds),

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imipramine, methimazole, minocycline, niacin, primaquine, propylthiouracil, topical tretinoin, and zidovudine (nails).

Obesity

See Nutrition, Chapter 29.

Gynecomastia

Essentials of Diagnosis

  • Enlargement of the male breast, often asymmetric or unilateral.

  • Glandular gynecomastia characterized by tenderness.

  • Fatty gynecomastia typically nontender.

  • Must be distinguished from tumors or mastitis.

General Considerations

Gynecomastia refers to a female-appearing male breast. Pubertal gynecomastia is common and the swelling usually subsides spontaneously within a year. Gynecomastia is particularly common in teenagers who are very tall or overweight. Gynecomastia develops in about 50% of athletes who abuse androgens and anabolic steroids. It is seen in Klinefelter's syndrome, which affects 1:500 men. (See section on Klinefelter's syndrome.) Gynecomastia can develop in HIV-infected patients treated with highly active antiretroviral therapy (HAART), especially in men receiving efavirenz or didanosine; breast enlargement resolves spontaneously in 73% of patients within 9 months. Gynecomastia is common among elderly men, particularly when there is associated weight gain. However, it can be the first sign of a serious disorder. Patients with Peutz-Jeghers syndrome are prone to development of gynecomastia caused by testicular tumors.

The causes of gynecomastia are multiple and diverse (Table 26-1).

Clinical Findings

A. Symptoms and Signs

Gynecomastia is graded according to severity: I, mild; II, moderate; III, severe. Fatty gynecomastia is usually diffuse and nontender. Glandular enlargement beneath the areola may be tender. Pubertal gynecomastia is characterized by tender discoid enlargement of breast tissue 2–3 cm in diameter beneath the areola.

Table 26-1. Causes of gynecomastia.

Idiopathic Bicalutamide
  Busulfan
Physiologic causes Chorionic gonadotropin
   Neonatal period Cimetidine
   Puberty Clomiphene
   Aging Cyclophosphamide
   Obesity Diazepam
     Diethylstilbestrol
Endocrine diseases Digitalis preparations
   Androgen resistance syndromes Estrogens (oral or topical)
Ethionamide
   Aromatase excess syndrome (sporadic or familial) Finasteride
Flutamide
Goserelin
   Diabetic lymphocytic mastitis HAART (highly active antiretroviral therapy)
   Hyperprolactinemia Haloperidol
   Hyperthyroidism Hydroxyzine
   Klinefelter's syndrome Isoniazid
   Male hypogonadism Ketoconazole
   Partial 17-ketosteroid reductase deficiency Leuprolide
Marijuana
     Meprobamate
Systemic diseases Methadone
   Chronic liver disease Methyldopa
   Chronic renal disease MetoclopramideMirtazapine
   Neurologic disorders
   Refeeding after starvation Molindone
   Spinal cord injury Nilutamide
     Omeprazole
     Opioids
Neoplasms Penicillamine
   Adrenal tumors Phenothiazines
   Bronchogenic carcinoma Progestins
   Carcinoma of the breast Protease inhibitors
   Hepatocellular carcinoma (rare) Reserpine
   Risperidone
   Testicular tumors Somatropin (growth hormone)
Drugs (partial list) Spironolactone
   Alcohol Testosterone
   Alkylating agents Thioridazine
   Amiodarone Tricyclic antidepressants
   Anabolic steroids  
   Androgens  

B. Laboratory Findings

Laboratory measurements of plasma levels of prolactin (PRL) (see Hyperprolactinemia) and the β-subunit of human chorionic gonadotropin (β-hCG). Detectable levels of β-hCG implicate a testicular tumor (germ cell or Sertoli cell) or other malignancy (usually lung or liver). Detectable low levels of serum β-hCG (< 5 mU/mL) may be reported in men with primary hypogonadism and high serum luteinizing hormone (LH) levels if the assay for β-hCG cross-reacts with LH. Measurements of plasma testosterone and LH are valuable in the diagnosis of primary or secondary hypogonadism.

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A low testosterone and high LH are seen in primary hypogonadism. High testosterone levels plus high LH levels characterize partial androgen resistance. Serum estradiol is determined but is usually normal; increased levels may result from testicular tumors, increased β-hCG, liver disease, obesity, adrenal tumors (rare), true hermaphroditism (rare), or gain of function mutations affecting the aromatase gene (rare). Many estrogens and substances with estrogenic activity are not detected by estradiol assays. Serum thyroid-stimulating hormone (TSH) (sensitive) and free thyroxine (FT4) levels are also determined. A karyotype (for Klinefelter's syndrome) is obtained in men with persistent gynecomastia without obvious cause.

Investigation of unclear cases should include a chest radiograph to search for metastatic or bronchogenic carcinoma. Needle biopsy with cytologic examination may be performed on suspicious areas of male breast enlargement (especially when unilateral or asymmetric) to distinguish gynecomastia from tumor or mastitis.

Treatment

Pubertal gynecomastia often resolves spontaneously within 1–2 years. Drug-induced gynecomastia resolves after the offending drug is removed. Spironolactone can be stopped, with substitution of a selective aldosterone antagonist such as eplerenone. Patients with painful or persistent (> 12 months) gynecomastia may be treated with a 3- to 9-month course of a selective estrogen receptor modulator (SERM; eg, raloxifene or tamoxifen). SERM therapy is much more effective for glandular (“lumpy”) gynecomastia than for diffuse fatty gynecomastia. There is some evidence that raloxifene, taken orally in a dose of 60 mg daily, may be the more effective drug. Aromatase inhibitors (eg, letrozole, anastrozole, or exemestane) are marginally effective and should not ordinarily be used for adolescent boys, since long-term therapy may prevent epiphyseal fusion. Surgical correction is reserved for patients with persistent or severe gynecomastia, since results are often disappointing. Endoscopically assisted transaxillary liposuction and subcutaneous mastectomy may produce acceptable results. Generally, it is prudent to treat patients for gynecomastia only when it becomes a troubling and continuing problem for them.

Lawrence SE et al: Beneficial effects of tamoxifen and raloxifene in the treatment of pubertal gynecomastia. J Pediatr 2004; 145:71.

Mira JA et al: Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. Antivir Ther 2004;9:511.

Ramon Y et al: Multimodality gynecomastia repair by cross-chest power-assisted superficial liposuction combined with endoscopic-assisted pull-through excision. Ann Plast Surg 2005; 55:591.

Rhoden EL et al: Treatment of testosterone-induced gynecomastia with the aromatase inhibitor, anastrozole. Int J Impot Res 2004;16:95.

Erectile Dysfunction & Diminished Libido in Men

Erectile dysfunction is a frequent problem. Psychogenic factors as well as endocrine, vascular, or neurologic abnormalities may be important. Hypogonadism of whatever origin is associated with lack of libido and erectile dysfunction. These can also be the first clinical manifestations of a hyperprolactinemic disorder. Other endocrine causes include hyperthyroidism, Addison's disease, and acromegaly. Impotence in men with diabetes may be related to inadequate penile blood flow or autonomic neuropathy. Vascular disease is a frequent factor in impotence in elderly men. Vascular claudication of the legs along with related impotence is known as Leriche's syndrome.

Many pharmacologic agents are known to cause varying degrees of impotence (Table 26-2). Selective serotonin reuptake inhibitors (SSRIs, eg, fluoxetine) cause reduced libido. SSRIs and clomipramine cause delayed ejaculation.

Evaluation and treatment of erectile dysfunction are covered in Chapters 23 and 25.

Cryptorchism

One or both testes may be absent from the scrotum at birth in about 20% of premature or low-birth-weight male infants and in 3–6% at full term infants. Cryptorchism is found in 1–2% of males after 1 year of age but must be distinguished from retractile testes, which require no treatment. Cryptorchism should be corrected before age 12–24 months in an attempt to reduce the risk of infertility, which occurs in up to 75% of men with bilateral cryptorchism and in 50% of men with unilateral cryptorchism. It is not clear, however, whether such early orchiopexy improves ultimate fertility. Some patients have underlying hypogonadism.

The ultimate incidence of significant testicular neoplasia is about 0.002% in normal males, 0.06% in cryptorchid males, and up to 5% in patients with intra-abdominal testes.

Table 26-2. Drugs causing erectile dysfunction.

Alcohol Marijuana
Amphetamines Methadone
Antihistamines Methyldopa
Barbiturates Metoclopramide
β-Blockers Monoamine oxidase inhibitors
Butyrophenones Opioids
Carbamazepine Phenothiazines
Cimetidine Sedatives
Clonidine Spironolactone
Cocaine Selective serotonin reuptake inhibitors
Guanethidine Thiazides
Ketoconazole Tricyclic antidepressants
Leuprolide  

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If the testes are not palpable, ultrasound or MRI can be used to locate them. Alternatively, hCG, 1500 units intramuscularly daily for 3 days, causes a significant rise in testosterone if the testes are present. Therapy with hCG results in a testicular descent rate of about 25%.

Orchiopexy decreases the risk of neoplasia when performed before 10 years of age. Orchiectomy after puberty is an option for intra-abdominal testes.

Henna MR et al: Hormonal cryptorchidism therapy: systematic review with metanalysis of randomized clinical trials. Pediatr Surg Int 2004;20:357.

Kolon TF et al: Cryptorchidism: diagnosis, treatment, and long-term prognosis. Urol Clin North Am 2004;31:469.

Bone Pain & Pathologic Fractures

Onset of pathologic fractures at an early age is seen in osteogenesis imperfecta (blue scleras may be present). Painful bowing of the bones and pseudofractures suggest rickets or osteomalacia. Vitamin D deficiency is a common cause of bone pain, and all patients with nontraumatic bone pain (or reduced bone density) should have a serum 25-hydroxyvitamin D determination. Any serum 25-hydroxyvitamin D level under 20 ng/mL (50 nmol/L) is considered low and an indication for vitamin D supplementation, although being considered in the “normal range” by many laboratories. Hyperparathyroidism or malignancy is suspected in patients with bone pain and hypercalcemia. Back pain or pathologic fractures in hypogonadal men and women implicate osteoporosis; such pain may be relieved with calcitonin. In cases of osteopenia of unknown cause, hyperthyroidism and Cushing's syndrome should also be considered. Bone pain may also occur as a result of primary or metastatic tumors, multiple myeloma, and Paget's disease; such pain may be relieved with bisphosphonates, such as intravenous zoledronic acid or oral alendronate. However, bisphosphonates themselves commonly cause bone pain.

Muscle Cramps & Tetany

Muscle cramps are usually caused by sports or occupational muscle injury. Nocturnal leg cramps are commonly idiopathic but are associated with diabetes mellitus, Parkinson's disease, central nervous system or spinal cord lesions, peripheral neuropathy, hemodialysis, peripheral vascular disease, and cisplatin or vincristine. Various other drugs can cause myalgias that patients describe as cramps (eg, cimetidine, cholestyramine). Alkalosis due to any cause (eg, severe vomiting or hyperventilation) may decrease ionized calcium and cause muscle cramping and paresthesias. Leg cramps during walking may be due to vascular insufficiency, hyperthyroidism, or hypothyroidism. A common cause for muscle pain, though not usually with cramping, is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy for hyperlipidemia; serum creatine kinase (CK) levels may be elevated in the presence of rhabdomyolysis, but are usually normal with statin-associated myopathy. Other medications can cause muscle cramping, including cholinesterase inhibitors, bisphosphonates, and chemotherapeutic agents (eg, imatinib). Acute arsenic intoxication can cause muscle cramps along with dysphagia, nausea, vomiting, and thirst. Muscle pain may be caused by dermatomyositis; CK levels are elevated. Diffuse muscle tenderness, especially with “trigger points” and normal serum CK levels, may indicate, fibromyalgia (see Chapter 20).

McArdle's disease is caused by muscle phosphorylase deficiency; patients present with muscle fatigue, cramping, and high serum CK levels; vitamin B6 (pyridoxine) supplementation reduces muscle cramps. Carnitine palmitoyltransferase II deficiency is a genetic disorder of lipid metabolism; presenting symptoms and signs include myalgia, cramping, myoglobinuria, and elevated serum CK levels. Other conditions that may cause muscle cramping include stiff man syndrome (abdominal and back cramping), Brody's disease, phosphoglycerate kinase deficiency (myoglobinuria), muscle phosphofructokinase deficiency (Tarui's disease), and neuromyotonia (Isaac's syndrome).

Diffuse, recurrent, or severe muscle cramping requires evaluation for hypocalcemia (see Table 21-8). Treatment of hypocalcemia is discussed in Chapter 21. Magnesium deficiency must be considered in tetany unresponsive to calcium.

For patients with recurrent, severe, or prolonged muscle cramping, gabapentin, 600–1200 mg/d orally, appears to be effective. Adverse effects of gabapentin may include leukopenia and central nervous system toxicities. Quinine, long used to prevent nocturnal muscle cramps, can cause arrhythmias, dizziness, hemolytic-uremic syndrome, and agranulocytosis. The US Food and Drug Administration has prohibited the marketing of quinine for leg cramps because of these side effects. Leg cramps, usually nocturnal, affect 45% of women during pregnancy; oral calcium or magnesium citrate supplementation twice daily may also improve cramping.

Exertional claudication caused by peripheral artery disease may be treated with oral pentoxifylline, cilostazol, angioplasty, or arterial bypass; the differential diagnosis includes neurogenic claudication, usually caused by spinal stenosis.

Recurrent cervicofacial and laryngeal dystonias, as well as hand cramps, have been successfully treated with injections of botulinum toxin.

de Carvalho M et al: Cramps, muscle pain, and fasciculations: not always benign? Neurology 2004;63:721.

Schwellnus MP et al: Serum electrolyte concentrations and hydration status are not associated with exercise associated muscle cramping (EAMC) in distance runners. Br J Sports Med 2004;38:488.

Mental Changes

Disturbances of mentation may be important indications of underlying endocrine disorders. Nervousness,

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irritability, apathy, and depression can be seen in both men and women with hypogonadism. Postpartum depression occurs in 10–15% of women. Premenstrual dysphoric disorder is common and may be due in part to an adverse reaction to progesterone. Oral or transdermal progestins also cause a similar syndrome. Anxiety and extreme irritability can be seen in patients with hyperthyroidism. Adult cretinism is the result of prolonged hypothyroidism in infancy. In adults, hypothyroidism is accompanied by mental slowness, depression, and lethargy. Occasionally, it may be manifested by delusional psychosis (“myxedema madness”). Pheochromocytoma may cause anxiety, confusion, or psychosis. Prolonged hypocalcemia from untreated hypoparathyroidism may be associated with intellectual deterioration. Hypoglycemia of any origin may cause confusion, abnormal speech, and behavioral or personality changes as well as sudden loss of consciousness, somnolence and prolonged lethargy, or coma; frank psychosis can occur but is rare. Mild hypercalcemia causes fatigue and emotional irritability. Severe hypercalcemia can cause confusion, psychosis, and coma. Confusion may occur in hypopituitarism or Addison's disease. Confusion, lethargy, and nausea may be the presenting symptoms of hyponatremia. Insomnia, mood changes, anxiety, and psychosis can be associated with Cushing's syndrome or high-dose corticosteroid administration. Rapid changes in corticosteroid status (either a sudden increase or a sudden decrease) may be associated with acute psychosis. Porphyria may cause affective and thought disorders, particularly during acute attacks.

Mental changes may result from vitamin deficiencies caused by malnutrition, malabsorption, and other conditions. Deficiency in vitamin B1 (thiamine) is usually seen in alcoholism and can cause Korsakoff's syndrome with typical memory loss and confabulation. Deficiency in vitamin B2 (riboflavin) may cause personality deterioration and occurs commonly with psychotropic and antimalarial drugs and with diabetes and other diseases. Vitamin B3 (niacin) deficiency is seen with poor nutrition, alcoholism, mercaptopurine toxicity, and malignant carcinoid syndrome and can cause irritability, dementia, dermatitis, and diarrhea. Vitamin B6 (pyridoxine) deficiency is frequently seen in alcoholics or during treatment with isoniazid or levodopa and can cause irritability, depression, and neuropathy. Deficiency of vitamin B12 (cobalamin) is caused by insufficient gastric intrinsic factor and may be seen at any age; however, it is more common in the elderly, affecting about 10% of people over age 70 years. Vitamin B12 deficiency may cause depression, irritability, paranoia, mania, psychotic symptoms, cognitive impairment, obsessive-compulsive disorder, and dementia. Although vitamin B12 deficiency is usually associated with other neurologic symptoms such as paresthesias and leg weakness, mental changes may occur in the absence of neurologic symptoms and without megaloblastic anemia. When serum vitamin B12 levels are borderline low, an elevated serum level of methylmalonic acid is an additional indication of vitamin B12 deficiency.

Disturbance in mentation is always an indication to evaluate for the endocrine and metabolic disorders discussed above. However, cognitive changes are more typically caused by organic brain or cerebrovascular disease, psychiatric problems, alcoholism, or drug abuse.

Diseases of the Hypothalamus & Pituitary Gland

Anterior pituitary gland function is controlled by hypothalamic hormones and by direct feedback inhibition. The posterior pituitary receives antidiuretic hormone and oxytocin from the hypothalamus, secreting them under central nervous system control (Table 26-3). Hypothalamic hormones generally stimulate the anterior pituitary except for dopamine, which inhibits the pituitary from spontaneously secreting PRL.

Anterior Hypopituitarism

Essentials of Diagnosis

  • Loss of one, all, or any combination of anterior pituitary hormones.

  • ACTH deficiency reduces adrenal secretion of cortisol, testosterone, and epinephrine; aldosterone secretion remains intact.

  • Growth hormone (GH) deficiency causes short stature in children; adults experience asthenia, obesity, and increased cardiac mortality.

  • PRL deficiency inhibits postpartum lactation.

  • TSH deficiency causes secondary hypothyroidism.

  • LH and follicle-stimulating hormone (FSH) deficiency cause hypogonadism and infertility in men and women.

General Considerations

Hypopituitarism can be caused by either hypothalamic or pituitary dysfunction. Patients with hypopituitarism may have single or multiple hormonal deficiencies. When one hormonal deficiency is discovered, others must be sought.

Mass lesions causing hypopituitarism include pituitary adenomas, granulomas, Rathke's cleft cysts, apoplexy, metastatic carcinomas, aneurysms, and brain tumors such as craniopharyngioma, meningioma, germinoma, glioma, chondrosarcoma, and chordoma of the clivus. Langerhans cell histiocytosis usually presents in youth with diabetes

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insipidus or hypopituitarism. Osteolytic bone lesions are noted on skeletal x-rays. Autoimmune hypophysitis, postpartum pituitary necrosis (Sheehan's syndrome), eclampsia-preeclampsia, sickle cell disease, and African trypanosomiasis are rare causes.

Table 26-3. Pituitary hormones.

Anterior pituitary
   Growth hormone (GH)1
   Prolactin (PRL)
   Adrenocorticotropic hormone (ACTH)
   Thyroid-stimulating hormone (TSH)
   Luteinizing hormone (LH)2
   Follicle-stimulating hormone (FSH)
Posterior pituitary
   Arginine vasopressin (AVP)3
   Oxytocin
1GH closely resembles human placental lactogen (hPL).
2LH closely resembles human chorionic gonadotropin (hCG).
3AVP is identical with antidiuretic hormone (ADH).

A pituitary tumor may be part of the syndrome of multiple endocrine neoplasia type 1 (MEN 1), with tumors of the parathyroid glands and pancreatic islets.

Hypopituitarism without mass lesions may be genetic or idiopathic, or may be caused by trauma, cranial radiation, surgery, encephalitis, hemochromatosis, autoimmunity, or stroke. It may also occur after coronary artery bypass grafting. About 25–30% of survivors of moderate to severe traumatic brain injury (Glasgow coma scale ≤ 13/15) have at least one anterior pituitary hormone deficiency. Following aneurysmal subarachnoid hemorrhage, at least one pituitary hormone deficiency develops in about 55% of survivors.

Physiologic isolated hypogonadotrophic hypogonadism is common, occurring with severe illness, malnutrition, and extreme prolonged exercise (in women). It is also commonly found among obese patients with type 2 diabetes mellitus. Long-term intrathecal administration of opioids causes hypogonadotropic hypogonadism in the overwhelming majority of patients; GH deficiency and secondary adrenal insufficiency each occurs in about 15% of such patients. High-dose oral methadone can also cause hypogonadotropic hypogonadism that may persist after stopping the drug.

Congenital combined pituitary hormone deficiency occurs in about 1:8000 births. Depending on the genetic defect, it may be transmitted as an autosomal recessive, autosomal dominant, or X-linked recessive trait. Mutations have been found in genes that encode transcription factors necessary for pituitary development. Mutations in the PROP1 gene are found in about 50% of patients with genetic combined pituitary hormone deficiency. Mutations in other genes, such as POU1F1, LHX3, LHX4, and HESX1, can also cause hypopituitarism. Some of these patients exhibit benign pituitary enlargement that may regress spontaneously.

Kallmann's syndrome is the most common cause of congenital isolated gonadotropin deficiency. It is usually sporadic but may be familial. Three different genetic inheritance patterns can occur: X-linked recessive (Kal 1), autosomal dominant (Kal 2), or autosomal recessive (Kal 3). Kallmann's syndrome has an incidence of 1:10,000 males and 1:50,000 females. It is associated with hyposmia caused by hypoplasia of the olfactory bulbs. In Kallmann's syndrome, about 50% of patients have unilateral renal agenesis; some patients may also exhibit cryptorchidism, sensorineural deafness, cerebellar dysfunction, bilateral synkinesis, nystagmus, cleft lip, or high-arched palate.

Clinical Findings

Manifestations of hypopituitarism vary depending on which specific hormones are lacking and whether their deficiency is partial or complete.

A. Symptoms and Signs

Gonadotropin deficiency includes loss of LH and FSH, which causes hypogonadism and infertility. Patients with isolated gonadotropin deficiency may present as delayed adolescence. (See also discussion of primary amenorrhea.) Congenital gonadotropin deficiency in males may be associated with congenital micropenis or cryptorchism.

Hypogonadotropic hypogonadism is also seen in patients with congenital adrenal hypoplasia, a rare X-linked disorder caused by a mutation in the DAX-1 gene. Boys with DAX-1 gene mutations usually present during infancy or childhood with adrenal insufficiency caused by failure to form the permanent zone of the adrenal cortex. Boys who survive beyond childhood usually fail to enter puberty as a result of hypogonadotropic hypogonadism. However, those with partial loss-of-function mutations in DAX-1 can present in adulthood with hypogonadotropic hypogonadism and subtle signs of adrenal failure.

In acquired gonadotropin deficiency, both men and women lose axillary, pubic, and body hair gradually, particularly if they are also hypoadrenal. Men may note diminished beard growth. Libido is diminished. Women have amenorrhea; men note decreased erections. Most patients are infertile. Androgen deficiency predisposes patients to osteopenia and muscle atrophy. (See section on secondary amenorrhea.)

TSH deficiency causes hypothyroidism with manifestations such as fatigue, weakness, weight change, and hyperlipidemia. (See Hypothyroidism and Myxedema.)

ACTH deficiency results in diminished cortisol secretion (see Adrenocortical Hypofunction). Symptoms may include weakness, fatigue, weight loss, and hypotension. Patients with partial ACTH deficiency continue to have some cortisol secretion and may not have symptoms until stressed by illness or surgery. Adrenal mineralocorticoid secretion continues, so manifestations of adrenal insufficiency in hypopituitarism are usually less striking than in bilateral adrenal gland destruction

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(Addison's disease); hyponatremia may occur, especially when ACTH and TSH deficiencies are both present.

GH deficiency in adulthood tends to cause mild to moderate central obesity, increased systolic blood pressure, and relative increases in low-density lipoprotein (LDL) cholesterol. GH deficiency also results in a small heart with reduced cardiac output, asthenia, and feelings of social isolation.

Panhypopituitarism is the absence of all anterior pituitary hormones. Combined pituitary hormone deficiency (CPHD) refers to a deficiency of several anterior pituitary hormones. Patients with PROP1 gene mutations gradually develop CPHD, usually presenting with short stature and growth failure due to GH and TSH deficiency; lack of pubertal development occurs due to deficiencies in FSH and LH. Patients with PROP1 gene mutations gradually develop ACTH-cortisol deficiency, and typically require corticosteroid replacement therapy by age 18 years. In addition to the manifestations noted above, patients with long-standing hypopituitarism tend to have dry, pale, finely textured skin. The face has fine wrinkles and an apathetic countenance.

B. Laboratory Findings

The fasting blood glucose may be low. Hyponatremia is often present. Hyperkalemia usually does not occur, since aldosterone production is not affected.

The free tetraiodothyronine (thyroxine, T4) level is low, and TSH is not elevated. Plasma levels of sex steroids (testosterone and estradiol) are low or low normal, as are the serum gonadotropins as well. Elevated PRL levels are found in patients with prolactinomas, acromegaly, and hypothalamic disease.

ACTH deficiency causes functional atrophy of the adrenal cortex within 2 weeks of pituitary damage. Therefore, the diagnosis of secondary hypoadrenalism may be confirmed by holding any corticosteroid medication on the day of the test and by administering cosyntropin (synthetic ACTH1–24), 0.25 mg (intramuscularly or intravenously); blood is drawn 30–60 minutes after the injection. A serum cortisol of ≥ 20 mcg/dL (550 nmol/mL), random or stimulated, rules out the diagnosis. A baseline ACTH level is low or normal in secondary hypoadrenalism, distinguishing it from primary adrenal disease.

Deficiency of epinephrine occurs with secondary adrenal insufficiency, since high local concentrations of cortisol are required to induce the production of the enzyme phenylethanolamine N-methyltransferase (PNMT) that catalyzes the conversion of norepinephrine to epinephrine in the adrenal medulla.

The diagnosis of GH deficiency is made difficult by the pulsatile nature of GH secretion and individual variability. GH deficiency is present in 96% of patients with three or more other pituitary hormone deficiencies. The insulin hypoglycemia test, long considered the “gold standard,” is actually unreliable, cumbersome, and uncomfortable; it is contraindicated in the elderly, in patients with cardiovascular or cerebrovascular disease, and in patients with any history of seizures, an abnormal electroencephalogram (EEG), or recent brain surgery. Other GH stimulation tests require the administration of intravenous arginine and oral carbidopa and levodopa (combination) in patients pretreated with propranolol or estrogen. However, these tests do not discriminate well between normal individuals and patients with presumed GH deficiency (patients with three or more other pituitary hormone deficiencies). Serum insulin-like growth factor (IGF-I) levels are in the normal range in about 50% of adults with GH deficiency. However, very low levels of IGF-I (< 84 mcg/L) are indicative of GH deficiency except in conditions that naturally suppress serum IGF-I (eg, malnutrition, prolonged fasting, oral estrogen, hypothyroidism, uncontrolled diabetes mellitus, liver failure). In GH deficiency, exercise-stimulated serum GH levels usually fail to rise and remain at < 5 ng/mL; however, by age 40 years, most normal adults have lost their GH response to exercise.

Because hemochromatosis can cause hypopituitarism, in patients with hypopituitarism without an established etiology, it is prudent to screen for hemochromatosis with a serum iron and transferrin saturation or ferritin.

C. Imaging

MRI provides the best visualization of parasellar lesions. In hemochromatosis, MRI shows a very hypointense anterior lobe on T1-weighted images, which is surrounded by hyperintense cerebrospinal fluid on T2-weighted images. The posterior pituitary usually has a high-intensity signal on sagittal T1-weighted MRI that is lacking in central diabetes insipidus. In Langerhans cell histiocytosis, MRI may reveal a mass lesion, thickening of the pituitary stalk, or be normal.

Differential Diagnosis

Reversible hypogonadotropic hypogonadism may occur with serious illness, malnutrition, or anorexia nervosa. The clinical situation and the presence of normal adrenal and thyroid function allow ready distinction from hypopituitarism. Profound hypogonadotropic hypogonadism develops in men who receive gonadotropin-releasing hormone (GnRH) therapy for prostate cancer; it usually persists following cessation of therapy. Hypogonadotropic hypogonadism usually develops in patients receiving high-dose methadone or chronic intrathecal infusion of opioids; both GH deficiency and secondary adrenal insufficiency occur in 15% of such patients. Secondary adrenal insufficiency may persist for many months following high-dose corticosteroid therapy.

Severe illness causes functional suppression of TSH and T4. Hyperthyroxinemia reversibly suppresses TSH. Administration of triiodothyronine (Cytomel) suppresses TSH and T4. Bexarotene, used to treat cutaneous T cell lymphoma, suppresses TSH secretion, resulting in temporary

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central hypothyroidism. Corticosteroids or megestrol treatment reversibly suppresses endogenous ACTH and cortisol secretion.

Complications

Patients with destructive lesions (eg, tumors) may develop complications related to them or to surgery or radiation therapy. Among patients with craniopharyngiomas, diabetes insipidus is found in 16% preoperatively and in 60% postoperatively. Hyponatremia often presents abruptly during the first 2 weeks following pituitary surgery. Visual field impairment may occur. Hypothalamic damage may result in morbid obesity as well as cognitive and emotional problems. Conventional radiation therapy results in an increased incidence of small vessel ischemic strokes and second tumors.

Patients with untreated hypoadrenalism and a stressful illness may become febrile and die in shock and coma.

Adults with GH deficiency have experienced an increased cardiovascular morbidity. Rarely, acute hemorrhage may occur in large pituitary tumors, manifested by rapid loss of vision, headache, and evidence of acute pituitary failure (pituitary apoplexy) requiring emergency decompression of the sella.

Treatment

Transsphenoidal removal of pituitary tumors will sometimes reverse hypopituitarism. Postoperative hyponatremia often occurs; serum sodium must be checked frequently for 2 weeks after pituitary surgery. Hypogonadism due to PRL excess usually resolves during treatment with dopamine agonists. Endocrine substitution therapy must be used before, during, and often permanently after such procedures.

GH-secreting tumors may respond to octreotide (see section on acromegaly). Radiation therapy with x-ray, gamma knife, or heavy particles may be necessary but increases the likelihood of hypopituitarism.

The mainstay of substitution therapy for pituitary insufficiency remains lifetime hormone replacement.

A. Corticosteroids

Hydrocortisone tablets, 15–30 mg/d orally in divided doses, should be given. Most patients do well with 15 mg in the morning and 5–10 mg in the late afternoon. Patients with partial ACTH deficiency (basal morning serum cortisol above 8 mg/dL [220 mmol/L]) require hydrocortisone replacement in lower doses of about 5 mg orally twice daily. Some patients feel better taking prednisone, 3–7.5 mg/d orally. A mineralocorticoid is rarely needed. To determine the optimal corticosteroid replacement dosage, it is necessary to monitor patients carefully for manifestations of overreplacement (Cushing's syndrome) or underreplacement. A serum white blood cell count (WBC) with a relative differential can be useful, since a relative neutrophilia and lymphopenia can indicate overreplacement with corticosteroid, and vice versa. Additional corticosteroids must be given during states of stress, eg, during infection, trauma, or surgical procedures. For mild illness, corticosteroid doses are doubled or tripled. For trauma or surgical stress, hydrocortisone is given in doses of 50 mg intramuscularly or intravenously every 6 hours and then reduced to normal doses as the stress subsides. Patients with adrenal insufficiency are advised to wear a medical alert bracelet describing their condition and treatment.

Patients with secondary adrenal insufficiency due to treatment with corticosteroids at supraphysiologic doses require their usual daily dose of corticosteroid during surgery and acute illness; supplemental hydrocortisone is not usually required.

B. Thyroid

Levothyroxine is given to correct hypothyroidism only after the patient is assessed for cortisol deficiency or is already receiving corticosteroids. (See Hypothyroidism.) The typical maintenance dose is about 1.6 mcg/kg body weight. However, dosage requirements vary widely, averaging 0.125 mg daily with a range of 0.025–0.3 mg daily. The optimal replacement dose of thyroxine for each patient must be carefully assessed clinically on an individual basis. Serum FT4 levels usually need to be in the high-normal range for adequate replacement. Assessment of serum TSH is useless for monitoring patients, since levels are always low with TSH deficiency.

C. Sex Hormones

Hypogonadotropic hypogonadism often develops in patients with hyperprolactinemia; it may be reversed with treatment of the hyperprolactinemia. (See Hyperprolactinemia.)

Androgen replacement is discussed in the section on male hypogonadism. Estrogen replacement is discussed in the section on female hypogonadism. Women with hypopituitarism and androgen deficiency may be treated with compounded dehydroepiandrosterone (DHEA) in doses of about 30 mg/d orally. DHEA therapy tends to increase pubic and axillary hair and improve libido, alertness, and stamina.

To improve spermatogenesis, hCG (equivalent to LH) may be given at a dosage of 2000–3000 units intramuscularly three times weekly and testosterone replacement is discontinued. The dose of hCG is adjusted to normalize serum testosterone levels. After 6–12 months of hCG treatment, if the sperm count remains low, hCG injections are continued along with injections of FSH: follitropin-β (synthetic recombinant FSH) or urofollitropins (urine-derived FSH). An alternative for patients with an intact pituitary (eg, Kallmann's syndrome) is the use of leuprolide (GnRH analog) by intermittent subcutaneous infusion. With either treatment, testicular volumes double within 5–12 months, and spermatogenesis occurs in most cases. With persistent treatment and the help of intracytoplasmic sperm injection for some cases, the total pregnancy

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success rate is about 70%. Clomiphene, 25–50 mg orally daily, can sometimes stimulate a man's own pituitary gonadotropins (when his pituitary is intact), thereby increasing testosterone and sperm production.

For fertility induction in females, ovulation may be induced with clomiphene, 50 mg daily for 5 days every 2 months. Follitropins and hCG can induce multiple births and should be used only by those experienced with their administration. (See Hypogonadism and Chapter 17.)

D. Human Growth Hormone (hGH)

Recombinant human growth hormone (rhGH) has been synthesized as a 191-amino acid sequence (somatropin) identical to hGH; an rhGH of 192 amino acids (somatrem) is also available and is of equal potency. Symptomatic adults with severe GH deficiency (serum IGF-I below 85 mcg/L) may be treated with a subcutaneous rhGH injection starting at a dosage of about 0.2 mg (0.6 IU)/day, administered three or four times weekly. The dosage of rhGH is increased every 2–4 weeks by increments of 0.1 mg (0.3 IU) until side effects occur or a sufficient salutary response and a normal serum IGF-I level are achieved. A sustained-release injectable suspension of GH has been developed (somatropin depot). It can be given once monthly and is therefore more convenient than standard rhGH preparations; however, its safety and dosing in adults remain to be established. If the desired effects (eg, improved energy and mentation, reduction in visceral adiposity) are not seen within 3–6 months at maximum tolerated dosage, rhGH therapy is discontinued.

During pregnancy, rhGH may be safely administered to women with hypopituitarism at their usual pregestational dose during the first trimester, tapering the dose during the second trimester, and discontinuing rhGH during the third trimester.

Oral estrogen replacement reduces hepatic IGF-I production. Therefore, prior to commencing rhGH therapy, oral estrogen is changed to a transdermal or transvaginal estradiol.

Side effects of rhGH therapy may include peripheral edema, hand stiffness, arthralgias, myalgias, headache, pseudotumor cerebri, gynecomastia, carpal tunnel syndrome, tarsal tunnel syndrome, hypertension, and proliferative retinopathy. Side effects are more common in older patients, those with greater weight and higher body mass index (BMI), and those with adult-onset GH deficiency. Such symptoms usually remit promptly after a sufficient reduction in dosage. Excessive doses of rhGH could cause acromegaly; patients receiving long-term therapy require careful clinical monitoring. Serum IGF-I levels should be kept in the normal range and periodic determinations of serum IGF-I levels are helpful in guiding therapeutic dosing.

GH should not be administered during critical illness since, in one study, administration of very high doses of rhGH to patients in an intensive care unit was shown to increase overall mortality. There is no role for GH replacement in the somatopause of aging.

E. Other Treatment

Selective transsphenoidal resection of pituitary adenomas can often restore normal pituitary function. Cabergoline, bromocriptine, or quinagolide may reverse the hypogonadism seen in hyperprolactinomas. (See Disorders of Prolactin Secretion.) Disseminated Langerhans cell histiocytosis may be treated with bisphosphonates to improve bone pain; treatment with 2-chlorodeoxyadenosine has been reported to produce complete remission.

Prognosis

The prognosis depends on the primary cause. Hypopituitarism resulting from a pituitary tumor may be reversible with dopamine agonists or with careful selective resection of the tumor. Spontaneous recovery from hypopituitarism associated with pituitary stalk thickening has been reported. Patients can also recover from functional hypopituitarism, eg, hypogonadism due to starvation or severe illness, suppression of ACTH by corticosteroids, or suppression of TSH by hyperthyroidism.

Functionally, most patients with hypopituitarism do very well with hormone replacement. Men with infertility who are treated with hCG/FSH or GnRH are likely to resume spermatogenesis if they have a history of sexual maturation, descended testicles, and a baseline serum inhibin level over 60 pg/mL. Women under age 40 years, with infertility due to hypogonadotropic hypogonadism, can usually have successful induction of ovulation.

Agha A et al: Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency. Clin Endocrinol (Oxf) 2004;60:688.

Böttner A et al: PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab 2004;89:5256.

Kreitschmann-Andermahr I et al: Prevalence of pituitary deficiency in patients after aneurysmal subarachnoid hemorrhage. J Clin Endocrinol Metab 2004;89:4986.

Leal-Cerro A et al: Prevalence of hypopituitarism and growth hormone deficiency in adults long-term after severe traumatic brain injury. Clin Endocrinol (Oxf) 2005;62:525.

Maison P et al: Impact of growth hormone (GH) treatment of cardiovascular risk factors in GH-deficient adults: a meta-analysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab 2004;89:2192.

Smith JC: Hormone replacement therapy in hypopituitarism. Expert Opin Pharmacother 2004;5:1023.

Verrees M et al: Pituitary tumor apoplexy: characteristics, treatment, and outcomes. Neurosurg Focus 2004;16:E6.

Posterior Hypopituitarism

Essentials of Diagnosis

  • Antidiuretic hormone (ADH) deficiency causes central diabetes insipidus with polyuria (2–20 L/d)

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    and polydipsia; hypernatremia occurs if fluid intake is inadequate.

  • Oxytocin deficiency causes lactation failure in postpartum women.

General Considerations

Diabetes insipidus is an uncommon disease characterized by an increase in thirst and the passage of large quantities of urine of low specific gravity (usually < 1.006 with ad libitum fluid intake). The urine is otherwise normal. It is caused by a deficiency of vasopressin or resistance to vasopressin.

Primary central diabetes insipidus (without an identifiable organic lesion noted on MRI of the pituitary and hypothalamus) accounts for about one-third of all cases of diabetes insipidus. Many such cases appear to be due to autoimmunity against hypothalamic arginine vasopressin (AVP)-secreting cells; pituitary stalk thickening can often be detected on pituitary MRI scanning. The cause may also be genetic. Familial diabetes insipidus occurs as a dominant genetic trait with symptoms developing at about 2 years of age. Diabetes insipidus also occurs in Wolfram syndrome, a rare autosomal recessive disorder that is also known by the acronym DIDMOAD (diabetes insipidus, type 1 diabetes mellitus, optic atrophy, and deafness). DIDMOAD manifestations usually present in childhood but may not occur until adulthood, along with depression and cognitive problems. Secondary central diabetes insipidus is due to damage to the hypothalamus or pituitary stalk by tumor, hypophysitis, anoxic encephalopathy, surgical or accidental trauma, infection (eg, encephalitis, tuberculosis, syphilis), sarcoidosis, or multifocal Langerhans cell (eosinophilic) granulomatosis (“histiocytosis X”). Metastases to the pituitary are more likely to cause diabetes insipidus (33%) than are pituitary adenomas (1%).

Vasopressinase-induced diabetes insipidus may be seen in the last trimester of pregnancy and in the puerperium; it is often associated with oligohydramnios, preeclampsia, or hepatic dysfunction. A circulating enzyme destroys native vasopressin; however, synthetic desmopressin is unaffected. The condition usually responds to desmopressin therapy (see below) and subsides spontaneously.

Nephrogenic diabetes insipidus is a disorder caused by a defect in the kidney tubules that interferes with water reabsorption. The polyuria is unresponsive to vasopressin. These patients have normal secretion of vasopressin. Congenital nephrogenic diabetes insipidus is present from birth and is due to defective expression of renal vasopressin V2 receptors or vasopressin-sensitive water channels. It occurs as a familial X-linked trait; adults often have hyperuricemia as well.

Acquired forms of vasopressin-resistant diabetes insipidus are usually less severe and are seen in pyelonephritis, renal amyloidosis, myeloma, potassium depletion, Sjögren's syndrome, sickle cell anemia, or chronic hypercalcemia. The disorder may occur also as a corticosteroid effect or as an acute side effect of diuretics. Certain drugs (eg, demeclocycline, lithium, foscarnet, or methicillin) may induce nephrogenic diabetes insipidus. The recovery from acute tubular necrosis may also be associated with transient nephrogenic diabetes insipidus. (See Kidney Disorders.)

Clinical Findings

A. Symptoms and Signs

The symptoms of the disease are intense thirst, especially with a craving for ice water, and polyuria, the volume of ingested fluid varying from 2 L to 20 L daily, with correspondingly large urine volumes. Partial diabetes insipidus presents with less intense symptoms and should be suspected in patients with unremitting enuresis. Most patients with diabetes insipidus are able to maintain fluid balance by continuing to ingest large volumes of water. However, diabetes insipidus may present with hypernatremia and dehydration in patients without free access to water, or with a damaged hypothalamic thirst center and altered thirst sensation. Diabetes insipidus is aggravated by administration of high-dose corticosteroids, which increases renal free water clearance.

B. Laboratory Findings

The diagnosis of diabetes insipidus as a cause of polyuria or hypernatremia requires clinical judgment. There is no single diagnostic laboratory test. Evaluation for diabetes insipidus should include an accurate 24-hour urine collection that is measured for volume and creatinine. A urine volume of < 2 L/24 h (in the absence of hypernatremia) essentially rules out diabetes insipidus. Serum is assayed for glucose, urea nitrogen, calcium, potassium, sodium, and uric acid. Hyperuricemia occurs in many patients with diabetes insipidus, since reduced vasopressin stimulation of the renal V1 receptor causes a reduction in the renal tubular clearance of urate.

If the clinical situation implicates central diabetes insipidus (and no other causes for polyuria are present; see Differential Diagnosis, below), a supervised “vasopressin challenge test” may be given: Desmopressin acetate is given in an initial dose of 0.05–0.1 mL (5–10 mcg) intranasally (or 1 mcg subcutaneously or intravenously), with measurement of urine volume for 12 hours prior to and 12 hours after administration. Serum sodium must be obtained immediately in the event of symptoms of hyponatremia. The dosage of desmopressin is doubled if the response is marginal. Patients with central diabetes insipidus notice a distinct reduction in thirst and polyuria; serum sodium stays normal except in some salt-losing conditions.

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In nonfamilial central diabetes insipidus, MRI of the pituitary and hypothalamus and of the skull is done to look for mass lesions. The pituitary stalk may be thickened, which may be a manifestation of Langerhans cell histiocytosis, sarcoidosis, or lymphocytic hypophysitis. Absence of a posterior pituitary “bright spot” on T1-weighted MRI is suggestive of central diabetes insipidus.

When nephrogenic diabetes insipidus is a diagnostic consideration, measurement of serum vasopressin is done during modest fluid restriction; typically, the vasopressin level is high.

Differential Diagnosis

Central diabetes insipidus must be distinguished from polyuria caused by diabetes mellitus, Cushing's syndrome or corticosteroid treatment, lithium, hypercalcemia, hypokalemia, and the nocturnal polyuria of Parkinson's disease. It must also be distinguished from nephrogenic diabetes insipidus (see above), the excessive fluid intake seen in psychogenic polydipsia, central nervous system sarcoidosis, and intravenous fluid administration.

Complications

If water is not readily available, the excessive output of urine will lead to severe dehydration. Patients with an impaired thirst mechanism are very prone to hypernatremia, particularly since they usually also have impaired mentation and forget to take their desmopressin. All the complications of the primary disease may eventually become evident. In patients who are receiving desmopressin acetate therapy, there is a danger of induced water intoxication.

Treatment

A. Diabetes Insipidus

Desmopressin acetate is the treatment of choice for central diabetes insipidus. It is also useful in diabetes insipidus associated with pregnancy or the puerperium, since desmopressin is resistant to degradation by the circulating vasopressinase.

Desmopressin is available as an oral preparation (0.1 or 0.2 mg tablets) that is given in a starting dose of 0.05 mg twice daily and increased to a maximum of 0.4 mg every 8 hours, if required. Oral desmopressin is particularly useful for patients with sinusitis from the nasal preparation. Mild increases in hepatic enzymes can occur with the oral preparation. Gastrointestinal symptoms and asthenia may also occur.

The nasal preparation (100 mcg/mL solution) is given every 12–24 hours as needed for thirst and polyuria. It may be administered via metered-dose nasal inhaler containing 0.1 mL/spray or via a plastic calibrated tube. Patients are started with 0.05–0.1 mL every 12–24 hours, and the dose is then individualized according to response.

Desmopressin is also available as a parenteral preparation containing 4 mcg/mL. For central diabetes insipidus, it is given intravenously, intramuscularly, or subcutaneously in doses of 1–4 mcg every 12–24 hours as needed to treat thirst or hypernatremia.

Adverse reactions to desmopressin have included nasal irritation, occasional agitation, and erythromelalgia. Hyponatremia is uncommon if minimum effective doses are used and the patient allows thirst to occur periodically.

Mild cases of diabetes insipidus require no treatment other than adequate fluid intake. Reduction of aggravating factors (eg, corticosteroids, which directly increase renal free water clearance) will improve polyuria. Both central and nephrogenic diabetes insipidus respond partially to hydrochlorothiazide, 50–100 mg/d orally (with potassium supplement or amiloride). Nephrogenic diabetes insipidus may respond to combined treatments of indomethacin-hydrochlorothiazide, indomethacin-desmopressin, or indomethacin-amiloride. Indomethacin, 50 mg orally every 8 hours, is effective in acute cases.

Psychotherapy is required for most patients with compulsive water drinking. Thioridazine and lithium are best avoided if drug therapy is needed, since they cause polyuria.

B. Oxytocin Deficiency

Women lacking oxytocin are unable to nurse their infants. Oxytocin induces the contraction of myoepithelial cells surrounding the mammary alveoli, which leads to the ejection of milk. Both oxytocin and milk removal are required for postpartum alveolar proliferation and successful lactation.

Nasal oxytocin (Syntocinon) is not available in the United States. It is used to promote milk let-down in normal postpartum women and with variable success in women with hypopituitarism. The dosage is one puff into each nostril in the sitting position 2–3 minutes before nursing.

Prognosis

Central diabetes insipidus appearing after pituitary surgery usually remits after days to weeks but may be permanent if the upper pituitary stalk is cut.

Chronic central diabetes insipidus is ordinarily more an inconvenience than a dire medical condition. Treatment with desmopressin allows normal sleep and activity. Hypernatremia can occur, especially when the thirst center is damaged, but diabetes insipidus does not otherwise reduce life expectancy, and the prognosis is that of the underlying disorder.

Oxytocin deficiency is a permanent condition. It does not affect life expectancy.

Smith CJA et al: Phenotype-genotype correlations in a series of Wolfram syndrome families. Diabetes Care 2004;27:2003.

Verbalis JG: Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab 2003;17:471.

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Acromegaly & Gigantism

Essentials of Diagnosis

  • Excessive growth of hands, feet, jaw, and internal organs; or gigantism before closure of epiphyses.

  • Amenorrhea, headaches, visual field loss, weakness.

  • Soft, doughy, sweaty handshake.

  • Elevated IGF-I.

  • Serum GH not suppressed following oral glucose.

General Considerations

GH exerts much of its growth-promoting effects through the release of IGF-I produced in the liver and other tissues.

Acromegaly is nearly always caused by a pituitary adenoma. These tumors may be locally invasive, particularly into the cavernous sinus. Less than 1% are malignant. Most are macroadenomas (over 1 cm in diameter). Acromegaly is usually sporadic but may rarely be familial. The disease may be associated with endocrine tumors of the parathyroids or pancreas (MEN 1). Acromegaly may also be seen in McCune-Albright syndrome and as part of Carney's complex (atrial myxoma, acoustic neuroma, and spotty skin pigmentation). Acromegaly is rarely caused by ectopic growth hormone-releasing hormone (GHRH) or GH secreted by a lymphoma, hypothalamic tumor, bronchial carcinoid, or pancreatic tumor.

Clinical Findings

A. Symptoms and Signs

Excessive GH causes tall stature and gigantism if it occurs before closure of epiphyses. Afterward, acromegaly develops. The term “acromegaly,” meaning extremity enlargement, seriously understates the manifestations. The hands enlarge and a doughy, moist handshake is characteristic. The fingers widen, causing patients to enlarge their rings. Carpal tunnel syndrome is common. The feet also grow, particularly in shoe width. Facial features coarsen since the bones and sinuses of the skull enlarge; hat size increases. The mandible becomes more prominent, causing prognathism and malocclusion. Tooth spacing widens.

Macroglossia occurs, as does hypertrophy of pharyngeal and laryngeal tissue; this causes a deep, coarse voice and sometimes makes intubation difficult. Obstructive sleep apnea may occur. A goiter may be noted. Hypertension (50%) and cardiomegaly are common. At diagnosis, about 10% of acromegalic patients have overt heart failure, with a dilated left ventricle and a reduced ejection fraction. Weight gain is typical, particularly of muscle and bone. Insulin resistance is usually present and frequently causes diabetes mellitus (30%). Arthralgias and degenerative arthritis occur. Overgrowth of vertebral bone can cause spinal stenosis. Colon polyps are common, especially in patients with skin papillomas. The skin may also manifest hyperhidrosis, thickening, cystic acne, and areas of acanthosis nigricans.

GH-secreting pituitary tumors usually cause some degree of hypogonadism, either by cosecretion of PRL or by direct pressure upon normal pituitary tissue. Decreased libido and impotence are common, as are irregular menses or amenorrhea. Secondary hypothyroidism sometimes occurs; hypoadrenalism is unusual. Headaches are frequent. Temporal hemianopia may occur as a result of the optic chiasm being impinged by a suprasellar growth of the tumor.

B. Laboratory Findings

The patient should be fasting for at least 8 hours (except for water), not acutely ill, and should not have exercised on the day of testing. A serum specimen is obtained and assayed for the following: IGF-I (increased to over five times normal in most acromegalics), PRL (cosecreted by many GH-secreting tumors), glucose (diabetes is common in acromegaly), liver enzymes and blood urea nitrogen (BUN) (hepatic or renal failure can misleadingly elevate GH), serum calcium (to screen for hyperparathyroidism), serum inorganic phosphorus (frequently elevated), serum free T4, and TSH (secondary hypothyroidism is common in acromegaly; primary hypothyroidism may increase PRL, and hyperthyroidism may occur as a result of excess TSH).

Glucose syrup (75 g) is then administered orally, and serum GH is measured 60 minutes afterward; acromegaly is excluded if the serum GH is less than 1 ng/mL (immunoradiometric assay [IRMA] or chemiluminescent assays) or less than 2 ng/mL (older radioimmunoassays) after glucose syrup, and if the serum IGF-I is normal.

C. Imaging

MRI shows a pituitary tumor in 90% of acromegalics. MRI is generally superior to CT scanning, especially in the postoperative setting. Radiographs of the skull may show an enlarged sella and thickened skull. Radiographs may also show tufting of the terminal phalanges of the fingers and toes. A lateral view of the foot shows increased thickness of the heel pad.

Differential Diagnosis

Active acromegaly must be distinguished from familial coarse features, large hands and feet, and isolated prognathism and from inactive (“burned-out”) acromegaly in which there has been a spontaneous remission due to infarction of the pituitary adenoma. GH-induced gigantism must be differentiated from familial tall stature and from aromatase deficiency. (See Osteoporosis.)

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Misleadingly high serum GH levels can be caused by exercise or eating just prior to the test; acute illness or agitation; hepatic or renal failure; malnourishment; diabetes mellitus; or concurrent treatment with estrogens, β-blockers, or clonidine.

Complications

Complications include hypopituitarism, hypertension, glucose intolerance or frank diabetes mellitus, cardiac enlargement, and cardiac failure. Carpal tunnel syndrome may cause thumb weakness and thenar atrophy. Arthritis of hips, knees, and spine can be troublesome. Cord compression may be seen. Visual field defects may be severe and progressive. Acute loss of vision or cranial nerve palsy may occur if the tumor undergoes spontaneous hemorrhage and necrosis (pituitary apoplexy). Patients with acromegaly are more likely to develop colon polyps.

Treatment

Endoscopic transnasal, transsphenoidal pituitary microsurgery removes the adenoma while preserving anterior pituitary function in most patients. Surgical remission is achieved in about 70% of patients followed over 3 years. GH levels fall immediately; diaphoresis and carpal tunnel syndrome often improve within a day after surgery. Transsphenoidal surgery is usually well tolerated, but complications occur in about 10% of patients, including infection, cerebrospinal fluid leak, and hypopituitarism. Hyponatremia can occur 4–13 days postoperatively and is manifested by nausea, vomiting, headache, malaise, or seizure. It is prudent to monitor serum sodium levels postoperatively. Dietary salt supplements for 2 weeks postoperatively may prevent this complication.

Patients who do not have a clinical or biochemical remission after surgery are treated with a dopamine agonist (eg, cabergoline), somatostatin analogs, pegvisomant, or a combination of these medications. Cabergoline may be used first, since it is an oral medication. Cabergoline therapy is most successful for tumors that secrete both PRL and GH, but can also be effective for patients with normal serum PRL levels. Therapy with cabergoline will shrink one-third of such tumors by more than 50%. The initial dose is 0.25 mg orally twice weekly, which is gradually increased to a maximum dosage of 1 mg twice weekly, if tolerated by the patient based upon serum GH and IGF-I levels. Side effects of cabergoline include nausea, fatigue, constipation, abdominal pain, and dizziness. Cabergoline is expensive.

Octreotide and lanreotide are somatostatin analogs that are given by subcutaneous injection. Short-acting octreotide acetate in doses of 50 mcg is injected three times daily. Responders who tolerate the drug are switched to long-acting octreotide acetate injectable suspension in a dosage of 20 mg intragluteally per month. The dosage may be adjusted—up to a maximum of 40 mg monthly—to maintain the serum GH between 1 and 2.5 ng/mL, keeping IGF-I levels normal. Lanreotide SR (not available in the United States) is given by subcutaneous injection at a dosage of 30 mg every 7–14 days. Lanreotide Autogel (not available in the United States) is a newer formulation that is administered by deep subcutaneous injection in doses of 60–120 mg every 28 days; this preparation is better tolerated than lanreotide SR. All somatostatin analogs are expensive and must be continued indefinitely or until other treatment has been effective. Octreotide long-acting release (LAR) preparations (Sandostatin LAR depot) are superior to shorter-acting octreotide, ultimately achieving serum GH levels under 2 ng/mL in 79% of patients and normal serum IGF-I levels in 53% of patients. Headaches often improve, and tumor shrinkage of about 30% may be expected. Acromegalic patients with pretreatment serum GH levels exceeding 20 ng/mL are less likely to respond to octreotide therapy. Side effects are experienced by about one-third of patients and include injection site pain, loose acholic stools, abdominal discomfort, or cholelithiasis.

Pegvisomant is a GH receptor antagonist that blocks the effects of GH. Pegvisomant therapy produces symptomatic relief and normalizes serum IGF-I levels in over 90% of acromegalic patients. The starting dosage is 10 mg subcutaneously daily. The maintenance dosage can be increased by 5–10 mg every 4–6 weeks, based on serum IGF-I levels and liver transaminase levels; the maximum dosage is 30 mg subcutaneously daily. Pegvisomant does not shrink GH-secreting tumors. Patients need to be monitored carefully with visual field examinations, GH levels, and MRI scanning of the pituitary. Side effects of pegvisomant can include injection site reactions, hepatitis, edema, flu-like syndrome, nausea, and hypertension. In acromegalic diabetics, hypoglycemic drugs are reduced to avoid hypoglycemia during pegvisomant therapy. The effectiveness of pegvisomant is reduced by coadministration of opioids or propoxyphene. Pegvisomant is extraordinarily expensive.

Acromegalic patients who have not had a complete remission with transsphenoidal surgery or medical therapy may be treated with stereotactic radiosurgery administered by gamma knife, heavy particle radiation, or adapted linear accelerator. Some medical centers are using pituitary gamma knife radiosurgery as the initial treatment with reported success rates of 20–90%. Radiosurgery precisely radiates the pituitary tumor in a single session and reduces radiation to the normal brain. However, it cannot be used for pituitary tumors with suprasellar extension due to the risk of damaging the optic chiasm. Radiosurgery can be used for pituitary tumors invading the cavernous sinus, since cranial nerves III, IV, V, and VI are less susceptible to radiation damage. Radiosurgery can also be used for patients who have not responded to conventional radiation therapy.

Prognosis

Patients with acromegaly have increased morbidity and mortality from cardiovascular disorders; those

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who are treated and have a glucose-suppressed serum GH level less than 2.5 ng/mL (radioimmunoassay) or under 1 ng/mL (immunofluorometric assay) and normal age-adjusted serum IGF-I levels have reduced morbidity and mortality. Patients with untreated or persistent acromegaly tend to have premature cardiovascular disease and progressive acromegalic symptoms. Transsphenoidal pituitary surgery is successful in 80–90% of patients with tumors less than 2 cm in diameter and GH levels less than 50 ng/mL. Extrasellar extension of the pituitary tumor, particularly cavernous sinus invasion, reduces the likelihood of surgical cure. Adjuvant medical therapy has been quite successful in treating patients who are not cured by pituitary surgery. Postoperatively, normal pituitary function is usually preserved. Soft tissue swelling regresses but bone enlargement is permanent. Hypertension frequently persists despite successful surgery. Conventional radiation therapy (alone) produces a remission in about 40% of patients by 2 years and 75% of patients by 5 years after treatment. Gamma knife or cyberknife radiosurgery reduces GH levels an average of 77%, with 20% of patients having a full remission after 12 months. Patients with pituitary adenomas that abut the optic chiasm can be treated with cyberknife radiosurgery, controlling tumor growth and preserving vision in most patients. Heavy particle pituitary radiation produces a remission in about 70% of patients by 2 years and 80% of patients by 5 years. Radiation therapy eventually produces some degree of hypopituitarism in most patients. Conventional radiation therapy may cause some degree of organic brain syndrome and predisposes to small strokes. Patients must receive lifelong follow-up, with regular monitoring of serum GH and IGF-I levels. Serum GH levels over 5 ng/mL and rising IGF-I levels usually indicate a recurrent tumor.

Hypopituitarism may occur, due to the tumor itself, pituitary surgery, or radiation therapy. Hypopituitarism may develop years following radiation therapy, so patients must have regular clinical monitoring of their pituitary function.

Castinetti F et al: Outcome of gamma knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. J Clin Endocrinol Metab 2005;90:4483.

Cozzi R et al: Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status. Clin Endocrinol (Oxf) 2004;61:209.

Feenstra J et al: Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet 2005; 365:1644.

Ferone D et al: Current diagnostic guidelines for biochemical diagnosis of acromegaly. Minerva Endocrinol 2004;29: 207.

Serri O et al: Long-term biochemical status and disease-related morbidity in 53 postoperative patients with acromegaly. J Clin Endocrinol Metab 2004;89:658.

Hyperprolactinemia

Essentials of Diagnosis

  • Women: Menstrual cycle disturbances (oligomenorrhea, amenorrhea); galactorrhea; infertility.

  • Men: Hypogonadism; decreased libido and erectile dysfunction; infertility.

  • Elevated serum PRL.

  • CT scan or MRI often demonstrates pituitary adenoma.

General Considerations

Elevated serum PRL can be caused by numerous conditions (Table 26-4). PRL-secreting pituitary tumors are more common in women than in men and are usually sporadic but may rarely be familial as part of MEN 1. Most are microadenomas (< 1 cm in diameter) that do not grow even with pregnancy or oral contraceptives. However, some giant prolactinomas can spread into the cavernous sinuses and suprasellar areas; rarely, they may erode the floor of the sella to invade the sinuses.

Table 26-4. Causes of hyperprolactinemia.

Physiologic Causes Pharmacologic Causes Pathologic Causes
Exercise
Idiopathic
Macroprolactinemia (“big prolactin”)Pregnancy
Puerperium
Sleep (REM phase)
Stress (trauma, surgery)
Suckling
Amoxapine
Amphetamines
Anesthetic agents
Antipsychotics (conventional and atypical)
Butyrophenones
Cimetidine and ranitidine (not famotidine or nizatidine)
Estrogens
Hydroxyzine
Methyldopa
Metoclopramide
Opioids
Nicotine
Phenothiazines
Protease inhibitors
Progestins
Reserpine
Risperidone
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Verapamil
Acromegaly
Chronic chest wall stimulation (postthoracotomy, postmastectomy, herpes zoster, breast problems, chest acupuncture, nipple rings, etc)
Cirrhosis
Hypothalamic disease
Hypothyroidism
Multiple sclerosis
Optic neuromyelitis
Pituitary stalk section
Prolactin-secreting tumors
Pseudocyesis (false pregnancy)
Renal failure (especially with zinc deficiency)
Spinal cord lesions
Systemic lupus erythematosus

Clinical Findings

A. Symptoms and Signs

Hyperprolactinemia due to any cause may result in hypogonadotropic hypogonadism and reduced fertility. Men usually have erectile dysfunction and diminished libido; gynecomastia sometimes occurs, but rarely with galactorrhea. Women may note oligomenorrhea or amenorrhea, though some women continue to menstruate normally. Galactorrhea, defined as lactation in the absence of nursing, is common. Of women with secondary amenorrhea and galactorrhea, about 70% have hyperprolactinemia. Untreated hypogonadism ultimately increases the risk for developing osteoporosis.

Pituitary prolactinomas may cosecrete growth hormone and cause acromegaly (see above). Large tumors may cause headaches, visual symptoms, and pituitary insufficiency.

B. Laboratory Findings

Evaluate for conditions known to cause hyperprolactinemia, particularly pregnancy (serum hCG), hypothyroidism (serum FT4 and TSH), renal failure (BUN and serum creatinine), cirrhosis (clinical evaluation and serum bilirubin and liver enzymes) and hyperparathyroidism (serum calcium). Men are evaluated for hypogonadism with determinations of serum total and free testosterone, LH, and FSH. Women who have amenorrhea are assessed for hypogonadism with determinations of serum

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estradiol, LH, and FSH. An assay for macroprolactinemia should be considered for patients with hyperprolactinemia who are relatively asymptomatic and have no apparent cause for hyperprolactinemia. Patients with pituitary macroadenomas (> 3 cm in diameter) should have PRL measured on serial dilutions of serum, since IRMA assays may otherwise report falsely low titers, the “high-dose hook effect.” Patients with macroprolactinomas or manifestations of possible hypopituitarism should be evaluated for hypopituitarism as described above.

C. Imaging

When hyperprolactinemia persists without obvious cause, MRI of the pituitary and hypothalamus is indicated. Small prolactinomas may thus be demonstrated, but clear differentiation from normal variants is not always possible.

Differential Diagnosis

The causes of hyperprolactinemia are shown in Table 26-4. Chronic nipple stimulation, nipple piercing, augmentation or reduction mammoplasty, and mastectomy may stimulate PRL secretion. The pituitary tumor of acromegaly can cosecrete GH and PRL. Hyperprolactinemia may also be idiopathic. Increased pituitary size is a normal variant in young women. About 10% of hyperprolactinemic patients are found to be secreting macroprolactin, a relatively inactive “big prolactin”; pituitary MRI is normal in 78% of cases.

The differential diagnosis for galactorrhea includes the small amount of breast milk that can be expressed from the nipple in many parous women that is not cause for concern. Nipple stimulation from nipple rings, chest surgery, or acupuncture can cause galactorrhea; serum PRL levels may be normal or minimally elevated. Some women can have galactorrhea with normal serum PRL levels and no discernible cause (idiopathic). Normal breast milk may be various colors besides white. Bloody galactorrhea requires an evaluation for breast malignancy.

Treatment

Medications known to increase PRL should be stopped if possible. Hyperprolactinemia due to hypothyroidism is corrected by thyroxine. Patients with hyperprolactinemia not induced by drugs, hypothyroidism, or pregnancy should be examined by pituitary MRI.

Women with microprolactinomas who have amenorrhea or are desirous of contraception may safely take oral contraceptives or estrogen replacement—there is minimal risk of stimulating enlargement of the microadenoma. Patients with infertility and hyperprolactinemia may be treated with a dopamine agonist in an effort to improve fertility. Women who elect to receive no treatment have an increased risk of developing osteoporosis; such women require periodic bone densitometry.

Pituitary macroprolactinomas (> 10 mm in diameter) have a higher risk of progressive growth, particularly during treatment with estrogen or testosterone replacement therapy or during pregnancy. Therefore, patients with macroprolactinomas should not be treated with sex hormone replacement therapy unless they are in remission

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with dopamine agonist medication or surgery. Pregnant women with macroprolactinomas should continue to receive treatment with dopamine agonists throughout the pregnancy to prevent tumor growth.

A. Dopamine Agonists

Dopamine agonists are the initial treatment of choice for patients with giant prolactinomas and those with hyperprolactinemia desiring restoration of normal sexual function and fertility. Of the ergot-derived dopamine agonists, cabergoline is usually the best tolerated and is prescribed beginning with a dosage of 0.25 mg orally once weekly for 1 week, then 0.25 mg twice weekly for the next week, then 0.5 mg twice weekly. Further dosage increases may be required monthly, based on serum PRL levels, up to a maximum of 1.5 mg twice weekly. Higher doses of cabergoline, (≥ 2 mg daily, have been reported to cause mitral valve regurgitation. Alternative drugs include bromocriptine (1.25–20 mg/d orally) and pergolide (0.125–2 mg/d orally). Women who experience nausea with oral preparations may find relief with deep vaginal insertion of cabergoline or bromocriptine tablets; vaginal irritation sometimes occurs. Quinagolide (Norprolac; not available in the United States) is a non-ergot-derived dopamine agonist for patients intolerant or resistant to ergot-derived medications; the starting dosage is 0.075 mg/d orally, increasing as needed and tolerated to a maximum of 0.6 mg/d.

Dopamine agonists are given at bedtime to minimize side effects of fatigue, nausea, dizziness, and orthostatic hypotension. These symptoms usually improve with dosage reduction and continued use. Erythromelalgia is rare. Dopamine agonists can cause a variety of psychiatric side effects that are not dose related and may take weeks to resolve once the dopamine agonist is discontinued. Therefore, dopamine agonists should be used judiciously in psychiatric patients whose antipsychotic medications have caused hyperprolactinemia.

With dopamine agonist treatment, 90% of patients with prolactinomas experience a fall in serum PRL to 10% or less of pretreatment levels; about 80% of treated patients achieve a normal serum PRL level. Shrinkage of a pituitary adenoma occurs early, but the maximum effect may take up to a year. Nearly half of prolactinomas—even massive tumors—shrink more than 50%. Such shrinkage of giant prolactinomas can result in spinal fluid rhinorrhea. Discontinuing therapy after months or years usually results in the reappearance of hyperprolactinemia and galactorrhea-amenorrhea, but some patients with microadenomas remain in remission.

Because dopamine agonists usually restore fertility promptly, many pregnancies have resulted; no teratogenicity has been noted with any of the dopamine agonists. However, women with microadenomas may have treatment safely withdrawn during pregnancy. Macroadenomas may enlarge significantly during pregnancy; if therapy is withdrawn, such patients must be monitored clinically with serum PRL determinations and with computer-assisted visual field perimetry. Women with macroprolactinomas who have responded to dopamine agonists may safely receive oral contraceptive agents as long as they continue receiving therapy.

B. Surgical Treatment

For most patients with prolactinomas, therapy with dopamine agonists is overwhelmingly preferable to surgery, particularly for giant prolactinomas that distort surgical fields. Transsphenoidal pituitary surgery may be urgently required for large tumors undergoing apoplexy or those severely compromising visual fields. It is also used electively for patients who do not tolerate or respond to dopamine agonists. Craniotomy is rarely indicated, since even large tumors can usually be decompressed via the transsphenoidal approach.

C. Radiation Therapy

Radiation therapy is reserved for patients with macroadenomas that are growing despite treatment with dopamine agonists. A single gamma knife or cyberknife treatment is preferable for certain patients whose optic chiasm is clear of tumor, since it is generally safer and more convenient than conventional radiation therapy. Conventional radiation therapy must be given over 5 weeks and carries a high risk of eventual hypopituitarism. Other possible side effects include some degree of memory impairment and an increased long-term risk of second tumors and small vessel ischemic strokes. After radiation therapy, patients are advised to take low-dose aspirin to reduce their stroke risk.

Colao A et al: Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treatment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis. J Clin Endocrinol Metab 2004;89:1704.

Delgrange E: Cabergoline and mitral regurgitation. N Engl J Med 2006;354:420.

Gibney J et al: The impact on clinical practice of routine screening for macroprolactin. J Clin Endocrinol Metab 2005;90: 3927.

Haddad PM et al: Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004; 64:2291.

Molitch ME: Medication-induced hyperprolactinemia. Mayo Clin Proc 2005;80:1050.

Sodi R et al: Testosterone replacement-induced hyperprolactinaemia: case report and review of the literature. Ann Clin Biochem 2005;42(Pt 2):153.

Diseases of the Thyroid Gland

Tests of Thyroid Function (Table 26-5)

The thyroid tests discussed in this section are ordinarily very helpful in the evaluation of thyroid disorders.

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However, many conditions and drugs alter serum T4 levels without affecting clinical status (Table 26-6).

Table 26-5. Appropriate use of thyroid tests.

  Test Comment
Screening Serum thyroid-stimulating hormone (TSH) (sensitive assay) Most sensitive test for primary hypothyroidism and hyperthyroidism
Free thyroxine (FT4) Excellent test
For hypothyroidism Serum TSH High in primary and low in secondary hypothyroidism
Antithyroglobulin and antithyroperoxidase antibodies Elevated in Hashimoto's thyroiditis
For hyperthyroidism Serum TSH (sensitive assay) Suppressed except in TSH-secreting pituitary tumor or pituitary hyperplasia (rare)
Triiodothyronine (T3) (radioiodine) Elevated
123I uptake and scan Increased uptake; diffuse versus “hot” areas on scan
Antithyroglobulin and antimicrosomal antibodies Elevated in Graves' disease
Thyroid-stimulating immunoglobulin (TSI); TSH receptor antibody (TSH-R Ab [stim]) Usually (65%) positive in Graves' disease
For nodules Fine-needle aspiration biopsy (FNAB) Best diagnostic method for thyroid cancer
123I uptake and scan Cancer is usually “cold”; less reliable than FNA1 biopsy
99mTc scan Vascular versus avascular
Ultrasonography Useful to assist FNA1 biopsy. Useful in assessing the risk of malignancy (multinodular goiter or pure cysts are less likely to be malignant). Useful to monitor nodules and patients after thyroid surgery for carcinoma.
1Fine-needle aspiration.

The tests most widely used in clinical practice are serum immunoassays for TSH and FT4. Assays for FT4 have largely supplanted measurements of total T4, resin T3 uptake (RT3U), and free thyroxine index (FT4I).

1. Serum Thyroid Tests

TSH Immunoassay

There is considerable debate about what constitutes a normal range for serum TSH levels. The normal range for ultrasensitive TSH levels is generally stated to be 0.4–5.5 mU/L. However, over 95% of normal individuals have serum TSH concentrations under 3.0 mU/L. There is a high risk of finding antithyroid antibodies in patients with serum TSH in the upper range of normal (3.0–5.5 mU/L), but most such patients are asymptomatic. The serum TSH level varies during the day, usually within the normal range, being higher in the early morning and after strenuous exercise, sleep deprivation, or working night shifts.

TSH levels as low as 0.01 mU/L can be detected by ultrasensitive “third-generation” assays. To diagnose hyperthyroidism, an assay sensitive to at least 0.1 mU/L (sensitive “second-generation” assay) should be used. Because of discrepancies between different TSH assay methods, it is prudent to recheck unexpected results with a different assay.

TSH levels are decreased in patients with primary hyperthyroidism (eg, Graves' disease, toxic multinodular goiter, toxic nodule, subacute thyroiditis, or release of stored hormone in Hashimoto's thyroiditis). They may also be suppressed in some clinically euthyroid individuals with autonomous thyroid secretion (eg, euthyroid Graves' ophthalmopathy). TSH can also be suppressed by metformin and by thyroid hormone administration in either excessive or adequate replacement amounts. TSH is also frequently low during severe nonthyroidal illness; distinction from hypopituitarism can usually be made clinically.

Dopamine and dopamine agonists (levodopa, bromocriptine) can cause suppression of TSH and may cause true secondary hypothyroidism during prolonged administration. Other conditions associated with decreased TSH include pregnancy (especially with morning sickness), hCG-secreting trophoblastic tumors, acute psychiatric illness (1% incidence), and urgent administration of corticosteroids. Certain drugs cause mild suppression of TSH without clinical hyperthyroidism; these include nonsteroidal anti-inflammatory

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drugs, amphetamine, octreotide, opioids, and certain calcium channel blockers (especially nifedipine; also verapamil, but not diltiazem).

Table 26-6. Factors causing misleading serum thyroxine (T4) measurements without affecting clinical status.1

Factors Increasing T4 Factors Decreasing T4
Laboratory error
AIDS (increased thyroid-binding globulin)Autoimmunity
Acute illness (eg, viral hepatitis, chronic active hepatitis; primary biliary cirrhosis; acute intermittent porphyria; AIDS)
High-estrogen states (may also increase total T3)
   Oral estrogen-containing contraceptives
   Pregnancy
   Estrogen replacement therapy
   Tamoxifen
Acute psychiatric problems
Hyperemesis gravidarum and morning sickness (may also increase T3)
Familial thyroid-binding abnormalities
Generalized resistance to thyroid hormone
Drugs
   Amiodarone
   Amphetamines
   Clofibrate
   Heparin (dialysis method)
   Heroin
   Levothyroxine (T4) replacement therapy
   Methadone (may also increase T3)
   Perphenazine
Laboratory error
Severe illness (eg, chronic renal failure, major surgery, caloric deprivation)
Acute psychiatric problems
Cirrhosis
Nephrotic syndrome
Hereditary thyroid-binding globulin deficiency
Drugs
   Androgens
   Asparaginase
   Carbamazepine
   Chloral hydrate
   Fenclofenac
   Fluorouracil
   Corticosteroids
   Halofenate (lowers triglycerides and uric acid; not marketed in the United States)
   Mitotane
   Nicotinic acid
   Oxcarbazepine
   Phenobarbital
   Phenylbutazone
   Phenytoin (T4 may be as low as 2 mcg/dL)
   Salicylates (large doses)
   Sertraline
   Triiodothyronine (T3) therapy
1Symptomatic hyperthyroidism or hypothyroidism may also be present incidentally.

In clinically euthyroid persons age 60 years or older, the TSH is very low (≤ 0.1 mU/L) in 3% and mildly low (0.1–0.4 mU/L) in 9%. The chance of developing atrial fibrillation is higher with very low TSH (2.8% yearly) than with normal TSH (1.1% yearly). Asymptomatic patients with very low TSH are followed closely but not treated unless atrial fibrillation or other manifestations of hyperthyroidism develop.

TSH levels are elevated in primary hypothyroidism, either clinical or subclinical. They may also be elevated or inappropriately normal in the very rare cases of hyperthyroidism due to pituitary neoplastic or nonneoplastic inappropriate secretion of thyrotropin. Autoimmune disease may also falsely elevate serum TSH levels by interfering with the assay. Assay interference can cause spuriously high serum TSH levels in patients with heterophile antibodies or anti-mouse antibodies. TSH may be elevated after strenuous exercise or in the morning after sleep deprivation. TSH may be transiently elevated during recovery from nonthyroidal illness and in about 14% of patients with acute psychiatric admissions; the TSH returns to normal in the great majority of these patients. TSH may be mildly elevated in some individuals, especially elderly women (10% incidence). Such patients with normal T4 levels must be carefully evaluated for subtle signs of hypothyroidism (eg, fatigue, depression, hyperlipidemia). About 18% later become definitely hypothyroid.

Free Thyroxine Immunoassay

FT4 is a direct measurement of the serum concentration of free (unbound) T4. FT4 represents only about 0.025% of the serum concentration of the total T4. It is the only metabolically active fraction of T4 that freely enters cells to produce its effects.

When performed properly, this assay is superior to the total T4 assay and FT4I, since it is not affected by variations in protein binding. It is the procedure of choice for following the thyroid's changing secretion of T4 during treatment for hyperthyroidism. Serum FT4 levels may be suppressed in patients with severe nonthyroid illness. In patients receiving heparin, measured levels of FT4 may be falsely high, particularly when a dialysis assay is used. Serum FT4 levels rise transiently in acute nonthyroidal illness, when thyroid-binding protein frequently falls.

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Thyroxine Immunoassay

This test measures the total serum concentration of T4 (bound and free). An increased serum T4 confirms a clinical diagnosis of hyperthyroidism, while a decreased serum T4 confirms a clinical diagnosis of hypothyroidism. It is affected by altered states of T4 binding (see Table 26-6). Therefore, this test is usually run with a resin T3 uptake to provide an FT4I (see below).

Resin T3 (or T4) Uptake (RT3U or RT4U)

This is an indirect inverse test of serum thyroid-binding proteins (TBPs)—ie, it is high when TBPs are low. The assay involves adding labeled T3 or T4 to the serum sample; it competes with the patient's T4 for binding to TBP. This mixture is then added to a thyroid hormone-binding resin. The resin is then assayed for its uptake of the label. A high resin uptake indicates that the patient's serum contains relatively low amounts of TBP or high levels of T4.

This test corrects a total serum T4 measurement for the effect of increased or decreased binding, creating a free T4 index (see below). A low resin uptake (high TBP) is seen with estrogen therapy, pregnancy, acute hepatitis, genetic TBP increase, and hypothyroidism. A low resin uptake with low TBP may be seen in severe illness. A high resin uptake (low TBP) is seen with hyperthyroidism and with chronic liver disease, nephrotic syndrome, anabolic steroid administration, and high-dose corticosteroid administration.

Free Thyroxine Index

The product of T4 and resin T3 uptake (T4 × T3 uptake) helps correct for abnormalities of T4 binding. A good FT4 assay is more accurate.

The FT4I, when calculated using the RT3U, may be elevated in euthyroid patients with familial dysalbuminemic hyperthyroxinemia. This is a benign autosomal dominant trait in which an abnormal albumin molecule binds T4 with much greater affinity than T3. The RT3U is not decreased (failing to compensate for the increased binding, as it would for thyroxine binding globulin [TBG] excess), because the T3 used in the RT3U assay is not significantly affected. Serum levels of FT4 and TSH are normal.

Total Triiodothyronine

This test is of value in the diagnosis of thyrotoxicosis with normal T4 values (T3 thyrotoxicosis). Determination of serum total triiodothyronine (TT3) can also be useful, along with serum TSH, to screen for excessive thyroxine replacement. TT3 levels are not useful for the diagnosis of hypothyroidism. Serum TT3 levels can be misleadingly elevated in women who are pregnant or who take oral estrogen, due to the high serum levels of TBG in these conditions. Note: When blood is collected in tubes using a gel barrier, certain immunoassays (eg, Immulite but not Axsym analyzers) report serum TT3 levels that are falsely elevated in 24% of normal patients.

Free Triiodothyronine

Free triiodothyronine (FT3) measures the very tiny amount of T3 that circulates unbound. It is useful in looking for hyperthyroidism or thyroxine overreplacement in women who are pregnant or taking oral estrogen.

2. Thyroid Radioactive Iodine Uptake & Scan

Radioiodine (123I or 131I) Uptake of Thyroid Gland

A. Elevated

Graves' disease, dietary iodine deficiency, toxic nodular goiter, pregnancy, early Hashimoto's thyroiditis, some thyroid enzyme deficiencies, nephrotic syndrome, recovery from subacute thyroiditis, and recovery from thyroid hormone suppression.

B. Low

Administration of iodides or iodine in any form (drugs, radiology contrast dyes, etc), antithyroid drugs, subacute thyroiditis, thyroid hormone administration, thyroid gland damage (from thyroiditis, surgery, or radioiodine), hypopituitarism, ectopic functioning thyroid tissue, azotemia, severe (high-turnover) Graves' disease, heart failure, and some thyroid enzyme abnormalities.

Radioiodine Scans

A rectilinear scan over the neck may be obtained after radioiodine administration, thereby obtaining a life-sized picture of thyroid uptake. Radioactive iodine (RAI) scans are useful also for detecting metastatic thyroid cancer. (See Thyroid Cancer.) Following administration of a treatment dose of 131I for thyroid cancer, a whole-body scan is useful for detecting metastases.

3. Other Thyroid Tests

Thyroid Antibodies

Antibodies against several thyroid constituents (thyroglobulin and thyroperoxidase) are most commonly found in Hashimoto's thyroiditis and Graves' disease. Antithyroid antibodies are found in about 5–10% of normal subjects. There is an increasing incidence with age. About 20% of hospitalized patients have detectable antithyroid antibodies. In the latter, the titers tend to be low, and they increase with age. Thyroid-stimulating antibody (TSAb, TSH-R Ab[stim]) serum titers are elevated in approximately 80% of patients with Graves' disease and in about 14% of patients with Hashitoxicosis. These titers—and those of antithyroglobulin and antithyroperoxidase antibodies—often decrease during

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pregnancy and during treatment of Graves' disease with antithyroid drugs. TSAb titers have been used with variable results to predict the rate of relapse of Graves' disease after long-term thiourea therapy.

Serum Thyroglobulin

The level of serum thyroglobulin rises in autoimmune thyroid disease, thyroid injury or inflammation, and thyroid cancer. Levels are of little value in diagnosing or distinguishing among these conditions, but they provide a useful marker in thyroid cancer to indicate recurrence of disease and the need for further studies and therapy. (See Thyroid Cancer.) Serum thyroglobulin is to be distinguished from serum TBG (see above).

Calcitonin Assay

This test is elevated in medullary thyroid carcinoma, azotemia, hypercalcemia, pernicious anemia, thyroiditis, and pregnancy. High levels are also seen in many other malignancies such as carcinomas of the lung (45%), pancreas, breast (38%), and colon (24%).

Fine-Needle Thyroid Biopsy

Aspiration of thyroid tissue with a fine needle (25 gauge) is helpful in the diagnosis of thyroid disorders, especially nodular lesions. This technique has become the preferred approach to the diagnosis of thyroid masses. (See Nodular Thyroid.)

4. Effect of Nonthyroidal Illness & Drugs on Thyroid Function Tests

Many factors affect thyroid function tests, causing misleading laboratory evidence of hypothyroidism or hyperthyroidism in patients who are clinically euthyroid. (See Table 26-6.)

Serum T4 is frequently low in patients with severe illness, caloric deprivation, or major surgery who have accelerated peripheral metabolism of serum T4 to reverse T3 (rT3). Furthermore, in most patients who are critically ill, there is a circulating inhibitor of thyroid hormone binding to serum TBPs. This causes the RT3U to be misleadingly low, causing the computed FT4I to be very low. The presence of a very low serum T4 in severe nonthyroidal illness indicates a poor prognosis.

Direct assays of FT4 often show low levels of FT4 in severe illness. Because studies of giving replacement T4 to such patients have shown no improvement in survival, they are considered “euthyroid.” Serum TSH tends to be suppressed in severe nonthyroidal illness, making the diagnosis of concurrent primary hypothyroidism quite difficult, although the presence of a goiter suggests the diagnosis.

The clinician must decide whether such severely ill patients (with a low serum T4 but nonelevated TSH) might have hypothyroidism due to pituitary insufficiency. Patients without symptoms of prior brain lesion or hypopituitarism are very unlikely to suddenly develop hypopituitarism during an unrelated illness. Patients with diabetes insipidus, hypopituitarism, or other signs of a central nervous system lesion may have T4 given empirically. Patients receiving prolonged dopamine infusions may develop true secondary hypothyroidism due to direct dopamine suppression of TSH-secreting cells.

Certain antiseizure medications cause low serum FT4 levels by accelerating hepatic conversion of T4 to T3; serum TSH levels are normal.

Ando T et al: Thyrotropin receptor antibodies: new insights into their actions and clinical relevance. Best Pract Res Clin Endocrinol Metab 2005;19:33.

Bowen RA et al: Effect of blood collection tubes on total triiodothyronine and other laboratory assays. Clin Chem 2005;51: 424.

Helfand M; U.S. Preventive Services Task Force: Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:128.

Thyroid Nodules & Multinodular Goiter

Essentials of Diagnosis

  • Single or multiple thyroid nodules are commonly found with careful thyroid examinations.

  • Thyroid function tests mandatory.

  • Thyroid biopsy for single or dominant nodules or for a history of prior head-neck or chest-shoulder radiation.

  • Ultrasound examination useful for biopsy and follow-up.

  • Clinical follow-up required.

General Considerations

Palpable enlargement of the thyroid (goiter) may be diffuse or nodular and is detectable in 4% of North American adults. The incidence of goiter is higher in iodine-deficient geographic areas (see Endemic Goiter, below). The presence of a goiter warrants further testing and follow-up. Most patients with goiter are euthyroid, but there is a high incidence of hypothyroidism or hyperthyroidism. Diffuse and multinodular goiters are ordinarily benign and may be caused by numerous conditions, eg, benign multinodular goiter, iodine deficiency, pregnancy (in areas of iodine deficiency), Graves' disease, Hashimoto's thyroiditis, subacute thyroiditis, or infections. A solitary thyroid nodule is most often a benign adenoma, colloid nodule, or cyst but may sometimes be a primary thyroid malignancy or (less frequently) a metastatic

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neoplasm. The risk of a palpable nodule being malignant is higher among patients with a history of head-neck radiation, a family history of thyroid cancer, or a personal history of another malignancy. The risk of malignancy is higher if a thyroid nodule is large, adherent to the trachea or strap muscles, or associated with lymphadenopathy.

Thyroid nodules are often discovered incidentally during radiologic procedures performed for other reasons. Nonpalpable thyroid nodules < 1 cm in diameter are benign in 98.4% of cases. Nodules that are palpable or ≥ 1 cm in diameter have a higher chance of being malignant. In patients with Hashimoto's thyroiditis, a palpable solitary thyroid nodule of ≥ 1 cm diameter has about an 8% chance of being malignant.

Clinical Findings (Table 26-7)

A. Symptoms and Signs

The thyroid is best examined in a well-lighted room. The seated patient is given water to drink and the anterior neck is observed during swallowing. The thyroid moves upward during swallowing and may be visible in a thin neck; enlargement or asymmetry of the thyroid may be noted. Palpation of the thyroid is best done from behind a seated patient using the second and third fingers of both hands. As the patient swallows water, thyroid nodules may be perceived moving beneath the fingers. The location of any nodules should be noted, along with their size, firmness, and tenderness. The neck should be examined for lymphadenopathy. An enlarged thyroid should be auscultated for bruits.

Most small thyroid nodules are asymptomatic and are discovered incidentally on routine neck inspection or palpation; some are discovered as an incidental finding during radiologic imaging of the neck. Graves' disease, toxic multinodular goiter, hyperfunctioning nodules, and subacute thyroiditis can cause hyperthyroidism. Hashimoto's thyroiditis may cause goiter and hypothyroidism.

A thyroid nodule or multinodular goiter can grow to become visible and of concern to the patient. Particularly large nodular goiters can become a cosmetic embarrassment. Nodules can grow large enough to cause discomfort, hoarseness, or dysphagia. Retrosternal large multinodular goiters can cause dyspnea due to tracheal compression. Large substernal goiters may cause superior vena cava syndrome, manifested by facial erythema and jugular vein distention that progress to cyanosis and facial edema when both arms are kept raised over the head (Pemberton's sign).

B. Laboratory Findings

Thyroid nodules are an indication for thyroid function testing. Serum determinations for TSH (sensitive assay) and FT4 are preferred. Tests for antithyroperoxidase antibodies and antithyroglobulin antibodies may also be helpful. Very high antibody levels are found in Hashimoto's thyroiditis. However, thyroiditis frequently coexists with malignancy, so suspicious nodules should always be biopsied.

Fine-needle aspiration (FNA) biopsy is the best way to assess a nodule for malignancy. A 25-gauge needle is used to biopsy suspicious nodules. The needle is attached to a syringe and special syringe holder. The biopsy

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is done without local anesthesia. The success rate of FNA biopsy is increased by ultrasound guidance. Care must be taken to avoid bloody dilution of the specimens. Material obtained is placed on a slide and a thin smear is obtained by laying a second slide over the material and then drawing the slides apart. One slide is air dried while the other is preserved in 95% alcohol. Two or more biopsies may be obtained. Reading by an experienced cytopathologist is mandatory.

Table 26-7. Clinical evaluation of thyroid nodules.1

Clinical Evidence Low Index of Suspicion High Index of Suspicion
History Family history of goiter; residence in area of endemic goiter Previous therapeutic radiation of head, neck, or chest; hoarseness
Physical characteristics Older women; soft nodule; multinodular goiter Young adults, men; solitary, firm nodule; vocal cord paralysis; enlarged lymph nodes; distant metastatic lesions
Serum factors High titer of antithyroid antibody; hypothyroidism; hyperthyroidism  
Fine-needle aspiration biopsy Colloid nodule or adenoma Papillary carcinoma, follicular neoplasm, medullary or anaplastic carcinoma
Scanning techniques
   Uptake of 123I “Hot” nodule “Cold” nodule
   Ultrasonogram Cystic lesion Solid lesion
   Roentgenogram Shell-like calcification Punctate calcification
Thyroxine therapy Regression after 0.05-0.1 mg/d for 6 months or more Increase in size
1Clinically suspicious nodules should be evaluated with fine-needle aspiration biopsy.

In one review of thyroid FNA biopsies, about 70% were benign, 5% malignant, 15% nondiagnostic, and 10% indeterminate or “suspicious.” With indeterminate “suspicious” FNA cytology, the risk of malignancy has been reported to be 15% for follicular neoplasms, 20% for Hurthle cell neoplasms, and 82% for papillary carcinoma. The risk of a nodule (with indeterminate FNA cytology) being malignant is even higher in young patients and those with nodules that are fixed or over 2 cm in diameter. Therefore, most patients with indeterminate FNA cytology undergo thyroid surgery. However, a subgroup of elderly patients with “suspicious” cytology (nodules < 4 cm in diameter) has a malignancy rate of just 5%; such patients may elect to be monitored every 4–6 months with palpation and ultrasound.

Cystic nodules yielding serous fluid are usually benign, but fluid should be submitted for cytologic testing. Cystic nodules yielding bloody fluid have a higher chance of being malignant. Repeat FNA biopsy is done if the cytology is nondiagnostic (eg, diluted with blood or hypocellular) and the lesion remains palpable.

False-positive thyroid FNA biopsies occur at a rate of about 4%. False-negative thyroid FNA biopsies also occur at an overall rate of about 4%, less commonly when performed under ultrasound and interpreted by cytopathologists at major university centers. False-negative thyroid FNAs delay surgical excision and lead to an increased risk of vascular and capsular invasion by the malignancy. Patients who have a negative thyroid FNA should have observational follow-up, ideally with both palpation and ultrasound; nodules that continue to grow should be rebiopsied or excised.

C. Imaging

Neck ultrasound should be performed on most patients with thyroid nodules, since it frequently adds important information. Ultrasound is more accurate than palpation in measuring the size of a nodule and can help determine whether a palpable nodule is part of a multinodular goiter, thus having less chance of being malignant. Ultrasound is also helpful in evaluating thyroid nodules. The following ultrasound characteristics of thyroid nodules increase the likelihood of malignancy: irregular margins, intranodular vascular spots, or microcalcifications. FNA biopsy is performed on such nodules—even if they are nonpalpable—if they are over 8 mm in diameter. Ultrasound-guided FNA biopsy is helpful in obtaining representative and adequate specimens, especially from complex thyroid nodules. Ultrasonography is generally preferred over CT and MRI because of its accuracy, ease of use, and lower cost.

RAI (123I or 131I) scans have limited utility in the evaluation of thyroid nodules. Hypofunctioning (cold) nodules have a somewhat increased risk of being malignant, but most are benign. Hyperfunctioning (hot) nodules are ordinarily benign but may sometimes be malignant. RAI scanning and uptake are helpful if a patient is found to have evidence of hyperthyroidism. (See Hyperthyroidism, below.)

Treatment

All thyroid nodules, including those with benign cytology, need to be followed by regular periodic palpation and rebiopsied if growth occurs. Thyroid ultrasound is useful for following nodules that are difficult to palpate. Patients with elevated levels of serum TSH are treated with T4 replacement. Otherwise, for small nodules, T4 is not required. For larger nodules (> 2 cm), if TSH levels are elevated or normal, “suppression” with levothyroxine sodium (0.05–0.1 mg daily) can be considered. Levothyroxine should not be administered if the baseline TSH is low, since that is an indication of autonomous thyroid secretion, such that levothyroxine treatment will be ineffective and liable to cause clinical thyrotoxicosis. Long-term levothyroxine suppression of TSH tends to keep nodules from enlarging, but only a few will actually shrink. Additional nodules develop in fewer treated patients. Suppressive levothyroxine therapy is most suitable for younger patients. All patients require regular careful clinical evaluation and thyroid palpation or ultrasound examinations. Levothyroxine suppression therapy should usually not be given to patients with cardiovascular problems since it may increase the risk for angina and arrhythmia. Levothyroxine suppression causes a small loss of bone density in many postmenopausal women. Bisphosphonate or other therapy for osteoporosis may be indicated. Patients at risk for osteoporosis are advised to have periodic bone density testing.

A. Solitary Thyroid Nodules

Palpable solitary thyroid nodules call for FNA biopsy. A solitary thyroid nodule in a patient with a remote history of radiation therapy to the head or neck (or exposure to nuclear fallout) is considered at high risk for malignancy and the nodule is resected. Cystic nodules can be managed by removal of fluid for cytologic examination, which may deflate the cyst. However, cysts tend to recur, requiring repeated aspirations. Solitary nodules in a patient with hyperthyroidism are an indication for RAI scan, which generally distinguishes toxic adenoma from Graves' disease. However, Graves' disease may occasionally be unilateral owing to agenesis of the contralateral lobe, so additional studies with antithyroid antibodies may be helpful. A “hot” nodule is usually benign but is resected to cure the hyperthyroidism.

B. Multinodular Goiters

A thyroid containing multiple nodules is likely to be a benign multinodular goiter. Nevertheless, FNA biopsy

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is performed on any nodule that is growing or is particularly dominant or hard. Large retrosternal goiters rarely harbor a malignancy but can be followed by CT scan or MRI. Continued growth or compressive symptoms are reasons for surgical excision. Patients found to be hyperthyroid may have a radioactive iodine scan and uptake for additional evaluation, especially if 131I is a therapeutic consideration.

C. Nonpalpable Thyroid Nodules

Nonpalpable small thyroid nodules are incidentally discovered in about 25–50% of scans of the neck (MRI, CT, ultrasound) done for other reasons. Such nodules are sometimes referred to as “thyroid incidentalomas.” In one series, only 2% of such thyroids were found to have a significant malignancy after surgical resection. However, other series have found a higher risk of malignancy in nonpalpable thyroid nodules. Therefore, ultrasound-guided FNA biopsy should be considered for nonpalpable thyroid nodules 1.5 cm in diameter. For nodules < 1.5 cm diameter, ultrasound-guided FNA biopsy should be considered for patients with a history of head-neck irradiation or a family history of thyroid cancer. Smaller thyroid nodules with a suspicious appearance on ultrasound (calcified, solitary, or irregular) should also be considered for ultrasound-guided FNA biopsy. For incidentally discovered thyroid nodules of borderline concern, follow-up thyroid ultrasound in 3–4 months may be helpful; growing lesions may be biopsied or resected.

Microscopic “micropapillary” carcinoma is a variant of normal, being found in 24% of thyroidectomies performed for benign thyroid disease when 2-mm sections were carefully examined. It thus appears that the overwhelming majority of these microscopic foci never become clinically significant. The surgical pathology report of such a tiny papillary carcinoma that is otherwise benign does not justify aggressive follow-up or treatment because a cancer diagnosis is unwarranted and harmful. All that may be required is yearly follow-up with palpation of the neck and mild TSH suppression by thyroxine.

Prognosis

The great majority of thyroid nodules are benign. Benign thyroid nodules may involute but usually persist or grow slowly. About 89% of thyroid nodules will increase their volume by ≥ 15% over 5 years; cystic nodules are less likely to grow. Cytologically benign nodules that grow are unlikely to be malignant; in one series, only 1 of 78 rebiopsied nodules was found to be malignant. The prognosis for patients with thyroid nodules that prove to be malignant is determined by the histologic type and other factors (see below). Overall, differentiated thyroid carcinoma has an excellent prognosis, but metastases do occur. Multinodular goiters tend to persist or grow slowly, even in iodine-deficient areas where iodine repletion usually does not shrink established goiters. Patients with small incidentally discovered nonpalpable thyroid nodules are at very low risk for malignancy, and even those that are malignant have a minor effect on morbidity and mortality.

Hegedüs L: Clinical practice. The thyroid nodule. N Engl J Med 2004;351:1764.

Kang HW et al: Prevalence, clinical and ultrasonographic characteristics of thyroid incidentalomas. Thyroid 2004;14:29.

Kessler A et al: Accuracy and consistency of fine-needle aspiration biopsy in the diagnosis and management of solitary thyroid nodules. Isr Med Assoc J 2005;7:371.

Liebeskind A et al: Rates of malignancy in incidentally discovered thyroid nodules evaluated with sonography and fine-needle aspiration. J Ultrasound Med 2005;24:629.

Nam-Goong IS et al: Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: correlation with pathological findings. Clin Endocrinol (Oxf) 2004;60:21.

Thyroid Cancer (Table 26-8)

Essentials of Diagnosis

  • Painless swelling in region of thyroid.

  • Thyroid function tests usually normal.

  • Past history of irradiation to head and neck region may be present.

  • Positive thyroid needle aspiration.

General Considerations

The incidence of papillary and follicular (differentiated) thyroid carcinomas increases with age. The female:male ratio is 3:1. In the United States, thyroid cancer is diagnosed in nearly 26,000 people yearly, and about 1 in every 250 people eventually receives this diagnosis. About 13% of persons in the United States are found to have microscopic thyroid cancer at autopsy. Clearly, most thyroid cancers remain microscopic and indolent. However, larger thyroid cancers (palpable or ≥ 1 cm in diameter) are more malignant and require treatment.

Table 26-8. Some characteristics of thyroid cancer.

  Papillary Follicular Medullary Anaplastic
Incidence Most common Common Uncommon Uncommon
Average age 42 50 50 57
Females 70% 72% 56% 56%
Deaths due to thyroid cancer 6% 24% 33% 98%
Invasion
   Juxtanodal +++++ + ++++++ +++
   Blood vessels + +++ +++ +++++
   Distant sites + +++ ++ ++++
Resemblance to normal thyroid + +++ + ±
123I uptake + ++++ 0 0
Degree of malignancy + ++ to +++ + to ++++ ++++++++

Papillary thyroid carcinoma is the most common thyroid malignancy. Pure papillary or mixed papillary-follicular carcinoma represents about 81% of all thyroid cancers. It usually presents as a single nodule, but it can arise out of a multinodular goiter. Papillary thyroid carcinoma is commonly multifocal within the gland, with other foci usually arising de novo rather than representing intraglandular metastases.

Papillary thyroid carcinoma is caused by certain genetic mutations or translocations. Activating mutations of the ras oncogene can cause benign thyroid adenomas or nodular goiter. Additional activating mutations in BRAF

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or TRK genes can lead to papillary carcinoma. About 45% of papillary thyroid carcinomas are caused by overexpression of the ret oncogene by the translocation of certain gene promoters to it, producing retPTC-1, retPTC-2, or retPTC-3. Radiation treatments to the head and neck region tend to cause retPTC-1. Nuclear fallout exposure tends to cause retPTC-3, resulting in more aggressive papillary thyroid carcinomas. Additional loss of the p53 tumor suppressor gene can cause progression of papillary thyroid carcinoma to anaplastic thyroid carcinoma.

Exposure to radiation therapy to the head and neck poses a particular threat to children who then have an increased lifetime risk of developing thyroid pathology, including papillary thyroid carcinoma; thyroid malignancy may emerge between 10 and 40 years after exposure, with a peak occurrence 20–25 years later. Following the Chernobyl explosion, the risk for developing papillary thyroid carcinoma was highest among children who were under 5 years old at the time of exposure; emergence of more aggressive papillary thyroid carcinoma occurred within 6–7 years after exposure.

Papillary thyroid carcinoma can occur in rare familial syndromes as an autosomal dominant trait, caused by loss of various tumor suppressor genes. Such syndromes (with associated features) include familial papillary carcinoma (with papillary renal carcinoma); familial nonmedullary thyroid carcinoma; familial polyposis (with large intestine polyps and gastrointestinal tumors); Gardner's syndrome (witlh small and large intestine polyps, fibromas, lipomas, osteomas); and Turcot's syndrome (with large intestine polyps and brain tumors).

Generally speaking, papillary carcinoma is the least aggressive thyroid malignancy. However, the tumor spreads via lymphatics within the thyroid, becoming multifocal in 60% of patients and involving both lobes in 30% of patients. About 80% of patients have microscopic metastases to cervical lymph nodes; palpable lymph node involvement is present in 15% of adults and 60% of youths. Unlike other forms of cancer, patients with papillary thyroid carcinoma who have palpable lymph node metastases do not have a particularly increased mortality rate; however, their risk of local recurrence is increased.

Occult metastases to the lung occur in 10–15% of differentiated thyroid cancer; such lung metastases may be first noted on the whole-body scan following 131I therapy. About 70% of small lung metastases resolve following 131I therapy; however, larger pulmonary metastases have only a 10% remission rate.

Chronic low-grade papillary carcinoma can sometimes undergo a late anaplastic transformation into an aggressive carcinoma.

Follicular thyroid carcinoma results from certain gene mutations or translocations. Aberrant DNA methylation, activation of the ras oncogene, and mutations of the MEN1 gene can result in benign follicular adenomas. Loss of function of PPARg or the 3P tumor suppressor gene can lead to follicular carcinoma, and additional loss of the p53 tumor suppressor gene can produce anaplastic carcinoma.

Follicular thyroid carcinoma and adenomas develop in patients with Cowden's disease, a rare autosomal dominant familial syndrome caused by loss of a tumor suppressor gene; such patients tend to have macrocephaly, multiple hamartomas, early-onset breast cancer, intestinal polyps, facial papules, and other skin and mucosal lesions.

Follicular and Hürthle cell carcinoma accounts for about 14% of thyroid malignancies and is generally more aggressive than papillary carcinoma. Rarely, some follicular carcinomas secrete enough T4 to cause thyrotoxicosis if the tumor load becomes significant. Metastases commonly are found in neck nodes, bone, and lungs. Most follicular thyroid carcinomas avidly absorb iodine, making possible diagnostic scanning and treatment with 131I after total thyroidectomy. Certain follicular histopathologic features are associated with a high risk of metastasis and recurrence: poorly differentiated

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and Hürthle cell (oncocytic) variants. The latter variants do not take up RAI.

Medullary thyroid carcinoma is often caused by an activating mutation of the ret oncogene on chromosome 10. Mutation analysis of the ret oncogene's exons 10, 11, 13, and 14 detects 95% of the mutations causing MEN 2A and 90% of the mutations causing familial medullary thyroid carcinoma. Patients with MEN 2B have activating mutations in exon 16 of the ret oncogene. These germline mutations can be detected by DNA analysis of peripheral white blood cells, allowing identification of gene carriers within the family. When a family with MEN 2A or familial medullary thyroid carcinoma does not have an identifiable ret oncogene mutation, gene carriers may still be identified using family linkage analysis. Somatic mutations of the ret oncogene can be identified in the tumors of 30% of patients with sporadic (nonfamilial) medullary thyroid carcinoma. (See Multiple Endocrine Neoplasia.)

Medullary thyroid carcinoma represents about 3% of thyroid cancers. About one-third of cases are sporadic, one-third are familial, and one-third are associated with MEN type 2. Therefore, discovery of a medullary thyroid carcinoma makes genetic analysis mandatory, as noted above. If a gene defect is discovered, related family members must have genetic screening for that specific gene defect. Even when no gene defect is detectable, family members should have regular thyroid surveillance. Medullary thyroid carcinoma arises from parafollicular thyroid cells that can secrete calcitonin, prostaglandins, serotonin, ACTH, corticotropin-releasing hormone (CRH), and other peptides. These peptides can cause symptoms and can be used as tumor markers. Early local metastases are usually present, usually to adjacent muscle and trachea as well as to local and mediastinal lymph nodes. Eventually, late metastases may appear in the bones, lungs, adrenals, or liver. Metastases to the neck may be detected by ultrasound. Metastases are best detected using [18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) whole-body scanning. Medullary thyroid carcinoma does not concentrate iodine.

Anaplastic thyroid carcinoma is caused by certain gene mutations, including inactivating mutations of the p53 tumor suppressor gene, as described above for papillary and follicular thyroid carcinomas. Anaplastic thyroid carcinoma represents about 2% of thyroid cancers. It usually presents in an older patient as a rapidly enlarging mass in a multinodular goiter. It is the most aggressive thyroid carcinoma and metastasizes early to surrounding nodes and distant sites. Local pressure symptoms include dysphagia or vocal cord paralysis. This tumor does not concentrate iodine.

Other thyroid malignancies together represent about 3% of thyroid cancers. Lymphoma of the thyroid is more common in older women. It usually presents as a rapidly enlarging, painful mass arising out of a multinodular or diffuse goiter affected by autoimmune thyroiditis, with which it may be confused microscopically. About 20% of cases have concomitant hypothyroidism. Thyroid lymphomas are most commonly B cell lymphomas (50%) or mucosa-associated lymphoid tissue (MALT; 23%); other types include follicular, small lymphocytic, and Burkitt's lymphoma and Hodgkin's disease. Thyroidectomy is rarely required. Metastatic cancers may sometimes involve the thyroid, particularly bronchogenic, breast, and renal carcinomas and malignant melanoma.

Clinical Findings

A. Symptoms and Signs

Thyroid carcinoma usually presents as a palpable, firm, nontender nodule in the thyroid. Most thyroid carcinomas are asymptomatic, but large thyroid cancers can cause neck discomfort, dysphagia, or hoarseness (due to pressure on the recurrent laryngeal nerve). About 3% of thyroid malignancies present with a metastasis, usually to local lymph nodes but sometimes to distant sites such as bone or lung. Metastatic functioning differentiated thyroid carcinoma can sometimes secrete enough thyroid hormone to produce thyrotoxicosis.

Medullary thyroid carcinoma frequently causes flushing and persistent diarrhea (30%), which may be the initial clinical feature. Patients with metastases often experience fatigue as well as other symptoms. Cushing's syndrome develops in about 5% of patients from secretion of ACTH or CRH. Signs of pressure or invasion of surrounding tissues are present in anaplastic or large tumors; recurrent laryngeal nerve palsy can occur.

B. Laboratory Findings

(FNA is discussed above in the section on nodular thyroid.) Thyroid function tests are generally normal unless there is concomitant thyroiditis. Follicular carcinoma may secrete enough T4 to suppress TSH and cause clinical hyperthyroidism.

Serum thyroglobulin is high in most metastatic papillary and follicular tumors, making this a useful marker for recurrent or metastatic disease. Caution must be exercised for the following reasons: (1) Circulating antithyroglobulin antibodies can cause erroneous thyroglobulin determinations. (2) Thyroglobulin levels may be misleadingly elevated in thyroiditis, which often coexists with carcinoma. (3) Certain thyroglobulin assays falsely report the continued presence of thyroglobulin after total thyroidectomy and tumor resection, causing undue concern about possible metastases. Therefore, unexpected thyroglobulin levels should prompt a repeat assay in another reference laboratory.

Serum calcitonin levels are usually elevated in medullary thyroid carcinoma, making this a marker for metastatic disease. However, serum calcitonin may be elevated in many other conditions such as thyroiditis, pregnancy, azotemia, hypercalcemia, and other malignancies, including pheochromocytomas, carcinoid tumors, and carcinomas of the lung, pancreas, breast, and colon.

Serum calcitonin and carcinoembryonic antigen (CEA) determinations should be obtained before surgery

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for medullary carcinoma, then regularly in postoperative follow-up: every 4 months for 5 years, then every 6 months for life. Calcitonin levels remain elevated in patients with persistent tumor but also in some patients with apparent cure or indolent disease. Therefore, rising levels of calcitonin (or CEA) are the best indication for recurrence. Serum calcitonin levels > 250 pg/mL are also an indication for recurrent or metastatic medullary thyroid carcinoma. Serum CEA levels are usually elevated with medullary carcinoma, making this a useful second marker; however, it is not specific for this carcinoma.

Because up to two-thirds of medullary thyroid carcinoma cases are familial or MEN 2 (both autosomal dominant), siblings and children of patients with medullary carcinoma are advised to have genetic testing to detect ret oncogene mutations. (See discussion of medullary thyroid carcinoma, above.)

C. Imaging

1. Radioactive iodine scanning

RAI (131I or 123I) thyroid and whole-body scanning are not usually helpful in the initial diagnosis of thyroid cancer. In the past, RAI scanning was performed in patients with thyroid nodules to determine whether they were “cold,” a sign of malignancy. However, this did not provide sufficient sensitivity and has been supplanted by FNA biopsy. Prior to thyroidectomy, whole-body RAI scanning is not very sensitive for metastatic disease, since the normal thyroid competes for RAI with metastases, which are less avid for RAI. Consequently, RAI scanning is used after thyroidectomy for surveillance as described below.

2. Ultrasound of the neck

Ultrasound of the neck is useful in determining the size and location of the malignancy as well as the location of any neck metastases. Neck ultrasound is a simple and useful procedure and should be performed routinely on all patients with thyroid cancer for the initial diagnosis and for follow-up.

3. CT scanning

CT scanning may demonstrate metastases and is particularly useful for localizing and following lung metastases. However, CT scanning is less sensitive than ultrasound for detecting metastases within the neck. Iodinated contrast should never be given prior to RAI scanning or RAI therapy, since the large amounts of iodine in contrast media competitively inhibit the uptake of RAI by the thyroid, greatly reducing the effectiveness of subsequent RAI scanning and therapy. Medullary carcinoma in the thyroid, nodes, and liver may calcify, but lung metastases rarely do so.

4. MRI

MRI is particularly useful for imaging bone metastases.

5. PET scanning

PET scanning is particularly useful for detecting thyroid cancer metastases that do not have sufficient iodine uptake to be visible on RAI scans. 18FDG-PET is quite sensitive and allows tumor volumetric determinations. The sensitivity of 18FDG-PET scanning for differentiated thyroid cancer is enhanced if the patient is hypothyroid or receiving thyrotropin, which increases the metabolic activity of differentiated thyroid cancer. Disadvantages of PET scanning include its lack of specificity for thyroid cancer as well as its expense and lack of availability in many locations.

Differential Diagnosis

Lymphocytic thyroiditis, multinodular goiter, and colloid nodules can be distinguished from malignancies by FNA biopsy. However, FNA cannot distinguish benign follicular adenoma from follicular carcinoma. Overall, in such “suspicious” cases, the risk of malignancy is about 20% higher in fixed lesions over 4 cm in diameter. The risk of malignancy is 5% for nodules in elderly patients with lesions under 4 cm in diameter having “suspicious” cytology.

Neuroendocrine carcinomas may metastasize to the thyroid and be confused with medullary thyroid carcinoma.

False-positive 131I scans are common with normal residual thyroid tissue and have been reported with Zenker's diverticulum, struma ovarii, pleuropericardial cyst, gastric pull-up, and 131I-contaminated bodily secretions. False-negative 131I scans are common in early metastatic differentiated thyroid carcinoma but occur also in more advanced disease, including 14% of bone metastases.

Complications

The complications vary with the type of carcinoma. Differentiated thyroid carcinomas may have local or distant metastases. One-third of medullary carcinomas may secrete serotonin and prostaglandins, producing flushing and diarrhea, and may be complicated by the coexistence of pheochromocytomas or hyperparathyroidism. The risks of radical neck surgery include permanent hypoparathyroidism and vocal cord palsy due to recurrent laryngeal nerve damage; permanent hypothyroidism is expected after thyroidectomy and should always be treated adequately.

Treatment of Differentiated Thyroid Carcinoma

A. Surgical Treatment

Surgical removal is the treatment of choice for thyroid carcinomas. Neck ultrasound is useful both preoperatively and in follow-up. For differentiated papillary and follicular carcinoma, thyroidectomy with limited removal of cervical lymph nodes is adequate. However, for patients with Hürthle cell carcinoma or medullary thyroid carcinoma who have metastases to lymph nodes, modified radical neck dissection is recommended. Highly skilled surgeons can perform near-total thyroidectomies with a less than 1% rate of serious complications (hypoparathyroidism or recurrent laryngeal nerve damage). Other series have reported up to an 11% incidence of permanent hypoparathyroidism after total thyroidectomy.

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Thyroidectomy requires at least an overnight hospital admission, since late bleeding, airway problems, and tetany can occur. Ambulatory thyroidectomy is potentially dangerous and should not be done.

The incidence of hypoparathyroidism may be reduced if accidentally resected parathyroids are immediately autotransplanted into the neck muscles. The advantage of near-total thyroidectomy for differentiated thyroid carcinoma is that multicentric foci of carcinoma are more apt to be resected and there is then less normal thyroid tissue to compete with cancer for 131I administered later for scans or treatment. Subtotal thyroidectomy is acceptable for adults under age 45 years who have a single small tumor (≤ 1 cm in diameter). Neck muscle dissections are usually avoided for differentiated thyroid carcinoma. T4 is prescribed in doses of 0.05–0.1 mg/d immediately postoperatively. The dosage is adjusted to keep the serum TSH slightly suppressed during long-term follow-up of differentiated thyroid carcinoma.

About 2–4 months after surgery, a whole-body 131I scan is performed. T4 is stopped for 6 weeks prior to the scan, thereby causing hypothyroidism; TSH then rises and stimulates iodide uptake and thyroglobulin release from residual tumor or normal thyroid. Iodine-containing foods and contrast media are avoided.

Metastases to the brain are best treated surgically, since treatment with radiation or RAI is ineffective. Patients with bulky recurrent tumor in the neck region also benefit from surgery.

B. Medical Treatment and Chemotherapy

Patients who have had a thyroidectomy for differentiated thyroid cancer must take thyroid hormone replacement for life. Serum TSH levels must be monitored. Patients with differentiated thyroid carcinoma, including Hürthle cell carcinoma, should be given oral thyroxine in doses that suppress serum TSH without causing clinical thyrotoxicosis. An ultrasensitive TSH assay should be used; serum TSH should be suppressed below 0.1 mU/L for patients with stage II disease and below 0.05 mU/L for patients with stage III-IV disease. Patients receiving T4 suppression therapy have been reported, as a group, to have slightly lower bone density than age-matched controls. However, for patients who are clinically euthyroid, T4 suppression therapy has a minimal effect upon bone and fracture risk. Nevertheless, patients receiving T4 suppression therapy are advised to have periodic bone densitometry.

Thyroid carcinomas are extraordinarily resistant to chemotherapy. Zoledronic acid, an intravenous bisphosphonate, has proven useful for osseous metastases from other solid tumors and has been used for patients with thyroid bone metastases, but its effectiveness is unknown.

C. Radioactive Iodine Therapy

Following total or near-total thyroidectomy, patients with differentiated thyroid carcinoma receive an RAI neck and whole-body scan, either while hypothyroid, or after thyrotropin administration. In patients with visible RAI uptake, those with stage II-IV cancer should be treated with adjuvant 131I therapy, when possible. The use of RAI therapy for patients with stage I differentiated thyroid cancer (with residual thyroid bed RAI uptake) is controversial; there has been no demonstrable improvement in survival in this group of patients following RAI therapy, although RAI therapy reduces the risk of local recurrence. Some groups advocate RAI therapy for patients with stage I disease whose primary tumor was over 1 cm in diameter. Patients must have demonstrated uptake of RAI on diagnostic scanning to warrant RAI therapy. For patients who have 131I therapy, the dose of 131I for thyroid “remnant ablation” (residual normal thyroid with perhaps thyroid cancer in the thyroid bed) in those with no nodal involvement is 30–100 mCi, with the higher doses given to patients with large primary tumors or tumors at the surgical margin. Patients with local lymph node involvement typically receive 100 mCi of 131I; patients with more extensive neck node involvement or distant metastases receive 150–200 mCi of 131I.

Prior to 131I therapy, patients must be allowed to become hypothyroid, since high TSH levels stimulate thyroid cancer cells to actively absorb more iodine, and hypothyroidism reduces the renal clearance of iodine. Being hypothyroid is uncomfortable for most patients. Because levothyroxine (T4) has a much longer half-life than T3, the following protocol is suggested to prepare patients for 131I therapy: 8 weeks prior to 131I therapy, levothyroxine replacement therapy is stopped and T3 (Cytomel) is substituted at a dose of 12.5 mcg orally twice daily; 6 weeks prior to 131I therapy, the Cytomel is increased to 25 mcg orally twice daily; 16 days prior to 131I therapy, the Cytomel is discontinued.

Recombinant human thyrotropin (rhTSH) injections do not stimulate RAI uptake sufficiently to prepare patients with stage II-IV cancer for 131I ablative therapy of thyroid cancer. Also, patients receiving thyrotropin injections are euthyroid and have a high renal clearance of RAI, reducing the effectiveness of 131I therapy. However, many centers are using rhTSH to stimulate 131I uptake for thyroid remnant ablation in patients with stage I cancer. Such patients can also have their T4 withdrawn for 1 week before the rhTSH and 131I therapy to allow endogenous TSH levels to rise and provide additional stimulation of RAI uptake. Thyrotropin stimulation is also useful for patients with functional metastases whose serum TSH is always suppressed.

Patients must follow a low-iodine diet for 2 weeks before 131I therapy. Just before therapy, serum is obtained for measurement of TSH (to make certain it is > 30 mcU/mL), thyroglobulin, and hCG (in all reproductive-age women). Pregnant women may not receive RAI therapy. Women are advised to avoid pregnancy for at least 4 months following 131I therapy. Men have been found to have abnormal spermatozoa for up to 6 months following 131I therapy and are advised to use contraceptive methods during that time.

Sodium 131I, 30–50 mCi (1110–1850 MBq), is administered orally to patients with an original papillary

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or follicular carcinoma ≥ 1.5 cm in diameter and also to patients having persistent RAI uptake in the thyroid bed following near-total thyroidectomy. Patients with extrathyroidal uptake from metastatic disease are given larger doses of about 125–150 mCi (5550 MBq) 131I orally in the hospital. A posttherapy whole-body scan performed 1 week after 131I treatment will often detect metastases that were not visible on pretreatment scans.

Four days following 131I therapy, Cytomel is resumed at a dose of 25 mcg orally twice daily for 1 week, reduced to 12.5 mcg twice daily for the next week. At the same time, T4 is resumed and continued at a full thyroid replacement dose.

About 35% of patients with metastatic differentiated thyroid carcinoma have poor uptake of RAI into metastases. Lithium inhibits the release of 131I from differentiated thyroid cancer and may increase the absorbed radiation dose; however, prospective treatment trials are lacking.

131I therapy in doses over 100 mCi (3799 MBq) can cause gastritis, temporary oligospermia, sialadenitis, and xerostomia. RAI therapy can cause neurologic decompensation in patients with brain metastases; it is advisable to treat such patients with prednisone 30–40 mg orally daily for several days before and after 131I therapy. Cumulative doses of 131I over 500 mCi can cause infertility, pancytopenia (4%), and leukemia (0.3%). The kidneys excrete RAI. To reduce the risk of radiation-induced side effects, patients receiving dialysis for renal failure require a dosage reduction to only 20% of the usual dose of 131I.

D. Treatment of other Thyroid Malignancies

Patients with anaplastic thyroid carcinoma are treated with local resection and radiation. Lovastatin, an HMG-CoA inhibitor, has been demonstrated to cause differentiation and apoptosis of anaplastic thyroid carcinoma cells in vitro; however, clinical studies have not been performed. Anaplastic thyroid carcinoma does not respond to 131I therapy and is resistant to chemotherapy.

Patients with thyroid MALT lymphomas have a low risk of recurrence after simple thyroidectomy. Patients with other thyroid lymphomas are best treated with external radiation therapy; chemotherapy is added for extensive lymphoma. Patients with systemic lymphomas involving the thyroid are usually treated with chemotherapy.

Patients with medullary thyroid carcinoma are treated surgically; repeated neck dissections are often required over time.

Patients with medullary thyroid carcinoma are advised to have genetic testing for ret protooncogene mutations. Patients who are discovered to have a germline mutation may require surveillance for other manifestations of MEN; genetic testing of first-degree relatives is also advisable. It is advisable that children with a ret protooncogene mutation have a prophylactic total thyroidectomy, ideally by age 6 years (MEN 2A) or at age 6 months (MEN 2B). Medullary thyroid carcinoma does not take up 131I.

E. External Radiation Therapy

External radiation may be delivered to bone metastases. Brain metastases do not usually respond to 131I and are best resected or treated with gamma knife radiosurgery.

F. Surveillance

Patients with differentiated thyroid carcinoma must be observed long term for recurrent or metastatic disease. Follow-up must include physical examinations and laboratory testing to ensure that patients remain clinically euthyroid with a suppressed TSH. To achieve suppression of serum TSH, the required dose of thyroxine may be such that serum FT4 levels may be slightly elevated; in that case, measurement of serum T3 or free T3 (women who are pregnant or receiving oral estrogens) can be useful to ensure the patient is not frankly hyperthyroid. Thyrotoxicosis can be caused by overreplacement with thyroxine or by the growth of functioning metastases.

Neck palpation has a sensitivity of only 16% for detecting cervical lymph node metastases. Therefore, a combination of surveillance techniques must be used to detect recurrent or metastatic thyroid cancer.

1. Neck ultrasound

Neck ultrasound should be used in all patients with thyroid carcinoma to supplement neck palpation. It is prudent to perform a thyroid/neck ultrasound in all patients with thyroid cancer preoperatively, 3 months postoperatively, and regularly thereafter. Ultrasound is more sensitive for lymph node metastases than either CT or MRI scanning. Small inflammatory nodes may be detected postoperatively and do not necessarily indicate metastatic disease, but follow-up is necessary. Ultrasound-guided FNA biopsy should be performed on suspicious lesions.

2. Serum thyroglobulin (Tg)

Thyroglobulin is produced by normal thyroid tissue and by most differentiated thyroid carcinomas. It is only after a total or near-total thyroidectomy and 131I remnant ablation that serum thyroglobulin (Tg) becomes a useful tumor marker for patients with differentiated papillary or follicular thyroid cancer. The usefulness of serum Tg is negated by the presence of anti-thyroglobulin antibodies. Anti-Tg antibodies tend to persist but may become less evident several years after total thyroidectomy and during the last trimester of pregnancy. For patients without serum anti-Tg antibodies, Tg measurement is a useful tumor marker.

Detectable levels of thyroglobulin are commonly encountered in patients who have had incomplete thyroidectomies and 131I remnant ablations and do not necessarily indicate the presence of residual or metastatic thyroid cancer. However, baseline or stimulated serum Tg levels ≥ 2 ng/mL indicate the need for a repeat neck ultrasound and further scanning. If serum Tg levels remain ≥ 2 ng/mL in the presence of normal scanning, it is prudent to repeat the serum Tg in a national reference laboratory. Rising serum levels of thyroglobulin are particularly worrisome.

In one series of patients with differentiated thyroid cancer following thyroidectomy, there was a 21% incidence

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of metastases in patients with serum Tg < 1 ng/mL (while receiving thyroxine for TSH suppression). Therefore, stimulated serum Tg measurements should be used and always with neck ultrasound. The usefulness of routinely doing a radioiodine scan (see below) in low-risk patients is controversial but continues to be done in most centers during stimulation following either rhTSH or thyroid hormone withdrawal, according to the protocols described below.

3. Radioactive iodine (RAI: 131I or 123I) whole-body scanning

Despite its limitations, RAI has traditionally been used to detect metastatic differentiated thyroid cancer and to determine whether the cancer is amenable to treatment with 131I. RAI scanning is particularly useful for high-risk patients and those with anti-thyroglobulin antibodies that make serum thyroglobulin determinations unreliable.

The 131I isotope may be used in scanning doses of < 3 mCi (111 MBq) or given within 2 weeks of RAI treatment to avoid “stunning” metastases such that they take up less of the RAI therapy dose. The radioisotope 123I may be used in scanning doses of 5 mCi (185 MBq), does not stun tumors, and allows single-photon emission computed tomography (SPECT) to better localize metastases. Initial RAI scanning is typically performed about 2–4 months following surgery for differentiated thyroid carcinoma. Whole-body scanning should be performed for at least 30 minutes for at least 140,000 counts and spot views of the neck should be obtained for at least 35,000 counts.

About 65% of metastases are detectable by RAI scanning, but only after optimal preparation: Patients should ideally have a total or near-total thyroidectomy, since any residual normal thyroid competes for RAI with metastases, which are less avid for iodine. To avoid nonradioactive iodine competitive inhibition of RAI uptake, intravenous iodinated contrast must be avoided for at least 2 months before scanning; patients must follow a low-iodine diet for at least 2 weeks before scanning and continue to limit iodine consumption until the scan is complete or until after 131I therapy. In addition, patients must have high levels of TSH to stimulate metastases to take up more RAI, making them visible on scanning. This can be accomplished by allowing the patient to become hypothyroid or by administering synthetic rhTSH. The use of rhTSH has become more widespread for surveillance scanning and stimulated thyroglobulin determinations following thyroidectomy for differentiated thyroid carcinoma, due to its convenience for the patient. However, rhTSH-stimulated scanning is slightly less sensitive than hypothyroid-stimulated scanning. For stage I-II patients, it is reasonable to perform a thyroid-withdrawal scan once; if it is negative and the serum thyroglobulin is < 2 ng/mL, an rhTSH scan can be performed 1 and 3 years thereafter.

a. Thyrotropin-stimulated serum Tg and radioiodine scanning

The use of recombinant human thyrotropin-α (Thyrogen; rhTSH) injections can replace thyroid withdrawal with much less discomfort for most patients. Thyrotropin stimulates uptake of RAI and production of thyroglobulin by differentiated thyroid cancer or residual thyroid. The use of rhTSH is particularly suited to “low-risk” patients: those with a small papillary thyroid carcinoma who have had a total or near-total thyroidectomy and have no known local or distal metastases and a serum thyroglobulin < 1 mcg/L during thyroxine suppression of serum TSH. In about 21% of such “low-risk” patients, rhTSH stimulates serum thyroglobulin to above 2 mcg/L; such patients have a 23% risk of local neck metastases and a 13% risk of distant metastases. Stimulated radioiodine neck and whole-body scanning can detect only about half of these metastases because they are small or not avid for iodine.

Thyrotropin must be kept refrigerated and may be administered according to the following protocol: Thyroxine replacement is held for 2 days before rhTSH and for 3 days afterward. On Monday and Tuesday, thyrotropin 0.9 mg is administered intragluteally (not intravenously). On Wednesday, serum is drawn for TSH and thyroglobulin determinations. Immediately thereafter, RAI is administered in a scanning dose (see above). On Friday, serum is drawn for thyroglobulin and the whole-body scan is performed.

Side effects of thyrotropin injections include nausea (11%) and headache (7%). Hyperthyroidism can occur in patients with significant metastases or residual normal thyroid. Thyrotropin has caused neurologic deterioration in 7% of patients with central nervous system metastases.

The combination of thyrotropin-stimulated scanning and thyroglobulin levels detects a thyroid remnant or cancer with a sensitivity of 84%. However, the presence of anti-thyroglobulin antibodies renders the serum thyroglobulin determination uninterpretable. Thyrotropin stimulation does not prepare patients for 131I treatment; they must be prepared for treatment by becoming hypothyroid as described below.

b. Thyroid withdrawal-stimulated serum Tg and radioiodine scanning

Patients are allowed to become hypothyroid; high levels of endogenous TSH stimulate the uptake of RAI and production of thyroglobulin by thyroid cancer or residual thyroid. Being hypothyroid is uncomfortable for most patients. Because T4 has a much longer half-life than T3, the following protocol is suggested to prepare patients for RAI scanning: Eight weeks prior to RAI scanning, levothyroxine replacement therapy is stopped and T3 (Cytomel) is substituted at a dose of 12.5 mcg orally twice daily. Six weeks prior to RAI scanning, the Cytomel is increased to 25 mcg twice daily. Seventeen days prior to RAI scanning, the Cytomel is discontinued. Prior to scanning, serum TSH is assayed to confirm that it is > 30 mcU/mL; serum hCG is assayed to screen for pregnancy; serum thyroglobulin titers are also determined. Following radioisotope scanning, or 4 days after 131I therapy (see above), Cytomel is resumed at a dose of 25 mcg twice daily for 1 week, reduced to 12.5 mcg twice daily for the next week. At

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the same time, T4 is resumed and continued at a full thyroid replacement dose.

Patients with papillary carcinoma should have at least two annual consecutively negative stimulated serum thyroglobulin determinations < 1mcg/L and normal RAI scans (if done) before they are considered to be in remission. Patients with persistent RAI uptake restricted to the thyroid bed need not have repeated 131I therapies if neck ultrasound appears benign and serum thyroglobulin is < 5 ng/mL. Further radioiodine or other scans may be required for patients with more aggressive papillary-follicular, follicular, or medullary thyroid carcinomas, prior metastases, rising serum thyroglobulin levels, or other evidence of metastases.

Patients often have a negative whole-body radioiodine scan but have serum thyroglobulin levels that are > 2 ng/mL. In such cases, another thyroglobulin assay should be sent to a different reference laboratory to confirm the accuracy of the thyroglobulin determination. Patients with serum Tg levels > 2 ng/mL require close continued monitoring. Those with progressively rising Tg levels are at high risk for occult thyroid cancer metastases. Other scanning methods may be used in an effort to detect such metastases. (See below.)

4. Positron emission tomography scanning

PET whole-body scanning using 18FDG-PET is a relatively sensitive method for detecting thyroid cancer metastases—particularly those that are not revealed on RAI scanning. PET scanning is particularly useful for detecting thyroid cancer metastases in patients with a detectable serum thyroglobulin (especially serum thyroglobulin levels > 10 ng/mL and rising) who have a normal whole-body RAI scan and an unrevealing neck ultrasound. PET scanning can be combined with a CT scan; the resultant PET/CT fusion scan is 60% sensitive for detecting metastases that are not visible by other methods. This scan is less sensitive for small brain metastases. 18FDG-PET scanning detects the metabolic activity of tumor tissue; for differentiated thyroid carcinoma, this scan is more sensitive when the patient is hypothyroid or pretreated with thyrotropin as described above. One problem with 18FDG-PET scanning is its lack of specificity. For example, false-positives can occur with benign hepatic tumors, sarcoidosis, radiation therapy, suture granulomas, reactive lymph nodes, or inflammation at surgical sites that can persist for months. False-positive uptake can also occur in muscles and brown fat in the neck and shoulders, axillae, mediastinum, perinephric regions, intercostal paravertebral spaces, and paravertebral muscles. A fusion 18FDG-PET/CT (no contrast) scan improves specificity but cannot distinguish thyroid carcinoma from other unrelated malignancies that may be present concurrently. Smaller metastases are often present on PET scanning before becoming visible on CT or even MRI scanning.

18FDG-PET scanning is particularly sensitive for detecting medullary thyroid carcinoma (MTC) metastases, and prescan thyrotropin does not improve the PET scan sensitivity for MTC.

5. Other scanning

Thallium-201 (201Tl) scans may be useful for detecting metastatic differentiated thyroid carcinoma when the 131I scan is normal but serum thyroglobulin is elevated. MRI scanning is particularly useful for imaging metastases in the brain, mediastinum, or bones. CT scanning is useful for imaging and monitoring pulmonary metastases.

Prognosis

Differentiated thyroid carcinoma carries a generally good prognosis, particularly for adults under age 45 years, despite the fact that about 15% of these patients are subsequently found to have metastases. The following characteristics imply a worse prognosis: older age, male sex, bone or brain metastases, large pulmonary metastases, and lack of 131I uptake into metastases. Certain papillary histologic types are associated with a higher risk of recurrence: tall cell, columnar cell, and diffuse sclerosing types. Staging and survival rates are presented in Table 26-9. Brain metastases are detected in 1%; they reduce median survival to 12 months, but their prognosis is improved by surgical resection. Patients with follicular carcinoma have a cancer mortality rate that is 3.4 times higher than patients with papillary carcinoma. The Hürthle cell variant of follicular carcinoma is more aggressive. Patients with primary tumors over 1 cm in diameter who undergo limited thyroid surgery (subtotal thyroidectomy or lobectomy) have a 2.2-fold increased mortality over those having total or near-total thyroidectomies. Patients who have not received 131I ablation have mortality rates that are increased twofold by 10 years and threefold by 25 years (over those who have received ablation). The risk of cancer recurrence is twofold higher in men than in women and 1.7-fold higher in multifocal than in unifocal tumors.

Table 26-9. Pathologic tumor-node-metastasis (pTNM) staging and tumor-related survival rates for adults with appropriately treated differentiated (papillary) thyroid carcinoma based upon patient age, primary tumor size and invasiveness (T), lymph node involvement (N), and distant metastases (M).1

Stage Description Five-Year Survival Ten-Year Survival
1 Under 45: any T, any N, no M Over 45: T ≤1 cm, no N, no M 99% 98%
2 Under 45: any T, any N, any M Over 45: T >1 cm limited to thyroid, no N, no M 99% 85%
3 Over 45: T beyond thyroid capsule, no N, no M; or any T, regional N, no M 95% 70%
4 Over 45: any T, any N, any M 80% 61%
From Alsanea O et al: Surgery 2000;128:1043; Loh KC et al: J Endocrinol Metab 1997;82:3553; and Hay ID: Endocrinol Metabol Clin North Am 1990;19:545.
1Patients having a relatively worse prognosis include those with follicular thyroid carcinoma and those with familial differentiated thyroid carcinoma.

Medullary thyroid carcinoma is typically fairly indolent but more aggressive than differentiated thyroid cancer. The overall 10-year survival rate is 90% when the tumor is confined to the thyroid, 70% for those with metastases to cervical lymph nodes, and 20% for those with distant metastases. Patients with sporadic disease usually have lymph node involvement at the time of diagnosis, whereas distal metastases may not be noted for years. Familial cases or those associated with MEN 2A tend to be less aggressive; the 10-year survival rate is higher, in part due to earlier detection. Medullary thyroid carcinoma that is seen in MEN 2B is more aggressive, arises earlier in life, and carries a worse overall prognosis. Women with medullary thyroid carcinoma who are under age 40 years also have a better prognosis. A better prognosis is also obtained in patients undergoing total thyroidectomy and neck dissection; radiation therapy reduces recurrence in patients with metastases to neck nodes. The mortality rate is increased 4.5-fold when primary or metastatic tumor tissue stains heavily for myelomonocytic antigen M-1. Conversely, tumors with heavy immunoperoxidase staining for calcitonin are associated

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with prolonged survival even in the presence of significant metastases.

Anaplastic thyroid carcinoma has a 1-year survival rate of about 10% and a 5-year survival rate of about 5%. Patients with fully localized tumors on MRI have a better prognosis.

Patients with localized lymphoma have nearly 100% 5-year survival. Those with disease outside the thyroid have a 63% 5-year survival. However, the prognosis is better for those with the MALT type. Patients presenting with stridor, pain, laryngeal nerve palsy, or mediastinal extension tend to fare worse.

Driedger AA et al: Two cases of thyroid carcinoma that were not stimulated by recombinant human thyrotropin. J Clin Endocrinol Metab 2004;89:589.

Fernandes JK et al: Overview of the management of differentiated thyroid cancer. Curr Treat Options Oncol 2005;6: 47.

Giles Y et al: The advantage of total thyroidectomy to avoid reoperation for incidental thyroid cancer in multinodular goiter. Arch Surg 2004;139:179.

Hamady ZZ et al: Surgical pathological second opinion in thyroid malignancy: impact on patients' management and prognosis. Eur J Surg Oncol 2005;31:74.

Kim TY et al: Metastasis to the thyroid diagnosed by fine-needle aspiration biopsy. Clin Endocrinol (Oxf) 2005;62:236.

Lin JD et al: Papillary thyroid carcinomas with lung metastases. Thyroid 2004;14:1091.

Mazzaferri EL et al: A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88:1433.

Robbins RJ et al: Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 2006;91:498.

Sawka AM et al: A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab 2004;89:3668.

Endemic Goiter

Essentials of Diagnosis

  • Common in regions of the world with low-iodine diets.

  • High rate of congenital hypothyroidism and cretinism.

  • Goiters may become multinodular and grow to great size.

  • Most adults with endemic goiter are found to be euthyroid; however, some are hypothyroid or hyperthyroid.

  • Impaired cognition and hearing may be subtle or severe in congenital hypothyroidism.

General Considerations

Approximately 5% of the world's population have goiters. Of these, about 75% are in persons dwelling in areas of iodine deficiency. Such areas are found in 115 countries, mostly in developing areas but also in Europe. In iodine-deficient patients, smoking or pregnancy can induce goiter growth.

In Pescopagano, Italy, 60% of adults have goiters. Hyperthyroidism (present or past) occurred in 2.9%; hypothyroidism was overt in 0.2% and subclinical in 3.8%. The incidence of thyroid cancer was less than 0.1%. Up to 0.5% of iodine-deficient populations have full-blown cretinism, with less severe manifestations of congenital hypothyroidism being even more common (eg, isolated deafness, short stature, or impaired mentation). Intelligence quotients in iodine-deficient adults are an average of 13 points lower than expected. Although iodine deficiency is the most common cause of endemic goiter, certain foods (eg, sorghum, millet, maize, cassava), mineral deficiencies (selenium, iron), and water pollutants can themselves cause goiter or aggravate a goiter proclivity caused by

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iodine deficiency. Pregnancy is associated with an increase in size of thyroid nodules and the emergence of new nodules. Some individuals are particularly susceptible to goiter owing to congenital partial defects in thyroid enzyme activity.

Clinical Findings

A. Symptoms and Signs

Endemic goiters may become multinodular and very large. Growth often occurs during pregnancy and may cause compressive symptoms.

Substernal goiters are usually asymptomatic but can cause tracheal compression, respiratory distress and failure, dysphagia, superior vena cava syndrome, gastrointestinal bleeding from esophageal varices, palsies of the phrenic or recurrent laryngeal nerves, or Horner's syndrome. Cerebral ischemia and stroke can result from arterial compression or thyrocervical steal syndrome. Substernal goiters can rarely cause pleural or pericardial effusions. The incidence of significant malignancy is less than 1%.

Some patients with endemic goiter may become hypothyroid. Others may become thyrotoxic as the goiter grows and becomes more autonomous, especially if iodine is added to the diet.

B. Laboratory Findings

The serum T4 is usually normal. Serum TSH is generally normal. TSH falls in the presence of hyperthyroidism if a multinodular goiter has become autonomous in the presence of sufficient amounts of iodine for thyroid hormone synthesis. TSH rises with hypothyroidism. Thyroid RAI uptake is usually elevated, but it may be normal if iodine intake has improved. Serum levels of antithyroid antibodies are usually either undetectable or in low titers. Serum thyroglobulin is often elevated.

Differential Diagnosis

Endemic goiter must be distinguished from all other forms of nodular goiter that may coexist in an endemic region (see above).

Prevention

Iodine supplementation was started in Switzerland in 1922, initially by adding 5 mg of potassium iodide per kilogram of salt, with later increases to the current level of 20 mg/kg salt. Iodized salt has greatly reduced the incidence of endemic goiter. Unfortunately, many iodine-deficient countries have inadequate programs for iodine supplementation. The minimum dietary requirement for iodine is about 50 mcg daily, with optimal iodine intake being 150–300 mcg daily. Iodine sufficiency is assessed by measurement of urinary iodide excretion, the target being more than 10 mcg/dL.

Initiating iodine supplementation in a geographic area causes an increased frequency of hyperthyroidism in the first year, followed by greatly reduced rates of toxic nodular goiter and Graves' disease thereafter.

Treatment

The addition of potassium iodide to table salt greatly reduces the prevalence of endemic goiter and cretinism but is less effective in shrinking established goiter. Concurrent deficiencies in both vitamin A and iodine increase the risk of endemic goiter and concurrent repletion of both iodide and vitamin A reduces goiter in endemic goiter regions. Dietary iodine supplementation increases the risk of autoimmune thyroid dysfunction, which may result in hypothyroidism or thyrotoxicosis. Excessive iodine intake may increase the risk of goiter. T4 supplementation can shrink goiters and reduce the risk of further goiter growth, but such treatment likewise carries a risk of inducing hyperthyroidism in individuals with autonomous multinodular goiters; therefore, T4 suppression should not be started in patients with suppressed TSH levels.

Adults with large multinodular goiter may require thyroidectomy for cosmesis, compressive symptoms, or thyrotoxicosis. Following partial thyroidectomy in iodine-deficient geographic areas, there is a high goiter recurrence rate, so total thyroidectomy is preferred when surgery is indicated. Certain patients may be treated with 131I for large compressive goiters. Such patients may rarely develop Graves' disease 3–10 months after treatment.

Bellantone R et al: Predictive factors for recurrence after thyroid lobectomy for unilateral non-toxic goiter in an endemic area: results of a multivariate analysis. Surgery 2004;136: 1247.

Valentino R et al: Screening a coastal population in Southern Italy: iodine deficiency and prevalence of goitre, nutritional aspects and cardiovascular risk factors. Nutr Metab Cardiovasc Dis 2004;14:15.

Hypothyroidism & Myxedema

Essentials of Diagnosis

  • Weakness, fatigue, cold intolerance, constipation, weight change, depression, menorrhagia, hoarseness.

  • Dry skin, bradycardia, delayed return of deep tendon reflexes.

  • Anemia, hyponatremia.

  • T4 and RAI uptake usually low.

  • TSH elevated in primary hypothyroidism.

General Considerations

Thyroid hormone deficiency may affect almost all body functions. The degree of severity ranges from mild and

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unrecognized hypothyroid states to striking myxedema. The fluid retention seen in myxedema is caused by the interstitial accumulation of hydrophilic mucopolysaccharides, which leads to lymphedema. Hyponatremia is the result of impaired renal tubular sodium reabsorption due to reductions in Na+-K+-ATPase. Cellular proteins are also affected in myxedema.

Hypothyroidism may be due to primary disease of the thyroid gland itself or lack of pituitary TSH. Florid hypothyroidism, ie, myxedema and cretinism, is readily recognized on clinical grounds alone, but mild hypothyroidism often escapes detection without screening (ie, serum TSH). Maternal hypothyroidism during pregnancy results in offspring with IQ scores that are an average 7 points lower than those of euthyroid mothers.

Goiter may be noted when hypothyroidism is due to Hashimoto's thyroiditis, iodide deficiency, genetic thyroid enzyme defects, drug goitrogens (lithium, iodide, propylthiouracil or methimazole, phenylbutazone, sulfonamides, amiodarone, interferon-α, interferon-β, interleukin-2), food goitrogens in iodide-deficient areas (eg, turnips, cassavas), or, rarely, peripheral resistance to thyroid hormone or infiltrating diseases (eg, cancer, sarcoidosis). A hypothyroid phase occurs in subacute (de Quervain's) viral thyroiditis following initial hyperthyroidism.

Goiter is usually absent when hypothyroidism is due to deficient pituitary TSH secretion, or destruction of the gland by surgery, external radiation, or 131I. Patients who have received central nervous system radiation for leukemia have a 15% chance of developing hypothyroidism years later. Patients with primary pulmonary hypertension have a 22% incidence of hypothyroidism.

Amiodarone, because of its high iodine content, causes clinically significant hypothyroidism in about 8% of patients. The T4 level is normal or low, and the TSH is elevated, usually over 20 ng/dL. Another 17% of patients develop milder elevations of TSH and are asymptomatic. Low-dose amiodarone is less likely to cause hypothyroidism. Cardiac patients with amiodarone-induced symptomatic hypothyroidism are treated with just enough T4 to relieve symptoms. Hypothyroidism usually resolves if amiodarone is discontinued. Patients with a high iodine intake from other sources may also develop hypothyroidism, especially if they have underlying lymphocytic thyroiditis.

Patients with chronic hepatitis C have an increased risk of autoimmune thyroiditis, with 21% having antithyroid antibodies and 13% having hypothyroidism. The risk of thyroid dysfunction is even higher when patients are treated with interferon. Interferon-α and interferon-β treatment can induce thyroid dysfunction (usually hypothyroidism, sometimes hyperthyroidism) in 6% of patients. Spontaneous resolution occurs in over 50% of cases once interferon is discontinued.

Clinical Findings

These may vary from the rather rare full-blown myxedema to mild states of hypothyroidism, which are far more common. Hypothyroidism is a common disorder; therefore, a clinician should request thyroid function tests for any patient with the nonspecific symptoms and signs of hypothyroidism.

A. Symptoms and Signs

1. Early

Frequent symptoms are fatigue, lethargy, weakness, arthralgias or myalgias, muscle cramps, cold intolerance, constipation, dry skin, headache, and menorrhagia. Physical findings may be few or absent. Features may include thin, brittle nails, thinning of hair, and pallor. Delayed relaxation of deep tendon reflexes and bradycardia are sometimes noted.

2. Late

The symptoms are variable but may include slow speech, absence of sweating, constipation, peripheral edema, pallor, hoarseness, decreased sense of taste and smell, muscle cramps, aches and pains, dyspnea, weight changes (usually gain, but weight loss is not rare), and diminished auditory acuity. Some women have amenorrhea; others have menorrhagia. Galactorrhea may also be present. Physical findings may include goiter, puffiness of the face and eyelids, typical carotenemic skin color, thinning of the outer halves of the eyebrows, thickening of the tongue, hard pitting edema, and effusions into the pleural, peritoneal, and pericardial cavities, as well as into joints. Cardiac enlargement (“myxedema heart”) is often due to pericardial effusion. The heart rate is slow; the blood pressure is more often normal than low, and reversible diastolic hypertension may be found. Hypothermia may be present. Pituitary enlargement due to hyperplasia of TSH-secreting cells, which is reversible following thyroid therapy, may be seen in long-standing hypothyroidism. Hypothyroidism rarely causes true obesity.

B. Laboratory Findings

The FT4 may be low or low normal. TSH is increased with primary hypothyroidism but is low or normal with pituitary insufficiency. Other laboratory abnormalities may often be seen: increased serum cholesterol, liver enzymes, and creatine kinase; increased serum PRL; and hyponatremia, hypoglycemia, and anemia (with normal or increased mean corpuscular volume). Titers of antibodies against thyroperoxidase and thyroglobulin are high in patients with Hashimoto's thyroiditis. Serum T3 is not a good test for hypothyroidism.

Some clinically euthyroid patients have mildly elevated levels of serum TSH (5–10 mIU/L) without any other manifestations of hypothyroidism; serum FT4 levels are normal. Such patients are said to have “subclinical hypothyroidism.”

Differential Diagnosis

Hypothyroidism can be mistaken for other conditions that cause states of asthenia, unexplained menstrual disorders, myalgias, constipation, weight change, hyperlipidemia, and anemia. Myxedema enters into the differential diagnosis of unexplained heart failure that does not respond to digitalis or diuretics, and unexplained ascites.

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The protein content of myxedematous effusions is high. The thick tongue may be confused with that seen in primary amyloidosis. Pernicious anemia may be suggested by the pallor and the macrocytic anemia sometimes seen in myxedema; the two disorders may even coexist. Some cases of depression, primary psychosis, and structural diseases of the brain have been confused with myxedema. The pituitary is often quite enlarged in primary hypothyroidism due to reversible hyperplasia of TSH-secreting cells; the concomitant hyperprolactinemia seen in hypothyroidism can lead to the mistaken diagnosis of a TSH-secreting or PRL-secreting pituitary adenoma.

A number of factors can lower serum T4 levels without causing true hypothyroidism (see Table 26-6). Autoimmune disease can cause false elevations of TSH by interfering with the assay. Serum TSH may be elevated transiently in acute psychiatric illness and during recovery from nonthyroidal illness. A high TSH can also be caused by thyrotropin-secreting pituitary tumors. Patients with TSH resistance, caused by a mutation in the gene encoding the TSH receptor, have high serum TSH levels despite usually being clinically and biochemically euthyroid.

Complications

Complications are mostly cardiac in nature, occurring as a result of advanced coronary artery disease and congestive failure, which may be precipitated by overly vigorous thyroid therapy. There is an increased susceptibility to infection. Megacolon has been described in long-standing hypothyroidism. Organic psychoses with paranoid delusions may occur (“myxedema madness”). Rarely, adrenal crisis may be precipitated by thyroid therapy. Hypothyroidism is a rare cause of infertility, which may respond to thyroid medication. Pregnancy in a woman with untreated hypothyroidism often results in miscarriage. On the other hand, if the hypothyroidism is due to autoimmune disease, it may improve during pregnancy. Sellar enlargement and even well-defined TSH-secreting tumors may develop in untreated cases. These tumors decrease in size after replacement therapy is instituted.

A rare complication of severe hypothyroidism is deep stupor, at times progressing to myxedema coma, with severe hypothermia, hypoventilation, hyponatremia, hypoxia, hypercapnia, and hypotension. Convulsions and abnormal central nervous system signs may occur. Myxedema coma is often induced by an underlying infection; cardiac, respiratory, or central nervous system illness; cold exposure; or drug use. It is most often seen in elderly women. The mortality rate from myxedema coma is high. Myxedematous patients are unusually sensitive to opioids and may die from average doses.

Refractory hyponatremia is often seen in severe myxedema. Inappropriate secretion of ADH has been observed in some patients, but a defect in distal tubular reabsorption of sodium and water has been demonstrated in many others.

Treatment

Levothyroxine (thyroxine; T4) is the treatment of choice. It is partially converted in the body to T3, the more active thyroid hormone. Hypothyroid patients who are taking thyroxine replacement typically have serum T3 levels that are lower than normal, owing to their lack of thyroidal T3 secretion. Oral administration of T3 causes abnormal peaks in serum T3 and the usefulness of T3 for hypothyroidism is controversial; a sustained-release T3 preparation is not commercially available.

In patients taking a certain daily dose of levothyroxine, significant increases in serum T4 levels are seen within 1–2 weeks, and near-peak levels are seen within 3–4 weeks. It is best taken in the morning with water, avoiding concomitant intake of foods and drugs that may interfere with its absorption (see below). Brand preparations of levothyroxine in the United States appear to be bioequivalent to each other and certain generics. Before therapy with thyroid hormone is commenced, the hypothyroid patient requires at least a clinical assessment for adrenal insufficiency, which would require concurrent treatment.

A. Beginning Treatment for Hypothyroidism

Patients without coronary insufficiency who are under age 60 years may receive starting doses of oral levothyroxine of 50–100 mcg/daily up to a maximum of 1.6 mcg/kg body weight daily. Women who are pregnant and significantly hypothyroid may begin therapy with levothyroxine at doses of 100–150 mcg orally daily. Patients with coronary disease or those who are over age 60 years are treated with smaller initial doses of levothyroxine, 25–50 mcg daily; higher initial doses may be used if such patients are severely hypothyroid. The dose can be increased by 25 mcg every 1–3 weeks until the patient is euthyroid. Hypothyroid patients with ischemic heart disease may begin thyroxine therapy following coronary artery angioplasty or bypass.

Patients with severe hypothyroidism require larger initial doses of levothyroxine, particularly since myxedema itself can interfere with the intestinal absorption of T4.

Myxedema coma is a medical emergency with a high mortality rate. It is caused by hypothyroidism but is usually precipitated by an acute illness or trauma. Patients have the manifestations of hypothyroidism as well as impaired mentation. Hyponatremia and hypoglycemia are often present. Levothyroxine sodium 400 mcg is given intravenously as a loading dose, followed by 100 mcg intravenously daily. The hypothermic patient is warmed only with blankets, since faster warming can precipitate cardiovascular collapse. Patients with hypercapnia require intubation and assisted mechanical ventilation. Infections must be detected and treated aggressively. Patients in whom concomitant adrenal insufficiency is suspected are treated with hydrocortisone, 100 mg intravenously, followed by 25–50 mg every 8 hours.

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B. Long-Term Treatment of Hypothyroidism

It is important to stress to the patient that levothyroxine therapy must be continued long-term and that regular clinical reassessments will be required for life. Most patients ultimately require levothyroxine in doses of 75–250 mcg orally daily.

For most hypothyroid patients, a stable maintenance dose can usually be found. However, the dosage requirement can rise, due to increased hepatic metabolism of thyroxine induced by certain medications: carbamazepine, phenobarbitol, phenytoin, rifabutin, rifampin, and the antitumor drug imatinib (Gleevec). Amiodarone can cause changes in thyroxine dose requirements by various mechanisms. Malabsorption of thyroxine can be caused by coadministration of thyroxine with certain medications: antacids, bile acid binding resins, calcium, didanosine, magnesium, and iron salts (including iron found in multivitamins with minerals).

Women with hypothyroidism typically require increased doses of T4 during pregnancy and during therapy with oral estrogen. Conversely, T4 dosage requirements for women often decrease with delivery, cessation of oral estrogen, and menopause.

There is no standardized optimal dose of levothyroxine, so each patient's dose must be based on careful clinical assessment. Although serum TSH levels can be helpful in determining optimal dosing, it is important not to rely entirely on this test alone.

During pregnancy, it is critical to administer adequate levothyroxine to a hypothyroid woman. Although the fetal thyroid begins secreting thyroid hormone at about 18 weeks of gestation, fetal thyroid development is not complete until term. Maternal T4 crosses the placenta, and the fetus is at least partially dependent upon maternal T4 for central nervous system development—particularly in the second trimester. Maternal hypothyroidism after the first trimester appears to cause some developmental delay in offspring. It is therefore important to carefully follow women with hypothyroidism during their pregnancies with serum TSH (FT4 concentrations in hypopituitarism) determinations every 4–6 weeks and to increase T4 replacement progressively as required.

There is considerable individual variation in the requirement for additional T4 replacement during pregnancy. For women receiving replacement thyroxine, it is prudent to increase thyroxine dosages by 30% as soon as pregnancy is confirmed.

The increased T4 dosage requirements during pregnancy are believed to be due to several factors: (1) Rising estrogen levels during pregnancy increase TBG serum concentrations, reducing FT4 levels. (2) Placental deiodinase promotes the turnover of T4. (3) Supplemental iron and prenatal multivitamins containing iron can bind to oral T4 and reduce its intestinal absorption. Similarly, supplemental calcium can also reduce T4 absorption. Therefore, it is important that patients take their T4 replacement at least 4 hours before or after such dietary supplements. Postpartum, T4 replacement requirements ordinarily return to prepregnancy levels.

Elevated serum TSH levels usually indicate underreplacement with levothyroxine. However, before increasing the T4 dosage, it is wise to (1) confirm that the patient is receiving the prescribed dosage of thyroxine replacement and (2) question the patient about compliance and the presence of angina. It is also important to consider the following: A high TSH in a patient receiving standard replacement doses of T4 may indicate malabsorption of levothyroxine due to concurrent administration with binding substances, particularly iron preparations, sucralfate, aluminum hydroxide antacids, calcium supplements, and soy milk or soy protein supplements. Bile acid-binding resins such as cholestyramine can bind T4 and impair its absorption even when administered 5 hours before the T4. Malabsorption of T4 can also occur in short bowel syndrome; therapy with medium chain triglyceride oil may improve absorption. Impaired absorption of T4 can also be caused by diarrhea of any cause or malabsorption due to sprue, regional enteritis, liver disease, or pancreatic exocrine insufficiency. Serum TSH may be elevated transiently in acute psychiatric illness and during recovery from nonthyroidal illness. Autoimmune disease can cause false elevations of TSH by interfering with the assay. A high TSH can also be caused by thyrotropin-secreting pituitary tumors. TSH may be increased by phenothiazines and atypical antipsychotics.

Suppressed serum TSH levels < 0.1 mU/L (using a sensitive assay) may indicate overreplacement with levothyroxine; if such a patient has manifestations of hyperthyroidism, the dosage of levothyroxine is reduced. However, some patients with suppressed serum TSH levels exhibit no symptoms of hyperthyroidism. For such patients, it is important to determine whether hypopituitarism or severe nonthyroidal illness is present, which can result in low serum TSH levels without hyperthyroidism. TSH can also be suppressed by certain medications, such as nonsteroidal anti-inflammatory drugs, opioids, nifedipine, verapamil, and urgent administration of corticosteroids. Absent such conditions, a clinically euthyroid patient with a low serum TSH should be given a lower dosage of levothyroxine. Patients who exhibit hypothyroid symptoms on the reduced dosage of levothyroxine may have their higher dosage resumed, unless they have coronary insufficiency.

Some hypothyroid patients treated with levothyroxine complain of hypothyroid-type symptoms, particularly fatigue, despite having normal or suppressed levels of TSH and normal levels of FT4. Such patients require careful assessment for other concurrent illnesses such as adrenal insufficiency, hypogonadism, anemia, or depression. If such conditions are treated and hypothyroid-type symptoms persist despite normal or low TSH levels, a serum T3 level (FT3 in pregnancy and women receiving oral estrogens) may help make the difficult decision about whether to increase the levothyroxine dose. If the serum T3 level is low or low normal, such a patient may benefit from a careful increase in T4 dosage; if a definite clinical benefit is achieved, the higher dose is

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continued. However, long-term monitoring for atrial arrhythmias and for osteoporosis is recommended for such patients, though such complications are uncommon in those who are clinically euthyroid. The malaise felt by some hypothyroid patients despite apparent optimal replacement therapy with T4 may be caused by a low concentration of T3 in certain tissues. Studies adding T3 to T4 therapy have not typically shown objective improvement, but patients tend to lose weight and to subjectively prefer combined T4/T3 mixtures to T4 alone. A Dutch double-blind study of 141 hypothyroid patients found that most patients subjectively preferred not T4 but a combined T4/T3 preparation in 5:1 or 10:1 ratios, such that TSH was often suppressed; satisfaction correlated with weight loss.

Prognosis

With early treatment, striking transformations take place both in appearance and mental function. Return to a normal state is usually the rule, but relapses will occur if treatment is interrupted. On the whole, response to thyroid treatment is most satisfactory. However, untreated hypothyroid patients in whom myxedema coma develops have a high mortality rate.

Hypothyroidism caused by interferon-α resolves within 17 months of stopping the drug in 50% of patients. Long-term maintenance therapy with unduly large doses of thyroid hormone can cause symptomatic hyperthyroidism.

Alexander EK et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241.

Antonelli A et al: Thyroid disorders in chronic hepatitis C. Am J Med 2004;117:10.

Appelhof BC et al: Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90:2666.

Casey BM et al: Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239.

Danzi S et al: Potential uses of T3 in the treatment of human disease. Clin Cornerstone 2005;(7 Suppl 2):S9.

Escobar-Morreale HF et al: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metab 2005;90:4946.

Rodriguez I et al: Factors associated with mortality of patients with myxoedema coma: prospective study in 11 cases treated in a single institution. J Endocrinol 2004;180:347.

Roos A et al: The starting dose of levothyroxine in primary hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med 2005;165:1714.

Tell R et al: Long-term incidence of hypothyroidism after radiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys 2004;60:395.

Wekking EM et al: Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 2005;153:747.

Hyperthyroidism (Thyrotoxicosis)

Essentials of Diagnosis

  • Sweating, weight loss or gain, anxiety, loose stools, heat intolerance, irritability, fatigue, weakness, menstrual irregularity.

  • Tachycardia; warm, moist skin; stare; tremor.

  • In Graves' disease: goiter (often with bruit); ophthalmopathy.

  • Suppressed TSH in primary hyperthyroidism; increased T4, FT4, T3, FT3.

General Considerations

The term “thyrotoxicosis” refers to the clinical manifestations associated with serum levels of T4 or T3 that are excessive for the individual (hyperthyroidism). The causes are many and diverse, as described below.

A. Graves' Disease

Graves' disease (known as Basedow's disease in Europe) is the most common cause of thyrotoxicosis. It is an autoimmune disorder affecting the thyroid gland, characterized by an increase in synthesis and release of thyroid hormones; the thyroid gland is typically enlarged. Graves' disease is much more common in women than in men (8:1), and its onset is usually between the ages of 20 and 40 years. It may be accompanied

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by infiltrative ophthalmopathy (Graves' exophthalmos) and, less commonly, by infiltrative dermopathy (pretibial myxedema). The thymus gland is typically hyperplastic and enlarged. Graves' disease may also be associated with other systemic autoimmune disorders such as pernicious anemia, myasthenia gravis, and diabetes mellitus. It has a familial tendency, and histocompatibility studies have shown an association with group HLA-B8 and HLA-DR3. The pathogenesis of the hyperthyroidism of Graves' disease involves the formation of autoantibodies that bind to the TSH receptor in thyroid cell membranes and stimulate the gland to hyperfunction. TSH-R Ab[stim] are demonstrable in the plasma of about 80% of patients with Graves' disease. Other antibodies such as antinuclear antibody (ANA) are generated in Graves' disease, with antithyroperoxidase or antithyroglobulin antibodies being increased in most patients. Patients with Graves' disease have an increased risk of developing Addison's disease, alopecia areata, celiac disease, diabetes mellitus type 1, myasthenia gravis, cardiomyopathy, and hypokalemic periodic paralysis.

B. Toxic Adenomas

Autonomous toxic adenomas of the thyroid may be single (Plummer's disease) or multiple (toxic multinodular goiter). These adenomas are not accompanied by infiltrative ophthalmopathy or dermopathy. Antithyroid antibodies are usually not present in the plasma, and tests for TSH-R Ab[stim] are negative.

C. Subacute Thyroiditis

Subacute thyroiditis typically presents with a moderately enlarged, tender thyroid, and hyperthyroidism. It is thought to be due to a viral infection. If the gland is nontender, the disorder is called “silent thyroiditis.” Hyperthyroidism is followed by hypothyroidism. During thyrotoxicosis, thyroid RAI uptake is low. A similar problem is seen with interleukin-2 therapy and after neck surgery for hyperparathyroidism. Patients taking lithium may rarely experience thyrotoxicosis due to silent thyroiditis. Symptoms mimic a manic episode such that the diagnosis is often missed.

D. Jodbasedow Disease

Jodbasedow disease, or iodine-induced hyperthyroidism, may occur in patients with multinodular goiters after intake of large amounts of iodine in the diet or in the form of radiographic contrast materials or drugs, especially amiodarone.

E. Thyrotoxicosis Factitia

Thyrotoxicosis factitia is due to ingestion of excessive amounts of exogenous thyroid hormone. Isolated epidemics of thyrotoxicosis have been caused by consumption of ground beef contaminated with bovine thyroid gland.

F. Struma Ovarii

Thyroid tissue is contained in about 3% of ovarian dermoid tumors and teratomas. This thyroid tissue may autonomously secrete thyroid hormone due to a toxic nodule or in concert with the woman's thyroid gland in Graves' disease or toxic multinodular goiter.

G. Pituitary Tumor

TSH hypersecretion by the pituitary may be caused by a tumor and is a rare cause of hyperthyroidism. Serum TSH is elevated or normal (determined by a sensitive TSH assay) in the presence of true thyrotoxicosis. No ophthalmopathy is present. Antithyroid antibodies and TSH-R Ab[stim] are usually normal. TSH hypersecretion may be caused by a pituitary adenoma, in which case it is known as “neoplastic inappropriate secretion of thyrotropin.” The tumor may present as a mass lesion following treatment of hyperthyroidism. The pituitary adenoma is usually removed by transsphenoidal surgery. Larger tumors may require radiation therapy; treatment with a somatostatin analog (octreotide, lanreotide) is also usually effective.

Hyperthyroidism is treated symptomatically with propranolol. This condition may also be due to pituitary hyperplasia, in which case it is known as “nonneoplastic inappropriate secretion of thyrotropin.” Pituitary hyperplasia may be detected on MRI scan as pituitary enlargement without a discrete adenoma being visible. This condition appears to be due to a diminished feedback effect of T4 upon the pituitary. It may be familial, but it can also be caused by prolonged untreated hypothyroidism, especially in youth. Hyperthyroid symptoms are treated with propranolol. Definitive treatment is with radioactive iodine or thyroid surgery.

H. Hashimoto's Thyroiditis

Hashimoto's thyroiditis may cause transient hyperthyroidism during the initial destructive phase. This is also seen in some patients receiving interferon-α, interferon-β, and interleukin-2.

I. Pregnancy and Trophoblastic Tumors

Postpartum thyroiditis is common, occurring in 5–9% of women in the first 6 months after delivery. Transient hyperthyroidism results from the release of stored thyroid hormone following damage to the thyroid by thyroperoxidase antibodies whose IgG subclasses activate the complement cascade. The damaged thyroid is then unable to produce thyroid hormone, and hypothyroidism ensues. Most of these women eventually return to a euthyroid state, but one-third of them remain hypothyroid. Therapy is with propranolol during the hyperthyroid phase, followed by T4 during hypothyroidism. Women with postpartum thyroiditis may experience depression. About 75% of women experience recurrence after a subsequent pregnancy.

Although hCG generally has a low affinity for the thyroid's TSH receptors, very high serum levels of hCG may cause sufficient receptor activation to cause thyrotoxicosis. Mild gestational hyperthyroidism may occur during the first 4 months of pregnancy, when hCG levels are very high. Pregnant women are more likely to have thyrotoxicosis and hyperemesis gravidarum if they have high serum levels of asialo-hCG, a subfraction of hCG with greater affinity for TSH receptors.

Thyrotoxicosis may also be caused by the high serum levels of hCG seen in molar pregnancy, choriocarcinoma, and testicular malignancies.

J. Thyroid Carcinoma

Metastatic functioning thyroid carcinoma is a rare cause of thyrotoxicosis.

K. Amiodarone-Induced Thyrotoxicosis

Amiodarone is used to treat cardiac arrhythmias. The drug is concentrated in thyroid, adipose tissue, heart, and skeletal muscle and is 38% iodine by weight; its elimination half-life can be as long as 100 days. Among patients in the United States taking amiodarone, hyperthyroidism develops in about 3%; the incidence of hyperthyroidism is higher in Europe and in iodine-deficient geographic areas. Hyperthyroidism can occur 4 months to 3 years after initiation of amiodarone and may develop many months after amiodarone has been discontinued. Thyrotoxicosis may cause angina or a relapse of the cardiac arrhythmia. Since high levels of T4 and FT4 are normally seen in patients

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taking amiodarone, suppressed TSH (sensitive assay) must be present along with a greatly elevated T4 (> 20 mcg/dL) or T3 (> 200 ng/dL). (Note: Hypothyroidism occurs in an additional 6% of patients receiving amiodarone after 2–39 weeks of therapy.) Amiodarone-induced thyrotoxicosis can occur by various mechanisms.

Type I amiodarone-induced thyrotoxicosis is caused by active elaboration of excessive thyroid hormone and may occur by either of two mechanisms: (1) Free iodine may cause toxic multinodular goiter in iodine-deficient patients with preexisting autonomous thyroid nodules (jodbasedow phenomenon). This is infrequently encountered in iodine-sufficient countries such as the United States. Thyroid RAI uptake ranges from low to high. (2) Excessive free iodine can trigger an immunologic attack on the thyroid; this may cause Graves' disease, commonly with diffuse thyroid enlargement and antithyroid peroxidase antibodies (70%). The presence of proptosis, TSH-R Ab[stim], or thyrotropin-binding inhibitory immunoglobulin (TBII) is diagnostic. Thyroid RAI uptake is usually negligible in the United States; however, up to 80% of such patients in Europe have detectable or normal RAI uptake.

Treatment of type I amiodarone-induced thyrotoxicosis usually requires a prolonged course of methimazole. After two doses of methimazole, iopanoic acid or sodium ipodate may be added to the regimen to further block conversion of T4 to T3; the recommended dosage for each is 500 mg orally twice daily for 3 days, followed by 500 mg once daily until thyrotoxicosis is resolved. β-Blockers may be required. Withdrawal of amiodarone does not have a significant therapeutic effect for several months. Therapy with 131I may be successful in some patients with adequate RAI uptake. Thyroidectomy is reserved for resistant cases.

Type II amiodarone-induced thyrotoxicosis is caused by destructive thyroiditis, which releases stored thyroid hormone from damaged cells; hyperthyroidism can last 1–3 months and may be followed by hypothyroidism. Thyroid RAI uptake is very low. Serum levels of interleukin-6 (IL-6) are usually quite elevated. Treatment consists of prednisone plus either iopanoic acid or ipodate sodium (see above). β-Blockers may be required. Withdrawal of amiodarone is not usually necessary. Because the condition is transient, thyroidectomy is rarely required.

Patients are likely to have type I amiodarone-induced thyrotoxicosis if they have a pretreatment history of multinodular goiter or autoimmune thyroid disease, if they have proptosis, or if they have elevated serum levels of antithyroperoxidase or antithyroglobulin antibodies or TSH-R Ab[stim]. A thyroid RAI uptake is not usually obtained in the United States but may be useful elsewhere. It may be necessary to obtain a thyroid ultrasound with color flow Doppler sonography. Ultrasound can usually detect thyroid nodularity characteristic of toxic multinodular goiter. In Graves' disease blood flow is normal or increased, whereas in destructive thyroiditis blood flow is decreased. In practice, the accuracy of this test depends on the proficiency of the ultrasonographer.

Patients in atrial fibrillation usually require anticoagulation with warfarin; close monitoring of the international normalized ratio (INR) is required, since both methimazole and hyperthyroidism potentiate the hypoprothrombinemia of anticoagulants. Hyperthyroidism increases the catabolism of vitamin K-dependent clotting factors, and methimazole potentiates anti-vitamin K activity. Changing thyroid levels also modify the coagulation profile.

Clinical Findings

A. Symptoms and Signs

Thyrotoxicosis due to any cause produces many different manifestations of variable intensity among different individuals. Patients may complain of nervousness, restlessness, heat intolerance, increased sweating, fatigue, weakness, muscle cramps, frequent bowel movements, or weight change (usually loss). There may be palpitations or angina pectoris. Women frequently report menstrual irregularities.

Hypokalemic periodic paralysis occurs in about 15% of Asian or Native American men with thyrotoxicosis. It usually presents abruptly with paralysis (and few thyrotoxic symptoms), often after intravenous dextrose, oral carbohydrate, or vigorous exercise. Attacks last 7–72 hours.

Signs of thyrotoxicosis may include stare and lid lag, fine resting finger tremors, moist warm skin, hyperreflexia, fine hair, and onycholysis. Chronic thyrotoxicosis may cause osteoporosis. A minority of patients develop clubbing and swelling of the fingers (acropachy). Graves' disease usually presents with additional findings of goiter (often with a bruit), but some patients have no palpable thyroid enlargement.

Cardiac manifestations of thyrotoxicosis commonly include a forceful heart beat, premature atrial contractions, and sinus tachycardia. Atrial fibrillation or atrial tachycardia occurs in about 8% of patients with thyrotoxicosis, more commonly in men, the elderly, and those with ischemic or valvular heart disease. Thyrotoxicosis itself can cause a thyrotoxic cardiomyopathy, and the onset of atrial fibrillation can precipitate congestive heart failure.

Ophthalmopathy is clinically apparent in 20–40% of patients with Graves' disease, but in no other condition causing hyperthyroidism. It usually consists of chemosis, conjunctivitis, and mild exophthalmos (proptosis). More severe lymphocytic infiltration of the eye muscles occurs in 5–10%, pushing the eye forward, producing clinical exophthalmos and sometimes diplopia due to extraocular muscle entrapment. The optic nerve may be compressed in severe cases, causing progressive loss of color vision, visual fields, and visual acuity. Corneal drying may occur with inadequate lid closure. Eye changes may sometimes be asymmetric or unilateral. The severity of the eye disease is not closely correlated with the severity of the thyrotoxicosis. Some patients with Graves' ophthalmopathy are clinically euthyroid.

Exophthalmometry should be performed on all patients with Graves' disease to document their degree of

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exophthalmos and detect progression of orbitopathy. The protrusion of the eye beyond the orbital rim is measured with a prism instrument (Hertel exophthalmometer). Maximum normal eye protrusion varies between kindreds and races, being about 22 mm for blacks, 20 mm for whites, and 18 mm for Asians.

Diplopia can also be caused by coexistent ocular myasthenia gravis, which is more common in Graves' disease and is usually mild, often with selective eye involvement. Acetylcholinesterase receptor antibody (AChR Ab) levels are elevated in only 36% of such patients, and a thymoma is present in 9%.

Graves' dermopathy (pretibial myxedema) occurs in about 3% of patients with Graves' disease, usually in the pretibial region. Glycosaminoglycan accumulation and lymphoid infiltration occur in affected skin, which becomes erythematous with a thickened, rough texture.

Thyroid acropachy is an extreme and unusual manifestation of Graves' disease. It presents with digital clubbing, swelling of fingers and toes, and a periosteal reaction of extremity bones. It is ordinarily associated with ophthalmopathy and thyroid dermopathy. Most patients are smokers. The presence of thyroid acropachy is an indication of the severity of the autoimmunity; most patients have high serum titers of thyroid-stimulating immunoglobulin. Patients with thyroid acropachy are at greater risk for having concurrent Graves' dermopathy and severe ophthalmopathy. However, acropachy itself does not usually cause clinical complaints.

B. Laboratory Findings

Serum T3, T4, thyroid resin uptake, and FT4 are usually all increased. Sometimes the T4 level may be normal but the serum T3 is elevated. Blood that is to be assayed for serum T3 should be collected in tubes without a gel barrier, which can cause false elevations in serum T3 in certain assays. A reliable sensitive TSH assay is the best test for thyrotoxicosis; it is suppressed except in the very rare cases of pituitary inappropriate secretion of thyrotropin. Other laboratory abnormalities may include hypercalcemia, increased alkaline phosphatase, anemia, and decreased granulocytes.

TSH-R Ab[stim] levels are usually high (75%). Second-generation TSH-R Ab assays using human recombinant TSH-R are more sensitive for Graves' disease. Antithyroglobulin or antithyroperoxidase antibodies are usually elevated in Graves' disease but are nonspecific. Serum ANA and anti-double-stranded DNA antibodies are also usually elevated without any evidence of lupus erythematosus or other collagen-vascular disease.

Patients with subacute thyroiditis often have an increased erythrocyte sedimentation rate.

Thyroid RAI uptake and scan is usually performed on patients with an established diagnosis of thyrotoxicosis. A high RAI uptake is seen in Graves' disease and toxic nodular goiter but can be seen in other conditions as well. A low radioactive iodine uptake is characteristic of subacute thyroiditis but can also be seen in other conditions. (For conditions affecting radioactive iodine uptake, see section on tests of thyroid function.)

C. Imaging

MRI of the orbits is the imaging method of choice to visualize Graves' ophthalmopathy affecting the extraocular muscles. CT scanning and ultrasound can also be used. Imaging is required only in severe cases or in euthyroid exophthalmos that must be distinguished from orbital tumors or other disorders.

Differential Diagnosis

True thyrotoxicosis must be distinguished from those conditions elevating serum T4 without affecting clinical status (see Table 26-6). Serum T3 can be misleadingly elevated when blood is collected in tubes using a gel barrier, which causes certain immunoassays (eg, Immulite but not Axsym analyzers) to report serum total T3 levels that are falsely elevated in 24% of normal patients.

Hyperthyroidism may be confused with anxiety neurosis or mania, but in the latter, the thyroid is not enlarged and thyroid function tests are usually normal. Problems of diagnosis occur in patients with acute psychiatric disorders, about 30% of whom have hyperthyroxinemia without thyrotoxicosis. The TSH is not suppressed, distinguishing psychiatric disorder from true hyperthyroidism. T4 levels return to normal gradually.

Exogenous thyroid administration will present the same laboratory features as thyroiditis. A rare pituitary tumor may resemble thyrotoxicosis with high levels of TSH.

Some states of hypermetabolism without thyrotoxicosis—notably severe anemia, leukemia, polycythemia, and cancer—rarely cause confusion. Pheochromocytoma is often associated with hypermetabolism, tachycardia, weight loss, and profuse sweating. Acromegaly may also produce tachycardia, sweating, and thyroid enlargement. Appropriate laboratory tests will easily distinguish these entities.

Cardiac disease (eg, atrial fibrillation, angina) refractory to treatment suggests the possibility of underlying (“apathetic”) hyperthyroidism. Other causes of ophthalmoplegia (eg, myasthenia gravis) and exophthalmos (eg, orbital tumor, pseudotumor) must be considered. Thyrotoxicosis must also be considered in the differential diagnosis of muscle weakness and osteoporosis. Diabetes mellitus and Addison's disease may coexist with thyrotoxicosis.

Complications

Cardiac complications of thyrotoxicosis include atrial fibrillation with a ventricular response that is difficult to control. Episodes of periodic paralysis induced by exercise or heavy carbohydrate ingestion and accompanied by hypokalemia may complicate thyrotoxicosis in Asian or Native American men. Hypercalcemia, osteoporosis,

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and nephrocalcinosis may occur. Decreased libido, impotence, decreased sperm count, and gynecomastia may be noted in men with hyperthyroidism.

Patients who have “subclinical hyperthyroidism” (suppressed TSH but normal FT4 and clinically euthyroid) generally do well without treatment. In most such patients, serum TSH reverts to normal within 2 years. No accelerated bone loss has been noted. In one series, one of seven patients with subclinical hyperthyroidism developed clinical hyperthyroidism after about 2 years.

Treatment

The methods used to treat thyrotoxicosis will vary according to the cause and severity of the hyperthyroidism, the patient's age, the clinical situation, and the desires of the patient.

A. Graves' Disease

The treatment of Graves' disease involves a choice of methods rather than a method of choice.

1. Propranolol

Propranolol is generally used for symptomatic relief until the hyperthyroidism is resolved. It effectively relieves the tachycardia, tremor, diaphoresis, and anxiety that occur with hyperthyroidism due to any cause. It is the initial treatment of choice for thyroid storm. The periodic paralysis seen in association with thyrotoxicosis is also effectively treated with β-blockade. It has no effect on thyroid hormone secretion. Treatment is usually begun with propranolol 20 mg orally, which is increased progressively until an adequate response is achieved, usually 20–40 mg four times daily. Doses as high as 80 mg four times daily are occasionally required. A long-acting (LA) propranolol formulation is available that provides more consistent relief; doses are 60, 80, 120, and 160 mg. Propranolol LA is initially given every 12 hours for patients with severe hyperthyroidism, due to accelerated metabolism of the propranolol; it may be given once daily as hyperthyroidism improves.

2. Thiourea drugs

Methimazole or propylthiouracil is generally used for young adults or patients with mild thyrotoxicosis, small goiters, or fear of isotopes. Carbimazole is another thiourea, available outside the United States, that is converted to methimazole in vivo. Aged patients usually respond particularly well. They may be administered long-term. These drugs are also useful for preparing hyperthyroid patients for surgery and elderly patients for radioactive iodide treatment. The drugs do not permanently damage the thyroid and are associated with a lower chance of posttreatment hypothyroidism (compared with radioactive iodide or surgery). Thioureas are usually continued for 12–24 months before being discontinued. When thiourea therapy is discontinued, there is a high recurrence rate for hyperthyroidism (about 50%). A better likelihood of long-term remission is seen in patients with small goiters or mild hyperthyroidism and those requiring small doses of thiourea. Patients whose thyroperoxidase and thyroglobulin antibodies remain high after 2 years of therapy have been reported to have only a 10% rate of relapse. Thiourea therapy may be continued long-term for patients who are tolerating it well.

Agranulocytosis occurs in about 0.3% of patients taking methimazole and about 0.4% of patients taking propylthiouracil. Agranulocytosis usually occurs in the first 60 days of therapy, and it develops in a few patients after 5 months of therapy. There is a genetic tendency to develop agranulocytosis with thiourea therapy; if a close relative has had this adverse reaction, other therapies should be considered for the patient. Patients are warned that if a sore throat or febrile illness develops, they should stop the drug while a WBC is rechecked. The agranulocytosis is generally reversible; recovery is not improved by filgrastim (granulocyte colony-stimulating factor [G-CSF]). Periodic surveillance of the WBC during treatment has been advocated, but the onset of agranulocytosis is generally abrupt.

Other side effects common to thiourea drugs include pruritus, allergic dermatitis, nausea, and dyspepsia. Antihistamines may control mild pruritus without discontinuation of the drug. Since the two thiourea drugs are similar, patients who have had a major allergic reaction from one should not be given the other.

Primary hypothyroidism may occur. The patient may become clinically hypothyroid for 2 weeks or more before TSH levels rise, having been suppressed by the preceding hyperthyroidism. Therefore, the patient's changing thyroid status is best monitored clinically and with serum levels of FT4. Rapid growth of the goiter usually occurs if prolonged hypothyroidism is allowed to develop; the goiter may sometimes become massive but usually regresses rapidly with thyroid hormone replacement.

a. Methimazole

Methimazole has the advantage of requiring less frequent dosing and fewer pills than propylthiouracil. Patients treated with methimazole (compared with those taking propylthiouracil) have a lower risk of developing fulminant hepatic necrosis; methimazole therapy is also less likely to cause 131I treatment failure. Rare complications peculiar to methimazole include serum sickness, cholestatic jaundice, loss of taste, alopecia, nephrotic syndrome, and hypoglycemia. Methimazole is given orally in initial doses of 30–60 mg once daily; it may also be administered twice daily to reduce the likelihood of gastrointestinal upset. The dosage is reduced as manifestations of hyperthyroidism resolve and as the FT4 level falls toward normal. Methimazole is discontinued 4 days prior to 131I therapy for Graves' disease and resumed at a lower dose 3 days after 131I therapy to avoid recurrence of hyperthyroidism. About 4 weeks after 131I therapy, methimazole may be discontinued if the patient is euthyroid.

b. Propylthiouracil

Propylthiouracil is the drug of choice during breast-feeding or pregnancy, possibly causing fewer problems in the newborn. Rare complications peculiar to propylthiouracil include arthritis,

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lupus erythematosus, aplastic anemia, thrombocytopenia, and hypoprothrombinemia. Acute hepatitis occurs rarely and is treated with prednisone but may progress to liver failure. Propylthiouracil is given orally in initial doses of 300–600 mg daily in four divided doses. The dosage and frequency of administration are reduced as symptoms of hyperthyroidism resolve and the FT4 level approaches normal. During pregnancy, the dose of propylthiouracil is kept below 200 mg/d to avoid goitrous hypothyroidism in the infant.

3. Iodinated contrast agents

These agents provide effective temporary treatment for thyrotoxicosis of any cause. Iopanoic acid (Telepaque) or ipodate sodium (Bilivist, Oragrafin) is given orally in a dosage of 500 mg twice daily for 3 days, then 500 mg once daily. These agents inhibit peripheral 5′-monodeiodination of T4, thereby blocking its conversion to active T3. Within 24 hours, serum T3 levels fall an average of 62%. For patients with Graves' disease, methimazole is begun first to block iodine organification; the next day, ipodate sodium or iopanoic acid may be added. The iodinated contrast agents are particularly useful for patients who are very symptomatically thyrotoxic (see Thyroid Storm, below). They offer a therapeutic option for patients with T4 overdosage, subacute thyroiditis, and amiodarone-induced thyrotoxicosis and for those intolerant to thioureas and for newborns with thyrotoxicosis (due to maternal Graves' disease). Treatment periods of 8 months or more are possible, but efficacy tends to wane with time. In Graves' disease, thyroid RAI uptake may be suppressed during treatment but typically returns to pretreatment uptake by 7 days after discontinuation of the drug, allowing 131I treatment.

4. Radioactive iodine (131I)

The administration of RAI is an excellent method of destroying overactive thyroid tissue (either diffuse or toxic nodular goiter). The RAI damages the cells that concentrate it. There are ample data to conclude that patients who are treated with RAI in adulthood do not have an increased risk of subsequent thyroid cancer, leukemia, or other malignancies. Similarly, individuals who were treated with RAI as teenagers have not shown any increased risk of malignancy in a 36-year retrospective study. Children born to parents previously treated with 131I show normal rates of congenital abnormalities.

Because fetal radiation is harmful, RAI should not be given to pregnant women. It is prudent to obtain a sensitive pregnancy test (serum β-hCG) on all women of reproductive age prior to 131I therapy.

Most patients may receive 131I while being symptomatically treated with just propranolol, which is then reduced in dosage as hyperthyroxinemia resolves. However, some patients (those with coronary diseases, the elderly, or those with severe hyperthyroidism) are usually rendered euthyroid with a thiouracil drug (see above) while the dosage of propranolol is reduced. Treatment with methimazole is discontinued for about 1 week prior to 131I therapy. A higher rate of 131I treatment failure has been reported in patients with Graves' disease who have been receiving methimazole or propylthiouracil. However, therapy with 131I will usually be effective if the methimazole is discontinued about 6 days before RAI therapy and if the therapeutic dosage of 131I is adjusted (upward) according to 123I uptake on the pretherapy scan.

Following 131I treatment for hyperthyroidism, Graves' ophthalmopathy appears or worsens in 15% of patients and improves in none, whereas during treatment with methimazole, ophthalmopathy worsens in 3% and improves in 2% of patients. Among patients receiving 3 months of prednisone following 131I treatment, preexistent ophthalmopathy worsens in none and improves in 67%.

Smoking increases the risk of having a flare in ophthalmopathy following 131I treatment and also reduces the effectiveness of prednisone treatment. Therefore, patients who smoke are strongly encouraged to quit prior to 131I treatment.

FT4 levels may sometimes drop within 2 months after 131I treatment, but then rise again to thyrotoxic levels, at which time thyroid RAI uptake is low. This phenomenon is caused by a release of stored thyroid hormone from injured thyroid cells and does not indicate a treatment failure. In fact, serum FT4 then falls abruptly to hypothyroid levels.

There is a high incidence of hypothyroidism several years after 131I even when small doses are given. However, hypothyroidism also occurs quite frequently years after surgical or medical treatment of Graves' disease, and eventual hypothyroidism may be part of the natural history of this condition. Lifelong clinical follow-up is mandatory, with measurements of FT4 and TSH when indicated.

5. Thyroid surgery

Thyroid surgery for Graves' disease and toxic nodular goiter has been performed less frequently as RAI treatment has become more widely accepted. Thyroidectomy may be performed for pregnant women whose thyrotoxicosis is not controlled with low doses of thioureas, and for women who desire to become pregnant in the very near future. Children with Graves' disease usually undergo thyroidectomy. Surgery is also an option for nodular goiters, when there is a suspicion for malignancy. The Hartley-Dunhill operation is the surgical procedure of choice for patients with Graves' disease; this operation consists of a total resection of one lobe and a subtotal resection of the other lobe, leaving about 4 g of thyroid tissue. Subtotal thyroidectomy of both lobes is often used, but ultimately results in a 9% recurrence rate for hyperthyroidism. Total thyroidectomy of both lobes poses an increased risk for hypoparathyroidism and damage to the recurrent laryngeal nerve.

Patients are ordinarily rendered euthyroid preoperatively with a thiourea drug. Ipodate sodium or iopanoic acid (500 mg orally twice daily) may be used in addition to a thiourea to accelerate the decline in serum T3. Propranolol is given until the serum T3 (or free T3) is normal preoperatively. Thyroid vascularity is reduced by preoperative treatment with either ipodate

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sodium or iopanoic acid (500 mg twice daily for 3 days) or iodine (eg, Lugol's solution, two or three drops orally daily for several days). If a patient undergoes surgery while thyrotoxic, larger doses of propranolol are given perioperatively to reduce the likelihood of thyroid crisis.

Morbidity includes possible damage to the recurrent laryngeal nerve, with resultant vocal cord paralysis. Hypoparathyroidism also occurs, which means that calcium levels must be checked postoperatively. When a thyroidectomy is performed by a competent, experienced neck surgeon, surgical complications are uncommon. Thyroid surgery should be performed as an inpatient, with at least an overnight observational period.

B. Toxic Solitary Thyroid Nodules

Hyperthyroidism caused by a single hyperfunctioning thyroid nodule may be treated symptomatically with propranolol as in Graves' disease. Definitive treatment is with surgery or RAI. For patients under age 40 years, surgery is usually recommended; patients are made euthyroid with a thiourea preoperatively and given several days of iodine, ipodate sodium, or iopanoic acid before surgery as in Graves' disease (see above). Transient postoperative hypothyroidism resolves spontaneously. Permanent hypothyroidism occurs in about 14% of patients by 6 years after surgery. Patients over age 40 years with a toxic solitary nodule are offered RAI. Permanent hypothyroidism occurs in about one-third of patients by 8 years after RAI. The nodule remains palpable in 50% and may grow in 10% of patients after RAI.

C. Toxic Multinodular Goiter

Hyperthyroidism caused by a toxic multinodular goiter may also be treated symptomatically with propranolol as in Graves' disease. This disorder usually affects older individuals, so RAI is ordinarily selected over surgery as the definitive treatment. Thioureas do reverse hyperthyroidism, but there is a 95% recurrence rate after they are stopped. Older patients who are quite thyrotoxic are rendered nearly euthyroid with methimazole, which is stopped at least 3 days before RAI treatment. Meanwhile, the patient follows a low-iodine diet; this is done to enhance the thyroid gland's uptake of RAI, which may be relatively low in this condition (compared to Graves' disease). Relatively high doses of RAI are usually required; recurrent thyrotoxicosis and hypothyroidism are common, so patients must be followed closely. Surgery is generally reserved for pressure symptoms or cosmetic indications. Patients are prepared for surgery as in Graves' disease (see above).

D. Subacute (de Quervain's) Thyroiditis

Patients with hyperthyroidism due to subacute thyroiditis are treated symptomatically with propranolol. Ipodate sodium or iopanoic acid, 500 mg orally daily, promptly corrects elevated T3 levels and is continued for 15–60 days until the serum FT4 level normalizes. The condition subsides spontaneously within weeks to months. Thioureas are ineffective, since thyroid hormone production is actually low in this condition. RAI is ineffective, since the thyroid's iodine uptake is low. Since periods of hypothyroidism may occur following the initial inflammatory episode, patients should have close clinical follow-up, with serum FT4 measurement when necessary. Prompt treatment of the transient hypothyroidism may reduce the incidence of recurrent thyroiditis. Pain can usually be managed with aspirin or other nonsteroidal anti-inflammatory drugs.

E. Hashimoto's Thyroiditis

Rarely, hyperthyroidism develops as a result of release of stored thyroid hormone during severe Hashimoto's thyroiditis. The thyroperoxidase or thyroglobulin antibodies are usually high, but RAI uptake is low, thus distinguishing it from Graves' disease. This is especially common in postpartum women, in whom it may be transient. Treatment is with propranolol. Patients are monitored carefully for the development of hypothyroidism and treated according to their thyroid status.

F. Treatment of Complications

1. Graves' ophthalmopathy

The risk of having a “flare” of ophthalmopathy following 131I treatment for hyperthyroidism is about 6% for nonsmokers and 23% for smokers. For acute, progressive exophthalmos, intravenous methylprednisolone, begun promptly, is superior to oral prednisone, possibly due to improved compliance. Methylprednisolone is given intravenously, 500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks. If oral prednisone is chosen for treatment, it must be given promptly in daily doses of 40–60 mg/d orally, with dosage reduction over several weeks. Higher initial prednisone doses of 80–120 mg/d are used when there is optic nerve compression. Prednisone alleviates eye symptoms in 64% of nonsmokers, but only 14% of smokers respond well. Thiazolidinediones (pioglitazone, rosiglitazone) may aggravate ophthalmopathy and should be avoided.

Progressive active exophthalmos may be treated with retrobulbar radiation therapy using a supervoltage linear accelerator (4–6 MeV) to deliver 20 Gy over 2 weeks to the extraocular muscles, avoiding the cornea and lens. Prednisone in high doses is given concurrently. Patients who respond well to orbital radiation include those with signs of acute inflammation, recent exophthalmos (< 6 months), or optic nerve compression. Patients with chronic proptosis and orbital muscle restriction respond less well. Retrobulbar radiation does not cause cataracts or tumors; however, it can cause radiation-induced retinopathy (usually subclinical) in about 5% of patients overall, mostly in diabetics.

For severe cases, orbital decompression surgery may save vision, though diplopia often persists postoperatively. General eye protective measures include wearing glasses to protect the protruding eye and taping the lids shut during sleep if corneal drying is a problem.

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Methylcellulose drops and gels (“artificial tears”) may also help. Tarsorrhaphy or canthoplasty can frequently help protect the cornea and provide improved appearance. Hypothyroidism and hyperthyroidism must be treated promptly.

2. Cardiac complications

a. Sinus tachycardia

Sinus tachycardia or heart pounding is usually present in thyrotoxicosis. Treatment consists of treating the thyrotoxicosis. A β-blocker (as described above) such as propranolol is used in the interim unless there is an associated cardiomyopathy.

b. Atrial fibrillation

Atrial fibrillation may be the presenting manifestation of hyperthyroidism and may precipitate heart failure. Persistent atrial fibrillation is present in 2.9% of men and 1.4% of women when hyperthyroidism is diagnosed. The incidence of atrial fibrillation in hyperthyroidism increases with age, reaching 8% in patients over age 70 years. Electrical cardioversion is unlikely to convert atrial fibrillation to normal sinus rhythm while the patient is thyrotoxic. Spontaneous conversion to normal sinus rhythm tends to occur in about 56% of patients with achievement of euthyroidism, but that likelihood decreases with age. Elective cardioversion may be used for those patients in whom atrial fibrillation persists for 4 months after resolution of hyperthyroidism. Hyperthyroidism must be treated immediately (see above). Other drugs, including digoxin, β-blockers, anticoagulants, may be required.

(1) Digoxin

Digoxin is used to slow a fast ventricular response to thyrotoxic atrial fibrillation; it must be used in larger than normal doses because of increased clearance and an increased number of cardiac cellular sodium pumps requiring inhibition. Digoxin doses are reduced as hyperthyroidism is corrected.

(2) β-Blockers

β-Blockers may also reduce the ventricular rate, but they must be used with caution—particularly in patients with cardiomegaly or signs of heart failure—since their negative inotropic effect may precipitate congestive heart failure. Therefore, an initial trial of a short-duration β-blocker should be considered, such as esmolol intravenously. If a β-blocker is used, doses of digoxin must be reduced.

(3) Anticoagulants

Anticoagulation is indicated to prevent arterial thromboembolism in thyrotoxicosis-induced atrial fibrillation in the following situations: left atrial enlargement on echocardiogram, global left ventricular dysfunction, recent congestive heart failure, hypertension, recurrent atrial fibrillation, or a history of previous thromboembolism. The doses of warfarin required in thyrotoxicosis are smaller than normal because of an accelerated plasma clearance of vitamin K-dependent clotting factors. Higher warfarin doses are usually required as hyperthyroidism subsides.

c. Heart failure

Heart failure due to thyrotoxicosis may be caused by extreme tachycardia, cardiomyopathy, or both. Very aggressive treatment of the hyperthyroidism is required in either case (see Thyroid Crisis, below). The tachycardia from atrial fibrillation is treated with digoxin as above. Intravenous furosemide is typically required. If tachycardia appears to be the main cause of the failure, β-blockers are administered cautiously as described above.

Congestive heart failure may occur as a result of low-output dilated cardiomyopathy in the setting of hyperthyroidism. It is uncommon and may be caused by an idiosyncratic severe toxic effect of hyperthyroidism upon certain hearts. Cardiomyopathy may occur at any age and without preexisting cardiac disease. β-Blockers and calcium channel blockers are avoided. Emergency treatment may include afterload reduction, diuretics, digoxin, and other inotropic agents while the patient is being rendered euthyroid. Heart failure usually persists despite correction of hyperthyroidism.

d. Apathetic hyperthyroidism

Apathetic hyperthyroidism may present with angina pectoris. Treatment is directed at reversing the hyperthyroidism as well as providing standard antianginal therapy. Coronary angioplasty or bypass grafting can often be avoided by prompt diagnosis and treatment.

3. Thyroid crisis or “storm”

This disorder, rarely seen today, is an extreme form of thyrotoxicosis that may occur with stressful illness, thyroid surgery, or RAI administration and is manifested by marked delirium, severe tachycardia, vomiting, diarrhea, dehydration, and, in many cases, very high fever. The mortality rate is high.

A thiourea drug is given (eg, methimazole, 15–25 mg orally every 6 hours or propylthiouracil, 150–250 mg orally every 6 hours). Ipodate sodium (500 mg/d orally) can be helpful if begun 1 hour after the first dose of thiourea. Iodide is given 1 hour later as Lugol's solution (10 drops three times daily orally) or as sodium iodide (1 g intravenously slowly). Propranolol is given (cautiously in the presence of heart failure; see above) in a dosage of 0.5–2 mg intravenously every 4 hours or 20–120 mg orally every 6 hours. Hydrocortisone is usually given in doses of 50 mg orally every 6 hours, with rapid dosage reduction as the clinical situation improves. Aspirin is avoided since it displaces T4 from TBG, raising FT4 serum levels. Definitive treatment with 131I or surgery is delayed until the patient is euthyroid.

4. Hyperthyroidism and pregnancy

The prevalence of hyperthyroidism in pregnancy—most commonly due to Graves' disease—is about 0.2%. Struma ovarii is rare. Diagnosis may be difficult, since normal pregnancy may be accompanied by tachycardia, warm skin, heat intolerance, increased sweating, and a palpable thyroid. Laboratory tests are helpful: The FT4 is clearly elevated, while the TSH is suppressed. However, apparent lack of full TSH suppression can be seen due to misidentification of hCG as TSH in certain assays. Although the total T4 is elevated in most pregnant women, values over 20 mcg/dL are encountered only in hyperthyroidism. The T3 resin uptake, which is low in normal pregnancy because of high TBG concentration, is normal or high in thyrotoxic

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subjects. Pregnancy can have a beneficial effect upon the thyrotoxicosis of Graves' disease, with decreasing antibody titers and decreasing FT4 levels as the pregnancy advances. However, there is an increased risk of thyroid storm, preeclampsia-eclampsia, congestive heart failure, premature delivery, and abruptio placentae. Newborns have an increased risk of intrauterine growth retardation, prematurity, and transient thyrotoxicosis from transplacental transfer of TSH-R Ab[stim]. Pregnant women with hyperthyroidism are treated with methimazole or propylthiouracil in the smallest dose possible, permitting mild hyperthyroidism to occur since it is usually well tolerated. The drug does cross the placenta and rarely may induce TSH hypersecretion and fetal goiter. Thyroid hormone administration to the mother does not prevent hypothyroidism in the fetus, since T4 and T3 do not freely cross the placenta. Fetal hypothyroidism is rare if the mother's hyperthyroidism is controlled with small daily doses of propylthiouracil (50–150 mg/d orally) or methimazole (5–15 mg/d orally). Thyroidectomy is reserved for women who are allergic or resistant to antithyroid drugs (usually due to noncompliance) or who have very large goiters.

During lactation, women treated with propylthiouracil secrete very little of it into breast milk. Methimazole is secreted in somewhat higher concentrations in breast milk. However, the use of either propylthiouracil or methimazole during breast-feeding does not significantly affect the infant's thyroid hormone levels, and both drugs are approved for nursing mothers by the American Academy of Pediatrics. No adverse reactions to these drugs (eg, rash, hepatic dysfunction, leukopenia) have been reported in breast-fed infants. Recommended doses are 20 mg or less daily for methimazole and 450 mg or less daily for propylthiouracil. It is recommended that the medication be taken just after breast-feeding.

5. Graves' dermopathy

An uncommon complication of Graves' disease, dermopathy is an abnormal thickening of the skin due to deposition of glycosaminoglycans. It is known as “pretibial myxedema” since it usually occurs in the anterior lower leg, sometimes also including the dorsum of the foot. Treatment involves application of a topical corticosteroid (eg, fluocinolone) with nocturnal plastic occlusive dressings.

6. Thyrotoxic hypokalemic periodic paralysis

Thyrotoxicosis must always be suspected in Asian or Native American men with sudden symmetric flaccid paralysis, hypokalemia, and hypophosphatemia, especially since classic signs of thyrotoxicosis may be lacking. Therapy with oral propranolol, 3 mg/kg, normalizes the serum potassium and phosphate levels and reverses the paralysis within 2–3 hours. No intravenous potassium or phosphate is ordinarily required. Intravenous dextrose and oral carbohydrate aggravate the condition and are to be avoided. Therapy is continued with propranolol, 60–80 mg every 8 hours (or sustained-action propranolol daily at equivalent daily dosage), along with a thiourea drug such as methimazole to treat the hyperthyroidism.

Prognosis

Graves' disease may rarely subside spontaneously and may even result in spontaneous hypothyroidism. However, it usually persists. The ocular, cardiac, and psychological complications can become very serious and persistent even after treatment. Patients with atrial fibrillation experience a spontaneous remission rate of 56% as thyroid levels decline with treatment. Permanent hypoparathyroidism and vocal cord palsy are risks of surgical thyroidectomy. Recurrences are common following thiourea therapy but also occur after low-dose 131I therapy or subtotal thyroidectomy. With adequate treatment and long-term follow-up, the results are usually good. However, despite treatment for their hyperthyroidism, women experience an increased long-term risk of death from thyroid disease, cardiovascular disease, stroke, and fracture of the femur. Posttreatment hypothyroidism is common. It may occur within a few months or up to several years after RAI therapy or subtotal thyroidectomy. Malignant exophthalmos has a poor prognosis unless treated aggressively.

Subclinical hyperthyroidism refers to asymptomatic individuals with a low serum TSH and normal FT4 and T3. Such patients generally do not progress to overt thyrotoxicosis. However, they may be at some increased risk for bone loss, so bone densitometry is performed periodically. In persons over age 60 years, serum TSH is very low (< 0.1 mU/L) in 3% and mildly low (0.1–0.4 mU/L) in 9%. The chance of developing atrial fibrillation is 2.8% yearly in elderly patients with very low TSH and 1.1% yearly in those with mildly low TSH. Asymptomatic persons with very low TSH are followed closely but are not treated unless they develop atrial fibrillation or other manifestations of hyperthyroidism.

Azizi F et al: Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. Eur J Endocrinol 2005;152:695.

Chi SY et al: A prospective, randomized comparison of bilateral subtotal thyroidectomy versus unilateral total and contralateral subtotal thyroidectomy for Graves' disease. World J Surg 2005;29:160.

Cooper DS: Antithyroid drugs. N Engl J Med 2005;352:905.

Diez JJ: Goiter in adult patients aged 55 years and older: etiology and clinical features in 634 patients. J Gerontol A Biol Sci Med Sci 2005;60:920.

He CT et al: Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves' hyperthyroidism. Clin Endocrinol (Oxf) 2004;60:676.

Holm IA et al: Smoking and other lifestyle factors and the risk of Graves' hyperthyroidism. Arch Intern Med 2005;165:1606.

Kahaly GJ et al: Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy. J Clin Endocrinol Metab 2005;90:5234.

McKeown NJ et al: Hyperthyroidism. Emerg Med Clin North Am 2005;23:669.

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Migneco A et al: Management of thyrotoxic crisis. Eur Rev Med Pharmacol Sci 2005;9:69.

Panzer C et al: Rapid preparation for severe hyperthyroid Graves' disease. J Clin Endocrinol Metab 2004;89:2142.

Wakelkamp IM et al: Orbital irradiation for Graves' ophthalmopathy: is it safe? A long-term follow-up study. Ophthalmology 2004;111:1557.

Woeber KA: Observations concerning the natural history of subclinical hyperthyroidism. Thyroid 2005;15:687.

Thyroiditis

Essentials of Diagnosis

  • Swelling of thyroid gland, sometimes causing pressure symptoms in acute and subacute forms; painless enlargement and rubbery firmness in chronic form.

  • Thyroid function tests variable.

  • Serum antithyroperoxidase and antithyroglobulin antibody levels usually elevated in Hashimoto's thyroiditis.

General Considerations

Thyroiditis may be classified as follows: (1) chronic lymphocytic (“Hashimoto's”) thyroiditis due to autoimmunity, (2) subacute thyroiditis, (3) suppurative thyroiditis, and (4) Riedel's thyroiditis.

Hashimoto's thyroiditis (also known as chronic lymphocytic or autoimmune thyroiditis) is an autoimmune condition and the most common thyroid disorder in the United States. Elevated serum levels of antithyroid antibodies are found in 3% of men and 13% of women. Women over the age of 60 years have a 25% incidence of elevated serum levels of antithyroid antibodies. The incidence of Hashimoto's thyroiditis varies by kindred and by race; in persons older than 12 years of age in the United States, elevated levels of antithyroid antibodies are found in 14.3% of whites, 10.9% of Mexican-Americans, and 5.3% of blacks. Subclinical thyroiditis is extremely common, as evidenced in autopsy series that have found focal thyroiditis in about 40% of women and 20% of men. However, only 1% of the population has serum antithyroid antibody titers greater than 1:6400.

Hashimoto's thyroiditis tends to be familial and is six times more common in women than in men. Its frequency is increased by dietary iodine supplementation. Certain drugs (amiodarone, interferon-α, interferon-β, interleukin-2, G-CSF) frequently induce thyroid autoantibodies. Childhood or occupational exposure to head-neck external beam radiation increases the lifetime risk of Hashimoto's thyroiditis.

Hashimoto's thyroiditis often progresses to hypothyroidism, which is usually permanent, remitting in fewer than 5% of cases. The development of hypothyroidism may be linked to thyrotropin receptor-blocking antibodies, which are detected in 10% of patients with Hashimoto's thyroiditis. Among patients with Hashimoto's thyroiditis, hypothyroidism is more likely to develop in smokers than in nonsmokers, possibly due to the thiocyanates found in cigarette smoke. High serum levels of thyroid peroxidase antibody also predict progression from subclinical hypothyroidism to symptomatic hypothyroidism.

Uncommonly, Hashimoto's thyroiditis causes acute destruction of thyroid tissue and release of stored thyroid hormone, causing transient thyrotoxicosis. Rarely, a hypofunctioning gland may become hyperfunctioning with the onset of coexistent Graves' disease; in patients with Graves' disease, Hashimoto's thyroiditis is usually present concurrently.

Clinical Findings

A. Symptoms and Signs

1. Hashimoto's thyroiditis

The thyroid gland is usually diffusely enlarged, firm, and finely nodular. One thyroid lobe may be asymmetrically enlarged, raising concerns about neoplasm. Patients with Hashimoto's thyroiditis who have a thyroid nodule should have an ultrasound-guided FNA biopsy, since the risk of concurrent papillary thyroid cancer is about 8% in such patients. Although patients may complain of neck tightness, pain and tenderness are not usually present. About 10% of cases are atrophic, the gland being fibrotic, particularly in elderly women.

Systemic manifestations of Hashimoto's thyroiditis are mostly related to ambient levels of thyroid hormone. However, depression and chronic fatigue are more common in such patients, even after correction of hypothyroidism. About one-third of patients with Hashimoto's thyroiditis have mild dry mouth (xerostomia) or dry eyes (keratoconjunctivitis sicca) of an autoimmune nature related to Sjögren's syndrome. It may be associated with myasthenia gravis, which is usually of mild severity, mainly affecting the extraocular muscles and having a relatively low incidence of detectable AChR Ab or thymic disease.

Hashimoto's thyroiditis is sometimes associated with adrenal insufficiency (Schmidt's syndrome) and other endocrine deficiencies as part of polyglandular autoimmunity. Thyroiditis is also more common in patients with other autoimmune conditions, such as inflammatory bowel disease or celiac disease (10%). Hashimoto's thyroiditis is very rarely associated with myocarditis, encephalopathy, or membranous nephropathy. Women with gonadal dysgenesis (Turner's syndrome) have a 15% incidence of significant thyroid dysfunction by age 40 years. Thyroiditis is also commonly seen in patients with hepatitis C. Women with Hashimoto's thyroiditis have an increased risk of miscarriage in the first trimester of pregnancy.

%Painless postpartum thyroiditis refers to autoimmune thyroiditis that occurs soon after delivery in 7.2% of

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women. Women in whom postpartum thyroiditis develops have a 70% chance of recurrence after subsequent pregnancies. It occurs most commonly in women who have high levels of thyroid peroxidase antibody in the first trimester of pregnancy or immediately after delivery. It is also more common in women with other autoimmunity or a family history of Hashimoto's thyroiditis. There is some evidence that the autoimmunity may be triggered by the accumulation of fetal cells in the maternal thyroid during pregnancy, a condition known as microchimerism. Postpartum thyroiditis is typically accompanied by hyperthyroidism that begins 1–6 months after delivery and persists for only 1–2 months. Then, hypothyroidism tends to develop in affected women beginning 4–8 months after delivery. Although 80% of affected women subsequently recover normal thyroid function, permanent hypothyroidism eventually develops in about 50% within 7 years. Permanent hypothyroidism is more common in women who are multiparous or who have had a spontaneous abortion.

Painless sporadic thyroiditis is thought to be a subacute form of Hashimoto's thyroiditis that is similar to painless postpartum thyroiditis except that it is not related to pregnancy. It accounts for about 1% of cases of thyrotoxicosis. Thyrotoxic symptoms are usually mild; a small, nontender goiter may be palpated in about 50% of such patients. High serum thyroid peroxidase antibody concentrations are found in only 50% of such patients. The course is similar to painless postpartum thyroiditis.

2. Subacute thyroiditis

Subacute thyroiditis—also called de Quervain's thyroiditis, granulomatous thyroiditis, and giant cell thyroiditis—is relatively common, accounting for about 5% of clinical thyroid disease. It usually presents as an acute, usually painful enlargement of the thyroid gland, often with dysphagia. The pain may radiate to the ears. Patients usually manifest a low-grade fever and fatigue. The manifestations may persist for weeks or months and may be associated with malaise. In patients who experience pain, it is called “painful subacute thyroiditis.” If there is no pain, it is called “silent thyroiditis.” Subacute thyroiditis often follows an upper respiratory infection and its incidence peaks in the summer. A viral etiology has been proposed but not firmly established. Thyrotoxicosis develops in 50% of affected patients and tends to last for several weeks. Subsequently, hypothyroidism develops that lasts 4–6 months. Normal thyroid function typically returns within 12 months, but 5% of patients develop persistent hypothyroidism. Young and middle-aged women are most commonly affected.

3. Suppurative thyroiditis

Suppurative thyroiditis is caused by an infection of the thyroid gland, usually bacterial. However, low-grade mycobacterial, fungal, and parasitic (eg, Pneumocystis jiroveci) infections have been described, frequently in patients with AIDS. Suppurative thyroiditis is quite rare, since the thyroid is resistant to infection, largely due to its high iodine content. Affected patients usually are febrile and have severe pain, tenderness, redness, and fluctuation in the region of the thyroid gland. It tends to affect patients with preexistent thyroid disease. It is also more likely to affect patients who are immunosuppressed or infirm.

4. Riedel's thyroiditis

Riedel's thyroiditis is also called invasive fibrous thyroiditis, Riedel's struma, woody thyroiditis, ligneous thyroiditis, and invasive thyroiditis. It usually causes hypothyroidism and may cause hypoparathyroidism as well. It is the rarest form of thyroiditis and is found most frequently in middle-aged or elderly women. Enlargement is often asymmetric; the gland is stony hard and adherent to the neck structures, causing signs of compression and invasion, including dysphagia, dyspnea, pain, and hoarseness. It is usually a manifestation of a multifocal systemic fibrosis syndrome, with anterior neck symptoms predominating. Related conditions include retroperitoneal fibrosis, fibrosing mediastinitis, sclerosing cervicitis, subretinal fibrosis, and biliary tract sclerosis. It may respond to therapy with tamoxifen (see Treatment, below).

B. Laboratory Findings

With hyperthyroidism due to subacute thyroiditis or Hashimoto's thyroiditis, serum FT4 levels tend to be proportionally higher than T3 levels, since the hyperthyroidism is due to the passive release of stored thyroid hormone, which is predominantly T4; this is in contrast to Graves' disease and toxic nodular goiter, where T3 is relatively more elevated. Because T4 is less active than T3, the hyperthyroidism seen in thyroiditis is usually less severe. Serum levels of TSH are suppressed in hyperthyroidism due to thyroiditis.

Thyroid autoantibodies are most commonly demonstrable in Hashimoto's thyroiditis but may also be present in the other types of thyroiditis. Patients with Hashimoto's thyroiditis and clinically evident disease usually have increased circulating levels of antithyroid peroxidase (90%) or antithyroglobulin (40%) antibodies. Antithyroid antibodies decline during pregnancy and are often undetectable in the third trimester. Once Hashimoto's thyroiditis has been diagnosed, monitoring of these antibody levels is not necessary. The serum TSH level is elevated if thyroid hormone is not elaborated in adequate amounts by the thyroid gland.

The erythrocyte sedimentation rate (ESR) is markedly elevated, and antithyroid antibodies are low, which helps differentiate this form of thyroiditis from others. Aspiration biopsy is usually not required but shows characteristic giant multinucleated cells.

In suppurative thyroiditis, the leukocyte count and ESR are usually elevated; when suspected, an FNA biopsy with Gram stain and culture is required.

C. Imaging

Ultrasound in cases of Hashimoto's thyroiditis typically shows a gland with characteristic diffuse heterogeneous density and hypoechogenicity. Ultrasound of the thyroid

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helps distinguish thyroiditis from multinodular goiter or thyroid nodules that are suspicious for malignancy. Ultrasound is also helpful in guiding FNA biopsy of small suspicious thyroid nodules. Color-flow Doppler ultrasonography can help distinguish thyroiditis from Graves' disease, since patients with Graves' disease have a hypervascular thyroid gland, whereas in thyroiditis there is normal or reduced vascularity.

RAI scan and uptake may be helpful in determining the cause of hyperthyroidism, distinguishing thyroiditis from Graves' disease, since patients with subacute thyroiditis exhibit a very low RAI uptake. In patients with chronic Hashimoto's thyroiditis (euthyroid or hypothyroid), RAI uptake may be normal or high with uneven uptake on the scan; scanning is not useful in making the diagnosis.

Complications

In the suppurative forms of thyroiditis, any of the complications of infection may occur; the subacute and chronic forms of the disease are complicated by the effects of pressure on the neck structures: dyspnea and, in Riedel's struma, vocal cord palsy. Hashimoto's thyroiditis may lead to hypothyroidism or transient thyrotoxicosis. Perimenopausal women with high serum levels of antithyroperoxidase antibodies have a higher relative risk of depression independently of ambient thyroid hormone levels. Graves' disease may sometimes develop. Papillary thyroid carcinoma or thyroid lymphoma may rarely be associated with chronic thyroiditis and must be considered in the diagnosis of uneven painless enlargements that continue in spite of treatment; such patients require FNA biopsy. Hashimoto's thyroiditis may be associated with Addison's disease, hypoparathyroidism, diabetes, pernicious anemia, biliary cirrhosis, vitiligo, and other autoimmune conditions.

Differential Diagnosis

Thyroiditis must be considered in the differential diagnosis of all types of goiters, especially if enlargement is rapid. The very low RAI uptake in subacute thyroiditis with elevated T4 and T3 is helpful. Chronic thyroiditis, especially if the enlargement is uneven and if there is pressure on surrounding structures, may resemble carcinoma, and both disorders may be present in the same gland. The subacute and suppurative forms of thyroiditis may resemble any infectious process in or near the neck structures. Thyroid autoantibody tests have been of help in the diagnosis of chronic lymphocytic (Hashimoto's) thyroiditis, but the tests are not specific and may also be positive in patients with multinodular goiters, malignancy (eg, thyroid carcinoma, lymphoma), and concurrent Graves' disease.

Treatment

A. Suppurative Thyroiditis

Treatment is with antibiotics and with surgical drainage when fluctuation is marked.

B. Subacute Thyroiditis

All treatment is empiric and must be continued for several weeks. Recurrence is common. The drug of choice is aspirin, which relieves pain and inflammation. Thyrotoxic symptoms are treated with propranolol, 10–40 mg orally every 6 hours. Iodinated contrast agents cause a prompt fall in serum T3 levels and a dramatic improvement in thyrotoxic symptoms. Sodium ipodate (Oragrafin, Bilivist) or iopanoic acid (Telepaque) is given orally in doses of 500 mg orally daily until serum FT4 levels return to normal. Transient hypothyroidism is treated with T4 (0.05–0.1 mg/d orally) if symptomatic.

C. Hashimoto's Thyroiditis

If hypothyroidism is present, levothyroxine should be given in the usual replacement doses (0.05–0.2 mg orally daily). In patients with a large goiter and normal or elevated serum TSH, T4 may be given in doses sufficient to suppress serum TSH in an effort to shrink the thyroid. Suppressive doses of T4 tend to shrink the goiter an average of 30% over 6 months. If the goiter does not regress, lower replacement doses of T4 may be given. If the thyroid gland is only minimally enlarged and the patient is euthyroid (with normal TSH levels), regular observation is in order, since hypothyroidism may develop subsequently—often years later. (See Hypothyroidism section.)

In one study involving 21 patients with Hashimoto's thyroiditis and subclinical hypothyroidism, simvastatin (20 mg orally daily) improved thyroid function over 8 weeks, possibly by stimulating apoptosis of certain types of lymphocytes. In another study, selenium selenite (200 mcg daily orally for 3 months) reduced the serum levels of antithyroperoxidase antibodies by 49% versus a 10% reduction in the placebo arm. The long-term effectiveness of statins or selenium therapy on the course of Hashimoto's thyroiditis is unknown.

Hyperthyroidism may develop in patients with Hashimoto's thyroiditis due to the release of stored hormone by the thyroid, which is caused by inflammation. This condition has variably been termed “hashitoxicosis” or “painless sporadic thyroiditis;” it is known as postpartum painless thyroiditis when it occurs in women after delivery. Such patients may have only mild thyrotoxicosis and may not require therapy. Patients who are more symptomatic may be treated with propranolol (see Subacute Thyroiditis); they should have a 24-hour 123I thyroid uptake and scan to determine whether Graves' disease may be present. In patients with low RAI uptake, propranolol is continued; sodium ipodate or iopanoic acid may also be given in doses of 500 mg daily orally until the patient is euthyroid to block the peripheral conversion of T4 to T3. Patients having low RAI uptake do not respond to thiourea medication. Because RAI is excreted in breast milk, nursing mothers having RAI scanning should always be scanned with 123I, since it is less toxic than 131I; breast milk must be pumped and discarded for 2 days after 123I scanning.

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D. Riedel's Struma

The treatment of choice for invasive fibrous thyroiditis, like that of its related conditions, is tamoxifen, 20 mg orally twice daily. Tamoxifen can induce partial to complete remissions in most patients within 3–6 months. Tamoxifen treatment must be continued for years. Its mode of action appears to be unrelated to its antiestrogen activity. Short-term corticosteroid treatment may be added for partial alleviation of pain and compression symptoms. Surgical decompression usually fails to permanently alleviate compression symptoms; such surgery is difficult due to dense fibrous adhesions, making surgical complications more likely.

Prognosis

In subacute thyroiditis, spontaneous remissions and exacerbations are common, and therapy is supportive; the disease process may smolder for months. Hashimoto's thyroiditis is occasionally associated with other autoimmune disorders (diabetes mellitus, Addison's disease, pernicious anemia, etc). In general, however, patients with Hashimoto's thyroiditis have an excellent prognosis, since the condition either remains stable for years or progresses slowly to hypothyroidism, which is easily treated. Women with postpartum thyroiditis usually regain normal thyroid function. Papillary thyroid carcinoma carries a relatively good prognosis when it occurs in patients with Hashimoto's thyroiditis.

Gullu S et al: In vivo and in vitro effects of statins on lymphocytes in patients with Hashimoto's thyroiditis. Eur J Endocrinol 2005;153:41.

Jung YJ et al: A case of Riedel's thyroiditis treated with tamoxifen: another successful outcome. Endocr Pract 2004;10:483.

Pearce EN et al: Thyroiditis. N Engl J Med 2003;348:2646.

Smyth PP et al: Sequential studies on thyroid antibodies during pregnancy. Thyroid 2005;15:474.

Stagnaro-Green A: Postpartum thyroiditis. Best Pract Res Clin Endocrinol Metab 2004;18:303.

The Parathyroids

The main physiologic effects of parathyroid hormone (PTH) are as follows: (1) It increases the osteoclastic activity in bone, with increased delivery of calcium and phosphorus to the circulation; (2) it increases the renal tubular reabsorption of calcium in the glomerular filtrate; (3) it inhibits the net absorption of phosphate and bicarbonate by the renal tubule; and (4) it stimulates the synthesis of 1,25-dihydroxycholecalciferol by the kidney. All of these steps result in a net increase in the amount of serum ionized calcium. Serum calcium is largely bound to albumin. Therefore, ionized calcium should be determined, or the serum calcium level should be corrected for serum albumin level as follows:

Hypoparathyroidism & Pseudohypoparathyroidism

Essentials of Diagnosis

  • Tetany, carpopedal spasms, tingling of lips and hands, muscle and abdominal cramps, psychological changes.

  • Positive Chvostek's sign and Trousseau's phenomenon.

  • Serum calcium low; serum phosphate high; alkaline phosphatase normal; urine calcium excretion reduced.

  • Serum magnesium may be low.

General Considerations

Hypoparathyroidism is most commonly seen following thyroidectomy, when it is usually transient but may be permanent. It may also occur after surgical removal of a parathyroid adenoma for primary hyperparathyroidism due to suppression of the remaining normal parathyroids and accelerated remineralization of the skeleton (hungry bone syndrome).

Calcium-sensing receptors (CaSR) on parathyroid gland cells sense the serum calcium concentration and alter PTH hormone secretion by way of G-protein-coupled mechanisms. Gain-of-function (constitutive activation) mutations of the CaSR gene essentially “fool” the parathyroid glands, resulting in hypocalcemia without elevations in serum PTH hormone levels. Such mutations cause “autosomal dominant hypocalcemia with hypercalciuria” (ADHH) from deficient secretion of PTH hormone. The prevalence of ADHH in the population is about 1 in 70,000 and it typically presents in infancy with hypocalcemic seizures.

Hypoparathyroidism, deafness, and renal dysplasia (HDR or Barakat) syndrome is an autosomal dominant condition caused by haploinsufficiency or mutations of the gene GATA3. The hypocalcemia is present from birth but may not be detected until the occurrence of mental retardation or hypocalcemic tetany. The mostly high-frequency deafness is present at birth. Various renal and vesicoureteral anomalies occur.

Hypoparathyroidism may also be seen in DiGeorge's syndrome, along with congenital cardiac and facial anomalies; hypocalcemia usually presents with

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tetany in infancy, but some cases are not detected until adulthood.

Parathyroid deficiency may also be the result of damage from heavy metals such as copper (Wilson's disease) or iron (hemochromatosis, transfusion hemosiderosis), granulomas, sporadic autoimmunity, Riedel's thyroiditis, tumors, or infection.

Functional hypoparathyroidism may also occur as a result of magnesium deficiency (malabsorption, chronic alcoholism), which prevents the secretion of PTH. Correction of hypomagnesemia results in rapid disappearance of the condition. Hypoparathyroidism may rarely occur after neck irradiation.

Polyglandular autoimmunity type I (PGA-1) is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). PGA-1 presents in childhood with at least two of the following manifestations: candidiasis, hypoparathyroidism, or Addison's disease. Cataracts, uveitis, alopecia, vitiligo, or autoimmune thyroid disease may also develop.

Fat malabsorption occurs in 20% of patients with PGA-1 and may present as weight loss, diarrhea, or malabsorption of vitamin D, a fat-soluble vitamin used to treat the hypoparathyroidism. The fat malabsorption may be due to a deficiency in the jejunal enteroendocrine cells that produce cholecystokinin, causing a reduction in bile acid secretion.

Pseudohypoparathyroidism is a group of disorders characterized by hypocalcemia due to renal resistance to PTH. There are several subtypes caused by different mutations involving the PTH receptor or its G protein or adenylyl cyclase. PTH levels are high and the PTH receptors in bone are typically not involved, such that bony changes of hyperparathyroidism may be evident. Various phenotypic abnormalities may be associated—classically, short stature, round face, obesity, short fourth metacarpals, ectopic bone formation, and mental retardation. Patients without hypocalcemia but sharing the phenotypic abnormalities are said to have “pseudopseudohypoparathyroidism.”

Clinical Findings

A. Symptoms and Signs

Acute hypoparathyroidism causes tetany, with muscle cramps, irritability, carpopedal spasm, and convulsions; tingling of the circumoral area, hands, and feet is almost always present. Symptoms of the chronic disease are lethargy, personality changes, anxiety state, blurring of vision due to cataracts, parkinsonism, and mental retardation.

Chvostek's sign (facial muscle contraction on tapping the facial nerve in front of the ear) is positive, and Trousseau's phenomenon (carpal spasm after application of a cuff) is present. Cataracts may occur; the nails may be thin and brittle; the skin is dry and scaly, at times with fungus infection (candidiasis), and there may be loss of hair (eyebrows); and deep tendon reflexes may be hyperactive. Papilledema and elevated cerebrospinal fluid pressure are occasionally seen. Teeth may be defective if the onset of the disease occurs in childhood.

B. Laboratory Findings

Serum calcium is low, serum phosphate high, urinary calcium low, and alkaline phosphatase normal. PTH levels are low. Serum magnesium should be determined since hypomagnesemia frequently accompanies hypocalcemia and may exacerbate symptoms and decrease parathyroid function.

C. Imaging

Radiographs or CT scans of the skull may show basal ganglia calcifications; the bones may be denser than normal. Cutaneous calcification may occur.

D. Other Examinations

Slit-lamp examination may show early posterior lenticular cataract formation. The electrocardiogram (ECG) shows prolonged QT intervals and T wave abnormalities. Patients with chronic hypoparathyroidism tend to have increased bone mineral density, particularly in the lumbar spine.

Complications

Acute tetany with stridor, especially if associated with vocal cord palsy, may lead to respiratory obstruction requiring tracheostomy. The complications of chronic hypoparathyroidism largely depend on the duration of the disease. There may be associated autoimmunity causing sprue syndrome, pernicious anemia, or Addison's disease. In long-standing cases, cataract formation and calcification of the basal ganglia are seen. Occasionally, parkinsonian symptoms or choreoathetosis develop. Ossification of the paravertebral ligaments may occur with nerve root compression; surgical decompression may be required. Seizures are common in untreated patients. Overtreatment with vitamin D and calcium may produce nephrocalcinosis and impairment of renal function.

Differential Diagnosis

The symptoms of hypocalcemic tetany may be confused with paresthesias, muscle cramps, or tetany due to respiratory alkalosis, in which the serum calcium is normal. In fact, hyperventilation tends to accentuate hypocalcemic symptoms. Chronic hypocalcemia can cause heart failure and be confused with myocardial infarction and ischemic cardiomyopathy.

At times hypoparathyroidism is misdiagnosed as idiopathic epilepsy, choreoathetosis, or brain tumor (on the basis of brain calcifications, convulsions, choked disks) or, more rarely, as “asthma” (on the basis of stridor and dyspnea). Hypocalcemia is frequently seen in patients with hypoalbuminemia; serum levels of ionized calcium are normal.

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Hypocalcemia may also be due to malabsorption of calcium, magnesium, or vitamin D; patients do not always have diarrhea. Hypocalcemia may also be caused by certain drugs: loop diuretics, plicamycin, phenytoin, alendronate, and foscarnet. In addition, hypocalcemia may be seen in cases of rapid intravascular volume expansion or due to chelation from transfusions of large volumes of citrated blood. Hypocalcemia is also frequently seen following parathyroidectomy for hyperparathyroidism. It is also observed in patients with acute pancreatitis. Hypocalcemia may develop in some patients with certain osteoblastic metastatic carcinomas (especially breast, prostate) instead of the expected hypercalcemia. Hypocalcemia with hyperphosphatemia (simulating hypoparathyroidism) is seen in azotemia but may also be caused by large doses of intravenous, oral, or rectal phosphate preparations and by chemotherapy of responsive lymphomas or leukemias.

Hypocalcemia with hypercalciuria may be due to a familial syndrome involving a mutation in the calcium-sensing receptor; such patients have levels of serum PTH that are in the normal range, distinguishing it from hypoparathyroidism. It is transmitted as an autosomal dominant disorder. Such patients are hypercalciuric; treatment with calcium and vitamin D may cause nephrocalcinosis.

Treatment

A. Emergency Treatment for Acute Attack (Hypoparathyroid Tetany)

This usually occurs after surgery and requires immediate treatment.

1. Airway

Be sure an adequate airway is present.

2. Intravenous calcium gluconate

Calcium gluconate, 10–20 mL of 10% solution intravenously, may be given slowly until tetany ceases. Ten to 50 mL of 10% calcium gluconate may be added to 1 L of 5% glucose in water or saline and administered by slow intravenous drip. The rate should be adjusted so that the serum calcium is maintained between 8 mg/dL and 9 mg/dL.

3. Oral calcium

Calcium salts should be given orally as soon as possible to supply 1–2 g of calcium daily. Liquid calcium carbonate (Titralac Plus), 500 mg/5 mL, may be especially useful. The dosage is 1–3 g calcium daily. Calcium citrate contains 21% calcium, but a higher proportion is absorbed with less gastrointestinal intolerance.

4. Vitamin D preparations

(Table 26-10.) Therapy should be started as soon as oral calcium is begun. The active metabolite of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), has a very rapid onset of action, and if toxicity develops it is not long-lasting. It is of great use in the treatment of acute hypocalcemia. Therapy is commenced at a dosage of 0.25 mcg orally each morning with upward dosage titration to near normocalcemia. Ultimately, doses of 0.5–2 mcg/d are usually required.

Calcifediol (25-hydroxyvitamin D3), another option for treatment, has an intermediate onset and duration of action; the usual starting dose is 20 mcg/d orally.

Dihydrotachysterol is faster in onset of action and is three times more potent than ergocalciferol. The usual daily maintenance dose is 0.125–1 mg/d orally. It is more expensive than vitamin D2.

5. Magnesium

If hypomagnesemia is present (chronic alcoholism, malnutrition, renal loss, drugs such as cisplatin, etc), it must be corrected to treat the resulting hypocalcemia. Acutely, magnesium sulfate is given intravenously, 1–2 g every 6 hours. Chronic magnesium replacement may be given as magnesium oxide tablets (600 mg), one or two per day, or as a combined magnesium and calcium preparation (Dolomite, others).

6. Transplantation of cryopreserved parathyroid tissue removed during prior surgery

Transplantation restores normocalcemia in about 23%.

B. Maintenance Treatment

The goal should be to maintain the serum calcium in a slightly low but asymptomatic range (8–8.6 mg/dL). This will minimize the hypercalciuria that would otherwise occur and provides a margin of safety against overdosage and hypercalcemia, which may produce permanent damage to renal function. Calcium supplementation (1–2 g/d) is given, along with a vitamin D preparation. Patients with chronic hypoparathyroidism may be treated with vitamin D2 (ergocalciferol). The usual dose ranges from 25,000 to 150,000 units/d. It is a slow-acting preparation, and if toxicity develops,

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hypercalcemia—treatable with hydration and prednisone—may persist for weeks after it is discontinued. Ergocalciferol usually produces a more stable serum calcium level than do the shorter-acting preparations. Despite its high cost, calcitriol is being used with increasing frequency for the treatment of chronic hypoparathyroidism; the maintenance dosage of calcitriol ranges from 0.25 mcg/d to 2.0 mcg/d. Monitoring of serum calcium at regular intervals (at least every 3 months) is mandatory.

Table 26-10. Vitamin D preparations used in the treatment of hypoparathyroidism.

  Available Preparations Daily Dose Duration of Action
Ergocalciferol ergosterol, (vitamin D2, calciferol) Capsules of 50,000 IU; 8000 IU/mL oral solution 25,000-200,000 units 6–18 weeks
Dihydrotachysterol (DHT) Tablets and capsules of 0.125, 0.2, and 0.4 mg; 0.2 mg/mL oral solution 0.2-1 mg 1–3 weeks
Calcitriol (Rocaltrol) Capsules of 0.25 and 0.5 mcg; 1 mcg/mL oral solution; 1 mcg/mL for injection 0.25-4 mcg ½-2 weeks

PTH acts upon the kidney to increase tubular reabsorption of calcium. Therefore, patients with hypoparathyroidism are prone to hypercalciuria and calcium nephrolithiasis during treatment. Target serum calcium levels should be 8–8.6 mg/dL, keeping it mildly low to avoid hypercalciuria. It is prudent to monitor urine calcium with “spot” urine determinations and keep the level below 30 mg/dL if possible. Hypercalciuria may respond to oral hydrochlorothiazide, usually given with a potassium supplement.

Caution: Phenothiazine drugs should be administered with caution to hypocalcemic patients, since they may precipitate extrapyramidal symptoms. Furosemide should be avoided, since it may worsen hypocalcemia.

Prognosis

The outlook is good if the diagnosis is made promptly and treatment instituted. Any dental changes, cataracts, and brain calcifications are permanent. Periodic blood chemical evaluation is required, since changes in calcium levels may call for modification of the treatment schedule. Hypercalcemia that develops in patients with seemingly stable, treated hypoparathyroidism may be a presenting sign of Addison's disease.

Tartaglia F et al: Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am J Surg 2005;190:424.

Tfelt-Hansen J et al: The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005;42:35.

Hyperparathyroidism

Essentials of Diagnosis

  • Patients frequently asymptomatic, detected by screening.

  • Renal stones, polyuria, hypertension, constipation, fatigue, mental changes.

  • Bone pain; rarely, cystic lesions and pathologic fractures.

  • Serum and urine calcium elevated; urine phosphate high with low to normal serum phosphate; alkaline phosphatase normal to elevated.

  • Elevated PTH.

General Considerations

Primary hyperparathyroidism is characterized by chronic poorly regulated excessive secretion of PTH by one or more parathyroid glands that results in hypercalcemia. It is an increasingly recognized disorder, present in up to 0.1% of adult patients examined. It can be seen at any age but is more frequent in persons over the age of 50 years and is three times more common in women than in men.

The disease is caused by hypersecretion of PTH, usually by a single parathyroid adenoma (80%), and less commonly by hyperplasia by two or more parathyroid glands (20%), or carcinoma (≤ 1%). However, when hyperparathyroidism presents before age 30 years, there is a higher incidence of multiglandular disease (36%) and carcinoma (5%). The size of the parathyroid adenoma correlates with the serum PTH level.

Parathyroid adenomas or hyperplasia can be familial (about 5%) and may be part of MEN types 1, 2A, and 2B. In MEN 1, multiglandular hyperparathyroidism is usually the initial manifestation and ultimately occurs in 90% of affected individuals. Hyperparathyroidism in MEN 2A is less frequent that in MEN 1 and is usually milder. Familial hyperparathyroidism can occur without multiple endocrine neoplasia. It can also occur in the hyperparathyroidism-jaw tumor syndrome, a rare autosomal dominant familial condition in which parathyroid cystic adenomas or carcinomas are associated with ossifying fibromas of the mandible and maxilla as well as renal lesions (cysts, hamartomas, Wilms tumors) (Table 26-11).

Table 26-11. Multiple endocrine neoplasia (MEN) syndromes: incidence of tumor types.

Tumor Type MEN 1 (Wermer's Syndrome) MEN 2A (Sipple's Syndrome) MEN 2B
Parathyroid 95% 20–50% Rare
Pancreatic 54%    
Pituitary 42%    
Medullary thyroid carcinoma   > 90% 80%
Pheochromocytoma   20–35% 60%
Mucosal and gastrointestinal ganglioneuromas   Rare > 90%
Subcutaneous lipoma 30%    
Adrenocortical adenoma 30%    
Thoracic carcinoid 15%    
Thyroid adenoma Occasional    
Facial angiofibromas and collagenomas 85%    

Hyperparathyroidism results in the excessive excretion of calcium and phosphate by the kidneys. PTH stimulates renal tubular reabsorption of calcium; however, hyperparathyroidism causes hypercalcemia and an increase in calcium in the glomerular filtrate that overwhelms tubular reabsorption capacity, resulting in hypercalciuria. At least 5% of renal stones are associated with this disease. Diffuse parenchymal calcification (nephrocalcinosis) is seen less commonly. Chronic bone resorption induced by excessive PTH in the circulation may produce diffuse demineralization, pathologic fractures, or cystic bone lesions throughout the skeleton (“osteitis fibrosa cystica”).

In chronic renal failure, hyperphosphatemia and decreased renal production of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) initially produce a decrease in ionized calcium. The parathyroid glands are stimulated (secondary hyperparathyroidism) and may enlarge, becoming autonomous (tertiary hyperparathyroidism). The bone disease seen in this setting is known as “renal osteodystrophy.” Diabetics seem somewhat less prone to develop this syndrome. Hypercalcemia often occurs after renal transplant but usually subsides spontaneously.

Parathyroid carcinoma is a rare cause of hyperparathyroidism but is more common in patients with severe

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hypercalcemia. About 50% of parathyroid carcinomas are palpable.

Clinical Findings

A. Symptoms and Signs

Hypercalcemia is typically discovered accidentally by routine chemistry panels. Most patients are asymptomatic. Parathyroid adenomas are usually so small and deeply located in the neck that they are almost never palpable; when a mass is palpated, it usually turns out to be an incidental thyroid nodule.

Although many patients with mild hypercalcemia offer no complaints, symptomatic patients are said to have problems with “bones, stones, abdominal groans, psychic moans, with fatigue overtones.” The manifestations are categorized as skeletal, urinary tract, and those associated with hypercalcemia.

1. Skeletal manifestations

Hyperparathyroidism causes a loss of cortical bone and a gain of trabecular bone. Bone mineral concentration tends to be decreased in the distal radius and in the midshaft of the femur but not in the femoral neck. Similarly, bone mineral is decreased in vertebral posterior processes but increased in the vertebral bodies. Significant bone demineralization is uncommon in mild hyperparathyroidism, but osteitis fibrosa cystica may present as pathologic fractures or as “brown tumors” or cysts of the jaw. More commonly, patients have bone pain and arthralgias.

2. Urinary tract manifestations

Polyuria and polydipsia may be present and are due to hypercalcemia-induced nephrogenic diabetes insipidus. Calcium-containing kidney stones are reported in about 18% of those with newly discovered primary hyperparathyroidism. Nephrocalcinosis and renal failure can occur.

3. Manifestations of hypercalcemia

Mild hypercalcemia is often asymptomatic. In more severe cases, thirst, anorexia, nausea, and vomiting are present. Constipation, fatigue, anemia, weight loss, and hypertension are commonly found. Pancreatitis occurs in 3%. Some patients have neuromuscular disorders such as muscle weakness, easy fatigability, or paresthesias. Depression, intellectual weariness, and increased sleep requirement are common. Pruritus and psychosis or even coma may accompany severe hypercalcemia. Calcium may precipitate in the corneas (“band keratopathy”) or soft tissue (calciphylaxis).

4. Hyperparathyroidism during pregnancy

About 67% of women with primary hyperparathyroidism during pregnancy experience complications such as nephrolithiasis, hyperemesis, pancreatitis, muscle weakness, cognitive changes, and hypercalcemic crisis. About 80% of fetuses experience complications of maternal hyperparathyroidism, including fetal demise, preterm delivery, low birth weight, postpartum neonatal tetany, and permanent hypoparathyroidism.

B. Laboratory Findings

The hallmark of primary hyperparathyroidism is hypercalcemia: serum calcium > 10.5 mg/dL or ionized calcium. In hyperproteinemic states, the total serum calcium may be elevated but the ionized fraction is normal, whereas in primary hyperparathyroidism, the ionized calcium is almost always over 5.4 mg/dL (1.4 mmol/L). In practice, serum ionized calcium determinations have not proved to be very helpful clinically. The serum phosphate is often low (< 2.5 mg/dL). The urine calcium excretion may be high or normal (averaging 250 mg/g creatinine) but it is usually low for the degree of hypercalcemia. There is an excessive loss of phosphate in the urine in the presence of hypophosphatemia (25% of cases) to low-normal serum phosphate.

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(In secondary hyperparathyroidism due to renal failure, the serum phosphate is high.) The alkaline phosphatase is elevated only if bone disease is present. The plasma chloride and uric acid levels may be elevated. Vitamin D deficiency is common in patients with hyperparathyroidism, and it is prudent to screen for vitamin D deficiency with a serum 25-OH vitamin D determination. Low serum 25-OH vitamin D levels (< 20 mcg/L; < 50 nmol/L) can aggravate hyperparathyroidism and its bone manifestations; vitamin D replacement may be helpful in treating patients with hyperparathyroidism. (See below.)

Elevated serum levels of PTH confirm the diagnosis of hyperparathyroidism. The best immunoassay recognizes the intact molecule at two different sites—the amino terminal and the carboxyl terminal ends—with two different antibodies. This assay, known as IRMA, is specific and sensitive, making it easier to distinguish primary hyperparathyroidism from other causes of hypercalcemia.

All patients with apparent hyperparathyroidism should be screened for familial benign hypocalciuric hypercalcemia with a 24-hour urine for calcium and creatinine. Patients should discontinue thiazide diuretics prior to this test. Calcium excretion of < 50 mg/24 hours (or < 5 mg/dL on a random urine) is not typical for primary hyperparathyroidism and indicates possible familial benign hypocalciuric hypercalcemia. (See below.)

C. Imaging

Preoperative sestamibi-iodine subtraction scanning and neck ultrasonography have been used to locate parathyroid adenomas in patients with hyperparathyroidism, in an effort to improve the outcome and limit the invasiveness of neck surgery. Parathyroid imaging is crucial for patients who have had prior neck surgery. However, the usefulness of preoperative parathyroid localizing imaging studies for first neck explorations remains controversial. Imaging is not useful for the diagnosis of hyperparathyroidism, which must be made by serum calcium and PTH determinations. Preoperative scanning does not improve the outcome of initial bilateral neck explorations performed by a surgeon with special expertise in parathyroid surgery. Therefore, preoperative imaging has been used mainly to improve the outcome for limited neck exploration, with only modest success. See Surgery, below. Small benign thyroid nodules are discovered incidentally in nearly 50% of patients with hyperparathyroidism who have imaging with ultrasound or MRI.

CT and MRI scanning are not ordinarily required or useful for initial preoperative parathyroid localizing studies, since these scanning techniques are less sensitive for identifying tiny parathyroid adenomas. However, for repeat neck operations and when ectopic parathyroids are suspected, MRI is preferred since it offers better soft tissue contrast than CT scanning and is less adversely affected by postoperative changes in the neck. Three-dimensional technetium-99m sestamibi scanning can also help localize ectopic parathyroid glands.

Bone radiographs are usually normal and are not required to make the diagnosis of hyperparathyroidism. There may be demineralization, subperiosteal resorption of bone (especially in the radial aspects of the fingers), or loss of the lamina dura of the teeth. There may be cysts throughout the skeleton, mottling of the skull (“salt-and-pepper appearance”), or pathologic fractures. Articular cartilage calcification (chondrocalcinosis) is sometimes found.

Patients with renal osteodystrophy may have ectopic calcifications around joints or in soft tissue. Such patients may exhibit radiographic changes of osteopenia, osteitis fibrosa, or osteosclerosis, alone or in combination. Osteosclerosis of the vertebral bodies is known as “rugger jersey spine.”

Complications

Pathologic fractures are more common in patients with hyperparathyroidism than in the general population. Urinary tract infection due to stone and obstruction may lead to renal failure and uremia. If the serum calcium level rises rapidly, clouding of sensorium, renal failure, and rapid precipitation of calcium throughout the soft tissues may occur. Peptic ulcer and pancreatitis may be intractable before surgery. Insulinomas or gastrinomas may be associated, as well as pituitary tumors (MEN type 1). Pseudogout may complicate hyperparathyroidism both before and after surgical removal of tumors. Hypercalcemia during gestation produces neonatal hypocalcemia.

In secondary hyperparathyroidism due to renal failure, high serum calcium and phosphate levels may cause disseminated calcification in the skin, soft tissues, and arteries (calciphylaxis); this can result in painful ischemic necrosis of skin and gangrene, cardiac arrhythmias, and respiratory failure. The actual serum levels of calcium and phosphate have not correlated well with calciphylaxis, but a calcium (mg/dL) × phosphate (mg/dL) product over 70 is usually present.

Differential Diagnosis

A. Artifact

A report of hypercalcemia may be due to laboratory error or excess tourniquet time and should always be repeated. Hypercalcemia may be due to high serum protein concentrations; in the presence of high or low serum albumin concentrations, a serum ionized calcium is more dependable than the total serum calcium concentration. Hypercalcemia may also be seen with dehydration; spurious elevations in serum calcium have been reported with severe hypertriglyceridemia, when the calcium assay uses spectophotometry.

B. Hypercalcemia of Malignancy

Many malignant tumors (breast, lung, pancreas, uterus, hypernephroma, etc) can produce hypercalcemia. In some cases (breast carcinoma especially), bony metastases are present. In others, no metastases to bone can be demonstrated. Most of these tumors secrete PTH-related

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protein (PTHrP), which has tertiary structural homologies to PTH and causes bone resorption and hypercalcemia similar to those of PTH. The clinical features of the hypercalcemia of cancer can closely simulate hyperparathyroidism. Serum phosphate is often low, but the plasma level of PTH by IRMA is low. Serum PTHrP may be elevated.

Multiple myeloma is a common cause of hypercalcemia in the older population. Many other hematologic cancers such as monocytic leukemia, T cell leukemia and lymphoma, Burkitt's lymphoma, etc, have also been associated with hypercalcemia. Multiple myeloma causes renal dysfunction; resultant increased levels of carboxyl terminal PTH may cause it to be confused with hyperparathyroidism if a carboxyl terminal PTH assay is used. Serum protein and urine electrophoresis and bone marrow biopsy establish the diagnosis.

C. Sarcoidosis and other Granulomatous Disorders

Macrophages and perhaps other cells present in granulomatous tissue have the ability to synthesize 1,25(OH)2D3. Hypercalcemia has been reported in patients with sarcoidosis, tuberculosis, berylliosis, histoplasmosis, coccidioidomycosis, leprosy, and even foreign-body granuloma. Increased intestinal calcium absorption and hypercalciuria are more common than hypercalcemia. Serum levels of 1,25(OH)2D3 are elevated. In patients with sarcoidosis, serum levels of angiotensin-converting enzyme (ACE) are usually elevated. 18FDG-PET scanning may localize hypermetabolic foci of active disease. Ketoconazole is an antifungal agent that inhibits macrophage 1-hydroxylation of 25-hydroxyvitamin D, thereby improving the hypercalcemia of sarcoidosis and tuberculosis. In all conditions, treatment is directed at the underlying disorder.

D. Calcium or Vitamin D Ingestion

Ingestion of large amounts of calcium (usually as an antacid) or vitamin D can cause hypercalcemia, which is reversible following its cessation. If it persists, the possibility of associated hyperparathyroidism should be strongly considered.

In vitamin D intoxication, patients may take large amounts of vitamin D for unclear reasons, so a check of all medications is important. Hypercalcemia may persist for several weeks. Serum levels of 25-hydroxycholecalciferol (25[OH]D3) are helpful to confirm the diagnosis. A brief course of corticosteroid therapy may be necessary if hypercalcemia is severe.

E. Familial Benign Hypocalciuric Hypercalcemia

Familial benign hypocalciuric hypercalcemia can be easily mistaken for mild hyperparathyroidism. It is a common autosomal dominant inherited disorder (prevalence: 1 in 16,000) caused by a loss-of-function mutation in the gene encoding the CaSR. CaSRs are found on the surface of the parathyroid glands and allow the parathyroid glands to vary PTH hormone secretion according to serum PTH levels. Reduced function of the CaSR causes the parathyroid glands to falsely “sense” hypocalcemia and inappropriately release slightly excessive amounts of PTH. At the same time, the renal tubule CaSRs are also affected, causing hypocalciuria. Familial benign hypocalciuric hypercalcemia is characterized by hypercalcemia, hypocalciuria (usually < 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated levels of PTH. These patients do not normalize their hypercalcemia after subtotal parathyroid removal and should not be subjected to surgery. The condition has an excellent prognosis and is easily diagnosed with a family history and urinary calcium clearance determination.

F. Adrenal Insufficiency

Hypercalcemia is common in untreated Addison's disease. This is partly due to disinhibition of calcium uptake by the renal tubule and gut. Additionally, Addison's disease can cause dehydration and hyperproteinemia, resulting in higher levels of nonionized calcium.

G. Hyperthyroidism

Increased bone turnover is a feature of thyrotoxicosis. Mild hypercalcemia may also be present.

H. Other Causes

Other causes of hypercalcemia are shown in Table 21-9. Modest hypercalcemia is also occasionally seen in patients taking thiazide diuretics or lithium; such patients may have an inappropriately nonsuppressed PTH level with hypercalcemia. Prolonged immobilization at bed rest may also cause hypercalcemia, especially in adolescents and patients with extensive Paget's disease of bone. Hypercalcemia is noted in up to one-third of acutely ill patients being treated in intensive care units, particularly patients with acute renal failure. Serum PTH levels are usually slightly elevated, consistent with mild hyperparathyroidism. Bisphosphonates can increase serum calcium in 20% and serum PTH becomes high in 10%, mimicking hyperparathyroidism.

Treatment

A. Surgical Parathyroidectomy

Parathyroidectomy is recommended for patients with symptomatic hyperparathyroidism, kidney stones, bone disease, and pregnancy.

Some patients with seemingly asymptomatic hyperparathyroidism may be surgical candidates for other reasons such as (1) serum calcium 1 mg/dL above the upper limit of normal with urine calcium excretion > 50 mg/24 h (off thiazide diuretics), (2) urine calcium excretion over 400 mg/24 h, (3) cortical bone density (wrist, hip) ≥ 2 SD below normal, (4) relative youth (under age 50–60 years), (5) difficulty ensuring medical follow-up, or (6) pregnancy. During pregnancy, parathyroidectomy is performed in the second trimester.

Patients who undergo surgery for “asymptomatic” hyperparathyroidism have been reported to have modest benefits in social and emotional function, with improvements

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in anxiety and phobias being reported in comparison to similar patients who are monitored without surgery.

An intraoperative “quick” serum PTH determination is advisable to document the removal of the correct gland; if the serum PTH does not drop to < 50% of the highest preremoval value 10 minutes after removal of an abnormal-looking parathyroid gland, cure is unlikely and the excision is expanded to a bilateral neck exploration. Intraoperative PTH determinations are less helpful at predicting cure in patients with multiple abnormal parathyroid glands when abnormal glands remain in the neck.

Preoperative parathyroid imaging has been used in an attempt to allow unilateral minimally invasive neck surgery. The usefulness of preoperative parathyroid imaging was evaluated in a series of 350 patients with sporadic primary hyperparathyroidism. A single gland was predicted by sestamibi in 83%, by ultrasound in 85%, and by concordance of both in 59% of patients. Unilateral neck exploration, directed by these studies, resulted in success rate of only 73%, 77%, and 82%, respectively, despite the intraoperative quick PTH assay predicting success. Even in patients with concordant sestamibi and ultrasound scans, and an intraoperative PTH drop of > 50%, at least one additional abnormal parathyroid gland is left behind in the contralateral neck in 15% of patients.

Bilateral neck exploration is usually advisable for all patients without preoperative localization studies for the following: (1) patients with a family history of hyperparathyroidism, (2) patients with a personal or family history of MEN, and (3) patients wanting an optimal chance of success with a single surgery. Patients undergoing unilateral neck exploration can have the incision widened for bilateral neck exploration if two abnormal glands are found or if the serum quick PTH falls by < 50%. Parathyroid glands are not uncommonly supernumerary (five or more) or ectopic (eg, intrathyroidal, carotid sheath, mediastinum).

Parathyroid hyperplasia is commonly seen with chronic renal failure. When surgery is performed, a subtotal parathyroidectomy is optimally treated surgically; three and one-half glands are usually removed, and a metal clip is left to mark the location of residual parathyroid tissue.

Parathyroid carcinoma can cause severe hypercalcemia associated with very high serum levels of PTH. Preoperative localizing studies usually detect a large invasive tumor. Therapy consists of en bloc resection of the tumor and the ipsilateral thyroid lobe. Metastases to local and to distant sites occur in about 50% of patients. Reoperation for neck recurrence is usually necessary. Adjuvant treatment includes radiation therapy. Intravenous bisphosphonate (zoledronic acid) and calcimimetic agents (NPS R-568) are used for treatment of hypercalcemia.

Complications: Serum PTH levels fall below normal in 70% of patients within hours after successful surgery, commonly causing hypocalcemic paresthesias or even tetany. Hypocalcemia tends to occur the evening after surgery or on the next day. Therefore, frequent postoperative monitoring of serum ionized calcium (or serum calcium plus albumin) is advisable beginning the evening after surgery. Once hypercalcemia has resolved, liquid or chewable calcium carbonate is given orally to reduce the likelihood of hypocalcemia. Symptomatic hypocalcemia is treated with larger doses of calcium; calcitriol (0.25–1 mcg daily orally) may be added, with the dosage depending on symptom severity. Magnesium salts are sometimes required postoperatively, since adequate magnesium is required for functional recovery of the remaining suppressed parathyroid glands.

In about 12% of patients having successful parathyroid surgery, PTH levels rise above normal (while serum calcium is normal or low) by 1 week postoperatively. This secondary hyperparathyroidism is probably due to “hungry bones” and is treated with calcium and vitamin D preparations. Such therapy is usually needed only for 3–6 months but is required chronically by some patients.

Hyperthyroidism commonly occurs immediately following parathyroid surgery. It is caused by release of stored thyroid hormone during surgical manipulation of the thyroid. Short-term treatment with propranolol may be required for several days.

B. Medical Measures

1. Fluids

Hypercalcemia is treated with a large fluid intake unless contraindicated. Severe hypercalcemia requires hospitalization and intensive hydration with intravenous saline. (See Chapter 21.)

2. Bisphosphonates

Intravenous bisphosphonates are potent inhibitors of bone resorption and can temporarily treat the hypercalcemia of hyperparathyroidism, malignancy, or immobilization. They may relieve bone pain as with patients with metastatic breast or prostate cancer. Pamidronate in doses of 30–90 mg (in 0.9% saline) is administered intravenously over 2–4 hours. Zoledronic acid 2–4 mg is administered intravenously over 15 to 20 minutes; it is quite effective but also very expensive. These drugs cause a gradual decline in serum calcium over several days that may last for weeks to months. Such intravenous bisphosphonates are used generally for patients with severe hyperparathyroidism in preparation for surgery. Oral bisphosphonates, such as alendronate, are not effective for treating the hypercalcemia or hypercalciuria of hyperparathyroidism. However, oral alendronate has been shown to improve bone mineral density in the lumbar spine and hip (not distal radius) and may be used for asymptomatic patients with hyperparathyroidism who have a low bone mineral density.

3. Calcimimetics

Cinacalcet hydrochloride is a calcimimetic agent that binds to sites of the parathyroid glands' extracellular calcium-sensing receptors (CaSR) to increase their affinity for extracellular calcium, thereby decreasing PTH secretion. Cinacalcet may be administered

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orally in doses of 30–250 mg daily. Patients with primary hyperparathyroidism have also been treated successfully with cinacalcet in oral doses of 30–50 mg twice daily, with 73% of patients achieving normocalcemia. Administering cinacalcet for secondary parathyroidism of renal failure causes a drop of serum PTH levels to < 250 pg/mL in 41% of patients receiving dialysis. Cinacalcet is given to patients with severe hypercalcemia due to parathyroid carcinoma at initial doses of 30 mg orally twice daily and increased progressively to 60 mg twice daily, then 90 mg twice daily to a maximum of 90 mg every 6–8 hours. Cinacalcet is usually well-tolerated but may cause nausea and vomiting, which are usually transient. It is very expensive.

4. Vitamin D and vitamin D analogs

a. Primary hyperparathyroidism

For patients with vitamin D deficiency, careful vitamin D replacement may be beneficial to patients with hyperparathyroidism. Aggravation of hypercalcemia does not ordinarily occur. Serum PTH levels may fall with vitamin D replacement in doses of 400 to 1200 units daily. Occasionally, larger doses are required to achieve normal 25-OH vitamin D levels.

b. Secondary and tertiary hyperparathyroidism associated with renal failure

Calcitriol, given orally or intravenously after dialysis, suppresses parathyroid hyperplasia of renal failure. Certain vitamin D analogs suppress PTH secretion but cause less hypercalcemia than calcitriol. Doxercalciferol (Hectorol) is administered three times weekly orally with hemodialysis to patients with azotemic secondary hyperparathyroidism in the following doses according to serum immunoradiometric PTH (iPTH) levels: give 10 mcg three times weekly for iPTH > 400 pg/mL and increase the dose by 2.5 mcg every 8 weeks if iPTH remains > 300 pg/mL, to a maximum dose of 20 mcg three times weekly. If iPTH drops to < 100 pg/mL, doxercalciferol is held for 1 week and the dose is reduced by at least 2.5 mcg. Paricalcitol (Zemplar) is administered intravenously during dialysis three times weekly in starting doses of 0.04–0.1 mcg/kg body weight; the dosage is increased for iPTH levels > 300 pg/mL to a maximum dose of 0.24 mcg/kg three times weekly; paricalcitol is held if iPTH levels drop to < 100 pg/mL.

5. Other measures

Patients with mild, asymptomatic hyperparathyroidism may be monitored closely medically. Such patients are advised to keep active, avoid immobilization, and drink adequate fluids. They need to avoid thiazide diuretics, large doses of vitamins A, and calcium-containing antacids or supplements. Serum calcium and albumin are checked about twice yearly, renal function and urine calcium once yearly, and three-site bone density (distal radius, hip, and spine) every 2 years.

Estrogen replacement, given to postmenopausal women, reduces hypercalcemia slightly. Similarly, raloxifene (a selective estrogen receptor modulator) also reduces the hypercalcemia of hyperparathyroidism, reducing serum calcium levels an average of 0.4 mg/dL. Digitalis preparations are avoided, since patients with hypercalcemia are sensitive to its toxic effects. Propranolol may be useful for preventing the adverse cardiac effects of hypercalcemia. Corticosteroid therapy is ineffective for treating hypercalcemia in hyperparathyroidism.

Renal osteodystrophy is caused by secondary hyperthyroidism during renal failure. It can be prevented or delayed by avoiding hyperphosphatemia by dietary avoidance of phosphate and with phosphate binding medication.

C. Monitoring Patients with Asymptomatic Primary Hyperparathyroidism

Patients with mild asymptomatic hyperparathyroidism may not need therapy. However, they should be monitored closely for the development of symptoms of hypercalcemia and worsening hypercalcemia. Patients should be evaluated every 6 months with determination of blood pressure and serum calcium. Rising serum calcium should prompt further evaluation and determination of PTH levels. Serum creatinine should be measured yearly. A bone density should ideally be determined every 1 to 2 years at 3 points: wrist, hip, and vertebrae.

Prognosis

Completely asymptomatic patients with mild hypercalcemia may be observed and treated medically without compromising survival. There can be unexplained exacerbations and partial remissions. Surgical removal of sporadic parathyroid adenomas generally results in a permanent cure. Patients with MEN 1 undergoing subtotal parathyroidectomy may experience long remissions, but hyperparathyroidism usually recurs.

Spontaneous cure due to necrosis of the tumor has been reported but is exceedingly rare. The bones, in spite of severe cyst formation, deformity, and fracture, will heal if a parathyroid tumor is successfully removed. The presence of pancreatitis increases the mortality rate. Acute pancreatitis usually resolves with correction of hypercalcemia, whereas subacute or chronic pancreatitis tends to persist. Significant renal damage may progress even after removal of an adenoma. Parathyroid carcinoma tends to invade local structures and may sometimes metastasize; repeat surgical resections and radiation therapy can prolong life. Aggressive surgical and medical management of parathyroid carcinoma can result in an 85% 5-year survival rate and a 57% 10-year survival rate.

Block GA et al: Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004;350: 1516.

Coburn JW et al: Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 2004;43:877.

Grey A et al: Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D in sufficiency. N Engl J Med 2005;90:2122.

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Lambert LA et al: Surgical treatment of hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Arch Surg 2005;140:374.

Peacock M et al: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90:135.

Rao DS et al: Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2004;89: 5415.

Siperstein A et al: Prospective evaluation of sestamibi scan, ultrasonography, and rapid PTH to predict the success of limited exploration for sporadic primary hyperparathyroidism. Surgery 2004;136:872.

Skinner MA et al: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005;353:1105.

Metabolic Bone Disease

The term “metabolic bone disease” denotes those conditions producing diffusely decreased bone density (osteopenia) and diminished bone strength. It is categorized by histologic appearance: osteoporosis (common; bone matrix and mineral both decreased) and osteomalacia (unusual; bone matrix intact, mineral decreased).

Osteoporosis

Essentials of Diagnosis

  • Asymptomatic to severe backache from vertebral fractures.

  • Spontaneous fractures often discovered incidentally on radiography; loss of height.

  • Serum PTH, calcium, phosphorus, and alkaline phosphatase usually normal.

  • Serum 25-hydroxyvitamin D levels often low as a comorbid condition.

  • Demineralization, especially of spine, hip, pelvis, and wrist.

General Considerations

Osteoporosis is the most common metabolic bone disease. Osteoporosis is caused by a reduction and disarray of bone's microarchitectural organic collagenous matrix, which normally accounts for about 40% of bone mass and provides bone's tensile strength. Inorganic calcium and phosphate compounds, largely calcium hydroxyapetite, mineralize the available collagenous bone matrix and normally provide about 60% of bone mass and most of bone's compressive strength.

Osteoporosis is estimated to cause 1.5 million fractures annually in the United States—mainly of the spine and hip. The morbidity and indirect mortality rates are very high. Since the usual form of the disease is clinically evident in middle life and beyond and since women are more frequently affected than men, it is often referred to as “postmenopausal” osteoporosis. It is characterized by a decrease in the amount of bone present to a level below which it is capable of maintaining the structural integrity of the skeleton. The rate of bone formation is often normal, whereas the rate of bone resorption is increased. There is a greater loss of trabecular bone than compact bone, accounting for the primary features of the disease, ie, crush fractures of vertebrae, fractures of the neck of the femur, and fractures of the distal end of the radius. Whatever bone is present is normally mineralized.

Osteogenesis imperfecta is caused by a major mutation in the gene encoding for type I collagen, the major collagen constituent of bone. This causes severe osteoporosis; spontaneous fractures occur in utero or during childhood. Certain polymorphisms in the genes encoding type I collagen are common, particularly in whites, resulting in collagen disarray and predisposing to hypogonadal (eg, menopausal) or idiopathic osteoporosis.

Etiology

The causes of osteoporosis are listed in Table 26-12.

Clinical Findings

A. Symptoms and Signs

Osteoporosis is usually asymptomatic until fractures occur. It may present as backache of varying degrees of severity or as a spontaneous fracture or collapse of a vertebra. Loss of height is common. Once osteoporosis is identified, a carefully directed history and physical examination must be performed to determine its cause (see Table 26-12).

B. Laboratory Findings

Serum calcium, phosphate, and PTH are normal. The alkaline phosphatase is usually normal but may be slightly elevated, especially following a fracture. Once osteoporosis is identified, further testing for thyrotoxicosis, hypogonadism, and vitamin D deficiency may be required. Celiac disease should be screened for with serum immunoglobulin A (IgA) endomysial antibody and tissue transglutaminase antibody determinations. Vitamin D deficiency is very common and serum determination of 25-hydroxyvitamin D should be obtained for every individual with low bone density. Serum 25-hydroxyvitamin D levels below 20 ng/mL are considered frank vitamin D deficiency. Lesser degrees of vitamin D deficiency (serum 25-hydroxyvitamin D levels between 20 ng/mL and 30 ng/mL) may also increase the risk for hip fracture. (See Osteomalacia, below.)

Table 26-12. Etiologic classification of osteoporosis.1

Hormone deficiency Genetic disorders
   Estrogen (women) Aromatase deficiency
   Androgen (men) Type I collagen mutations
Hormone excess Osteogenesis imperfecta
   Cushing's syndrome or corticosteroid administration Idiopathic juvenile and adult osteoporosis
   Thyrotoxicosis Ehlers-Danlos syndrome
   Hyperparathyroidism Marfan's syndrome
Immobilization and microgravity Homocystinuria
Tobacco Miscellaneous
Alcoholism Celiac disease
Malignancy, especially multiple myeloma Anorexia nervosa
Medications Protein-calorie malnutrition
   Excessive vitamin D intake Vitamin C deficiency
   Excessive vitamin A intake Copper deficiency
   Heparin therapy Liver disease
  Rheumatoid arthritis
  Uncontrolled diabetes mellitus
  Systemic mastocytosis
1See Table 26-14 for causes of osteomalacia.

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C. Bone Densitometry

Dual energy x-ray absorptiometry (DXA) can determine the bone mineral density of the hip or spine. Peripheral DXA (pDXA) can measure the bone density of the forearm, finger, and heel. Single-energy x-ray absorptiometry (SXA) measures bone density in the wrist or heel. These tests deliver negligible radiation, and the measurements are quite accurate. Typically, DXA is used to determine the bone density of the lumbar spine and hip. Bone densitometry should be performed on all patients who are at risk for osteoporosis or osteomalacia (Table 26-13). Bone densitometry cannot distinguish osteoporosis from osteomalacia; in fact, both are often present. Also, the bone mineral density does not directly measure bone quality and is only fairly successful at predicting fractures. Vertebral bone mineral density may be misleadingly high in compressed vertebrae and in patients with extensive arthritis. DXA also overestimates the bone mineral density of taller persons and underestimates the bone mineral density of smaller persons. Quantitative computed tomography (QCT) delivers more radiation but is more accurate in the latter situations.

Bone mineral density in typically expressed in gm/cm2, for which there are different normal ranges for each bone and for each type of DXA-measuring machine. The “T score” is a simplified way of reporting bone density in which the patient's bone mineral density is compared to the young normal mean and expressed as a standard deviation score. The World Health Organization has established criteria for defining osteoporosis in postmenopausal white women, based on T score:

  • T score ≥ -1.0: Normal.

  • T score -1.0 to -2.5: Osteopenia (“low bone density”).

  • T score < -2.5: Osteoporosis.

  • T score < -2.5 with a fracture: Severe osteoporosis.

This classification is somewhat arbitrary and there really is no bone mineral density fracture threshold; instead, the fracture risk increases about twofold for each standard deviation drop in bone mineral density. In fact, most women with fragility fractures have bone densities above -2.5. Surveillance DXA bone densitometry is recommended for postmenoapausal women with a frequency according to their T scores: obtain DXA every 5 years for T scores -1.0 to -1.5, every 3–5 years for scores -1.5 to -2.0, and every 1–2 years for scores under -2.0.

The “Z score” is used to express bone density in premenopausal women, younger men, and children, The Z score is a statistical term that is used for expressing an individual's bone density as standard deviation from age-matched, race-matched, and sex-matched means.

Differential Diagnosis

Osteoporosis has many causes (see Table 26-12). Additionally, osteopenia and fractures can be caused by osteomalacia (see below) and bone marrow neoplasia such as myeloma or metastatic bone disease. These conditions coexist in many patients.

Table 26-13. Indications for measuring bone density.

Chronic (> 1 month) corticosteroid (> 6 mg prednisone) therapy
Chronic diseases associated with osteoporosis
Alcoholism
Anorexia nervosa
Hypogonadism of any cause: women or men
Hyperparathyroidism
Hyperthyroidism
Liver disease
Low body mass index (BMI < 19 kg/m2)
Immobilization (eg, paraplegia)
Inflammatory bowel disease
Protein-calorie malnutrition
Renal failure
Chronic disorders associated with osteomalacia
Hypocalcemia
Hypophosphatemia
Malabsorption
Nephrotic syndrome
Renal failure
Vitamin D deficiency
Family history of osteoporosis or hip fracture
Fracture following minimal or no trauma
Fracture following minimal trauma
Loss of height or thoracic kyphosis (dowager's hump)
Radiologic suspicion for low bone density
Radiologic diagnosis of vertebral crush deformity

Treatment

A. Specific Measures

Several treatment options are available, so a regimen is tailored to each patient. Generally, treatment is indicated for all women with osteoporosis (T scores below -2.5)

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and for all patients who have had fragility fractures. Prophylactic treatment should also be considered for patients with advanced osteopenia (T scores between -2.0 and -2.5).

1. Bisphosphonates

Bisphosphonates work similarly, inhibiting osteoclast-induced bone resorption. They increase bone density significantly and reduce the incidence of both vertebral and nonvertebral fractures. Bisphosphonates have also been effective in preventing corticosteroid-induced osteoporosis. To ensure intestinal absorption, oral bisphosphonates must be taken in the morning with at least 8 oz of plain water at least 30 minutes before consumption of anything else. The patient must remain upright after taking bisphosphonates to reduce the risk of esophagitis. These medications are excreted in the urine. However, no dosage adjustments are required for patients with creatinine clearances above 35 mL/min. There has been little experience giving bisphosphonates to patients with severe renal insufficiency; if given, the dose would need to be greatly reduced and serum phosphate levels monitored.

Bisphosphonates may be given orally once monthly or weekly; which is more convenient than daily therapy and equally effective. Available oral preparations include alendronate, 70 mg orally once weekly (tablet or solution), and risedronate, 35 mg orally once weekly. Both these medications reduce the risk of both vertebral and nonvertebral fractures. Studies sponsored by the manufacturer of alendronate found that alendronate was significantly more potent than risedronate and equally well tolerated. Another bisphosphonate, ibandronate sodium, is taken once monthly in a dose of 150 mg orally. Once-monthly ibandronate is convenient and reduces the risk of vertebral fractures but not nonvertebral fractures; its effectiveness has not been directly compared with other bisphosphonates. Oral bisphosphonates can cause esophagitis, especially in patients with hiatal hernia and gastroesophageal reflux.

For patients who cannot tolerate oral bisphosphonates or for whom oral bisphosphonates are contraindicated, intravenous bisphosphonates are available. Zoledronic acid is a third-generation bisphosphonate and a potent osteoclast inhibitor. It can be given every 6–12 months in doses of 2–4 mg intravenously over 15–30 minutes. Pamidronate is an older parenteral bisphosphonate that can be given in doses of 30–60 mg by slow intravenous infusion in normal saline solution every 3–6 months. Transient postinfusion fever occurs fairly commonly (26%). Osteonecrosis of the jaw has been reported in patients receiving intravenous zoledronic acid and pamidronate for treatment of hypercalcemia and bone metastases, for which the drugs had been administered more frequently than for osteoporosis.

Both oral and parenteral bisphosphonates can cause bone, joint, or muscle pains as well as fatigue. Pains can be migratory or diffuse and can vary in severity from mild to incapacitating. The onset of pain is variable and may occur anytime from 1 day to 1 year after therapy is initiated, with a mean of 14 days. The pain can be transient, lasting several days and usually resolving spontaneously but typically recurring with subsequent doses. When the bisphosphonate is discontinued, most patients experience gradual relief of pain. Some women taking alendronate or risedronate for osteoporosis have experienced painful, necrotic, nonhealing lesions of the jaw after tooth extraction. For patients with painful exposed bone, treatment is 90% effective (without resolution of the exposed bone) using antibiotics along with 0.12% chlorohexidine antiseptic mouth wash. Patients receiving bisphosphonates must receive regular dental care and try to avoid dental extraction. Another reported adverse effect reported with bisphosphonates is ocular inflammation, manifested by blurred vision, eye pain, uveitis, conjunctivitis, and scleritis, which remits after discontinuation of the drug. Other side effects can include nausea, anemia, dyspnea, and leg edema. In patients taking bisphosphonates, hypercalcemia is seen in 20% and serum PTH levels increase above normal in 10%, mimicking primary hyperparathyroidism.

All bisphosphonates inhibit osteoclastic bone resorption by binding to active bone remodeling sites and inhibiting osteoclasts; the half-life of alendronate in bone is 10 years. The effects of long-term bisphosphonate therapy on bone strength are unknown.

2. Sex hormones

Hypogonadal women who take estrogen replacement therapy have a lower risk of developing

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osteoporosis. Postmenopausal estrogen replacement is valuable as an osteoporosis prevention measure and this should be one factor in the complex decision about whether to take hormone replacement therapy. Low doses of estrogen appear to be adequate to prevent postmenopausal osteoporosis. (see Hormone Replacement Therapy, HRT). Once osteoporosis has developed, estrogen replacement is not an effective treatment. Although HRT does increase bone mineral density in postmenopausal women with osteoporosis, it has not been demonstrated to significantly reduce fracture rates. Treatment with a selective estrogen receptor modulator should also be considered (see raloxifene below). Men with hypogonadism may be treated with testosterone (see Male Hypogonadism).

3. Selective estrogen receptor modulators

Raloxifene, 60 mg/d orally, can be used by postmenopausal women in place of estrogen for prevention of osteoporosis. Bone density increases about 1% over 2 years in postmenopausal women versus 2% increases with estrogen replacement. It reduces the risk of vertebral fractures by about 40% but does not appear to reduce the risk of nonvertebral fractures. Raloxifene produces a reduction in LDL cholesterol but not the rise in HDL cholesterol seen with estrogen. It has no direct effect on coronary plaque. Unlike estrogen, raloxifene does not reduce hot flushes; in fact, it often intensifies them. It does not relieve vaginal dryness. Unlike estrogen, raloxifene does not cause endometrial hyperplasia, uterine bleeding, or cancer, nor does it cause breast soreness. The risk of breast cancer is reduced 76% in women taking raloxifene for 3 years. Since it is a potential teratogen, it is contraindicated in premenopausal women.

Raloxifene increases the risk for thromboembolism and should not be used by women with such a history. Leg cramps can also occur.

4. Calcitonin

A nasal spray of calcitonin-salmon (Miacalcin) is available that contains 2200 units/mL in 2-mL metered-dose bottles. The usual dose is one puff (0.09 mL, 200 IU) once daily, alternating nostrils. Nasal administration causes significantly less nausea and flushing than the parenteral route. However, nasal symptoms such as rhinitis and epistaxis occur commonly; other less common adverse reactions include flu-like symptoms, allergy, arthralgias, back pain, and headache. Five years of therapy increases bone 2–3% and reduces the number of new vertebral fractures. Both nasal and parenteral calcitonin have analgesic effects on bone pain; reduction of pain may be noted within 2–4 weeks after commencing therapy. Calcitonin reduces the incidence of vertebral fractures, but its effect upon nonvertebral fractures has not been established.

5. Vitamin D and calcium

Adequate dietary intakes of vitamin D and calcium are required throughout life to maintain peak bone mass and reduce the risk of subsequent osteoporosis and osteomalacia.

Vitamin D supplementation is useful for the prevention of osteomalacia and postmenopausal osteoporosis. It reduces the incidence of vertebral fractures by 37% and may slightly reduce the incidence of nonvertebral fractures. Oral vitamin D is given in doses of 400–1000 IU daily. Higher doses of vitamin D may be required for patients with serum levels of 25-hydroxyvitamin D below 20 ng/mL and those with intestinal malabsorption.

Calcium supplementation alone has only a minor effect on the prevention of osteoporosis and such supplementation has not been established to reduce fracture risk significantly. Nevertheless, it is recommended for patients at high risk for osteoporosis (see above) and for those with established osteoporosis. Calcium supplements may reduce the risk of colon cancer. Calcium supplementation may be given as calcium citrate (0.4–0.7 g elemental calcium per day) or calcium carbonate (1–1.5 g elemental calcium per day).

6. Teriparatide

Teriparatide (Forteo, Parathar) is an analog of PTH. Teriparatide stimulates the production of new collagenous bone matrix that must be mineralized. Patients receiving teriparatide must have sufficient intake of vitamin D and calcium. When administered to patients with osteoporosis in doses of 20 mcg/d subcutaneously for 2 years, teriparatide dramatically improves bone density in most bones except the distal radius. The recommended dose should not be exceeded, since teriparatide has caused osteosarcoma in rats when administered in very high doses. The drug should not be used by patients with Paget's disease of bone or by patients with open epiphyses or hypercalcemia. Patients with a past history of osteosarcoma or chondrosarcoma should not use this medication. Side effects may include dizziness and leg cramps. Teriparatide is approved only for a 2-year course of treatment.

Precautions: Hypercalcemia may develop in patients who are taking teriparatide if they also take corticosteroids and thiazide diuretics along with oral calcium supplementation.

Following a course of teriparitide, a course of bisphosphonates should be considered in order to retain the improved bone density.

B. General Measures

For prevention and treatment of osteoporosis, the diet should be adequate in protein, total calories, calcium, and vitamin D. Pharmacologic corticosteroid doses should be reduced or discontinued if possible. Thiazides may be useful if hypercalciuria is present. High-impact physical activity (eg, jogging) significantly increases bone density in men and women. Stair-climbing increases bone density in women. Patients who cannot exercise vigorously should be encouraged to engage in other exercise regularly, thereby increasing strength and reducing the risk of falling. Weight training is also helpful to increase muscle strength as well as bone density. Measures should be taken to avoid falls at home (eg, adequate lighting, handrails on stairs, handholds in bathrooms). Patients who have weakness or balance problems must use a

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cane or a walker; rolling walkers should have a brake mechanism. Balance exercises (eg, tai chi) can reduce the risk of falls. Patients should be kept active; bedridden patients should be given active or passive exercises. The spine may be adequately supported (though braces or corsets are usually not well tolerated), but rigid or excessive immobilization must be avoided. Alcohol and smoking should be avoided.

Prognosis

The prognosis is good for preventing postmenopausal osteoporosis in women if estrogen or raloxifene is started early in menopause and maintained for years. However, the adverse effects of oral combined HRT are now known, reducing its use. Hypogonadal women, especially those not receiving HRT, must assure sufficient intake of vitamin D and calcium to prevent osteomalacia; but this does not prevent osteoporosis. Bone mineral density densitometries can detect whether progressive osteopenia or frank osteoporosis is developing. Bisphosphonates can reverse progressive osteopenia and osteoporosis and decrease fracture risk.

Hypogonadal men are also at risk for developing osteoporosis. Testosterone administration can prevent osteoporosis. Men with prostate cancer may not receive testosterone replacement and should be monitored with bone densitometries. Bisphosphonate therapy can reverse progressive osteopenia and osteoporosis in men.

Black DM et al: One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med 2005;353:555.

Bone HG et al: Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;18: 1189.

Cosman F et al: Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 2005;353:566.

Genant HK et al: Treatment with raloxifene for 2 years increases vertebral bone mineral density as measured by volumetric quantitative computed tomography. Bone 2004; 35:1164.

Grant AM et al; RECORD Trial Group: Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621.

Jackson RD et al; Women's Health Initiative Investigators: Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669.

Johnell O et al: Raloxifene reduces risk of vertebral fractures and breast cancer in postmenopausal women regardless of prior hormone therapy. J Fam Pract 2004;53:789.

McClung MR et al: Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 2005;165:1762.

Stenson WF et al: Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 2005;165:393.

Osteomalacia

Essentials of Diagnosis

  • Painful proximal muscle weakness (especially pelvic girdle); bone pain and tenderness.

  • Decreased bone density from diminished mineralization of osteoid.

  • Laboratory abnormalities may include increases in alkaline phosphatase, decreased 25-hydroxyvitamin D, or hypocalcemia, hypocalciuria, hypophosphatemia, secondary hyperparathyroidism.

  • Classic radiologic features may be present.

General Considerations

Defective mineralization of the growing skeleton in childhood causes permanent bone deformities (rickets). Defective skeletal mineralization in adults is known as osteomalacia.

Osteomalacia is commonly caused by a deficiency in vitamin D. Ergocalciferol (vitamin D2) is derived from plants and is used in most pharmaceutical preparations of vitamin D. Cholecalciferol (vitamin D3) is synthesized in the skin, under the influence of ultraviolet radiation, from 7-dehydrocholesterol. Both vitamin D2 and vitamin D3 are used to fortify foods and have equivalent potency. Two sequential hydroxylations are necessary for full biologic activity: The first one takes place in the liver—to 25(OH)D3—and the second one in the kidney, resulting in the formation of the most potent biologic metabolite of vitamin D, 1,25(OH)2D3. The main action of vitamin D is to increase the absorption of calcium and phosphate from the intestine. However, vitamin D appears to have other systemic effects, since 1,25(OH)2D receptors are also found in other tissues, including the parathyroids, bones, kidneys, skin, brain, pituitary, activated lymphocytes, and various tumors.

Etiology (Table 26-14)

Osteomalacia is a common disorder and is caused by any condition that results in inadequate calcium or phosphate mineralization of bone osteoid.

Table 26-14. Causes of osteomalacia.1

Vitamin disorders
   Decreased availability of vitamin D
   Insufficient sunlight exposure
   Nutritional deficiency of vitamin D
   Malabsorption
   Nephrotic syndrome
   Vitamin D-dependent rickets type I
   Liver disease
   Chronic renal failure
   Phenytoin, carbamazepine, or barbiturate therapy
Dietary calcium deficiency
Phosphate deficiency
   Decreased intestinal absorption
   Nutritional deficiency of phosphorus
   Malabsorption
   Phosphate-binding antacid therapy
   Increased renal loss
   X-linked hypophosphatemic rickets
   Tumoral hypophosphatemic osteomalacia
   Association with other disorders, including paraproteinemias, glycogen storage diseases, neurofibromatosis, Wilson's disease, and Fanconi's syndrome
Disorders of bone matrix
   Hypophosphatasia
   Fibrogenesis imperfecta
   Axial osteomalacia
Inhibitors of mineralization
   Aluminum
   Bisphosphonates
1See Table 26-12 for causes of osteoporosis.

A. Vitamin D Deficiency and Resistance

Vitamin D deficiency impairs the intestinal absorption of calcium and is the most common cause of osteomalacia. Vitamin D deficiency (serum 25[OH]D < 50 nmol/L or < 20 ng/mL)

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was found in 24.3% of postmenopausal women from 25 countries in the MORE study. The incidence varied: < 1% in Southeast Asia, 29.3% in the United States, and 36% in Italy. Severe vitamin D deficiency (serum 25[OH]D < 25 nmol/L or < 10 ng/mL) was found in 4.1% of these women; 3.5% in the United States and 12.5% in Italy. Vitamin D deficiency is particularly common in the institutionalized elderly, with the incidence exceeding 60% in some groups not receiving vitamin D supplementation. In one study of elderly individuals age 98 years or older, 95% had undetectable levels of vitamin D. Deficiency of vitamin D may arise from insufficient sun exposure, malnutrition, or malabsorption (due to pancreatic insufficiency, cholestatic liver disease, sprue, inflammatory bowel disease, jejunoileal bypass, Billroth type II gastrectomy, etc). Cholestyramine binds bile acids necessary for vitamin D absorption. Patients with severe nephrotic syndrome lose large amounts of vitamin D-binding protein in the urine, and osteomalacia may also develop.

Vitamin D-dependent rickets type I is caused by a rare autosomal recessive defect in renal synthesis of 1,25(OH)2D. It presents in childhood with rickets; osteomalacia develops in adults unless treated with oral calcitriol in doses of 0.5–1 mcg daily. Vitamin D-dependent rickets type II (now better known as hereditary 1,25[OH]2D-resistant rickets) is caused by a genetic defect in the 1,25(OH)2D receptor. It presents in childhood with rickets and alopecia. Adults respond variably to oral calcitriol in very large doses (2–6 mcg daily).

Anticonvulsants (eg, phenytoin, carbamazepine, valproate, phenobarbital) inhibit the hepatic production of 25(OH)D and sometimes cause osteomalacia. Phenytoin can also directly inhibit bone mineralization. Serum levels of 1,25(OH)2D are usually normal.

B. Deficient Calcium Intake

Rickets and osteomalacia continue to be common problems in many tropical countries despite adequate exposure to sunlight. A nutritional deficiency of calcium can occur in any severely malnourished patient. Some degree of calcium deficiency is common in the elderly, since intestinal calcium absorption declines with age. Ingestion of excessive wheat bran also causes calcium malabsorption.

C. Phosphate Deficiency

Phosphatonin is a circulating peptide that inhibits sodium-dependent phosphate transport in the renal tubule; high levels of this peptide cause excessive phosphaturia, resulting in hypophosphatemia. X-linked hypophosphatemic rickets is associated with high levels of phosphatonin, probably caused by familial or sporadic mutations in PHEX endopeptidase, which fails to cleave phosphatonin.

Oncogenic osteomalacia is caused by excessive production of phosphatonin by a wide variety of soft tissue tumors (87% benign). The condition is characterized by hypophosphatemia, excessive phosphaturia, reduced serum 1,25(OH)2D concentrations, and osteomalacia. Excessive renal phosphate losses are also seen in proximal renal tubular acidosis and Fanconi's syndrome. Some cases of hyperphosphaturia are idiopathic.

Other causes of hypophosphatemic osteomalacia include poor nutrition, alcoholism, or chelation of phosphate in the gut by aluminum hydroxide antacids, calcium acetate (Phos-Lo), or sevelamer hydrochloride (Renagel).

D. Aluminum Toxicity

Bone mineralization is inhibited by aluminum. Osteomalacia may occur in patients receiving long-term renal hemodialysis with tap water dialysate or from aluminum-containing antacids used to reduce phosphate levels. Osteomalacia may develop in patients being maintained on long-term total parenteral nutrition if the casein hydrolysate used for amino acids contains high levels of aluminum.

E. Hypophosphatasia

Skeletal alkaline phosphatase is an enzyme that is necessary to form normal bone. Alkaline phosphatase cleaves pyrophosphate, an inhibitor of mineralization, thereby allowing normal mineralization of the bone matrix. There are four distinct alkaline phosphatase isomers;

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only one is found in bone and it is also in liver and kidney and is therefore known as tissue-nonspecific alkaline phosphatase (“bone” alkaline phosphatase).

Hypophosphatasia, a deficiency of tissue-nonspecific alkaline phosphatase effect, is a rare genetic cause of osteomalacia that is commonly misdiagnosed as osteoporosis. The incidence in the United States is about 1 in 100,000 live births; about 1 in 300 adults is a carrier. More than 60 different mutations in the gene encoding tissue-nonspecific alkaline phosphatase (designated ALPL) have been described, and transmission can be autosomal recessive or autosomal dominant. The phenotypic presentation of hypophosphatasia is extremely variable. At its worst extreme, it can present as a stillborn without dentition or calcified bones. At its mildest, hypophosphatasia can present in middle age with premature loss of teeth, foot pain (due to metatarsal stress fractures), thigh pain (due to femoral pseudofractures), or arthritis (due to chondrocalcinosis). Serum alkaline phosphatase (collected in a non-EDTA tube) is low for age in patients with hypophosphatasia. To confirm the diagnosis, a 24-hour urine should be assayed for phosphoethanolamine, a substrate for tissue-nonspecific alkaline phosphatase, whose excretion is always elevated in patients with hypophosphatasia. Prenatal genetic testing, by way of chorionic villus biopsy, is available for the infantile form of hypophosphatasia. There is no proven therapy for hypophosphatasia, except for supportive care. Teriparatide, a useful therapy for osteoporosis, has been administered to some patients with hypophosphatasia, but its long-term efficacy is unknown.

F. Fibrogenesis Imperfecta Ossium

This rare condition sporadically affects middle-aged patients, who present with progressive bone pain and pathologic fractures. Bones have a dense “fishnet” appearance on x-ray. MRI of unfractured bone shows low signal intensity on both T1- and T2-weighted imaging. Serum alkaline phosphatase levels are elevated. Some patients have a monoclonal gammopathy, indicating a possible plasma cell dyscrasia causing an impairment in osteoblast function and collagen disarray. Remission has been reported after repeated courses of melphalan, corticosteroids, and vitamin D analog over 3 years.

Clinical Findings

The clinical manifestations of defective bone mineralization depend on the age at onset and the severity. In adults, osteomalacia is typically asymptomatic at first. Eventually, bone pain occurs, along with muscle weakness due to calcium deficiency. Fractures may occur with little or no trauma.

Diagnostic Tests

Serum is obtained for calcium, albumin, phosphate, alkaline phosphatase, PTH, and 25[OH]D3 determinations. Bone densitometry helps document the degree of osteopenia. X-rays may show diagnostic features.

In one series of biopsy-proved osteomalacia, alkaline phosphatase was elevated in 94% of patients; the calcium or phosphorus was low in 47% of patients; 25(OH)D3 was low in 29% of patients; pseudofractures were seen in 18% of patients; and urinary calcium was low in 18% of patients. 1,25(OH)2D3 may be low even when 25(OH)D2 levels are normal.

Bone biopsy is not usually necessary but is diagnostic of osteomalacia if there is significant unmineralized osteoid.

Differential Diagnosis

Osteomalacia usually can be distinguished from osteoporosis by the relative absence of biochemical abnormalities in the latter. Phosphate deficiency must be distinguished from hypophosphatemia seen in hyperparathyroidism.

Prevention & Treatment

Prevention of vitamin D deficiency may be achieved with adequate sunlight exposure and vitamin D supplements. In the United States, the current recommended daily allowance (RDA) of vitamin D is at least 10 mcg (400 IU) daily. However, in sunlight-deprived individuals (eg, veiled women, confined patients, or residents of higher latitudes during winter), the RDA should be 1000 IU daily. In such individuals, vitamin D supplements should be given prophylactically. Patients receiving long-term phenytoin therapy may be treated prophylactically with vitamin D, 50,000 IU orally every 2–4 weeks.

Vitamin D deficiency is treated with ergocalciferol (D2), 50,000 IU orally once or twice weekly for 6–12 months, followed by at least 1000 IU daily. Ergocalciferol has a long duration of action and may also be given orally every 2 months in doses of 50,000 IU. In patients with intestinal malabsorption, oral doses of 25,000–100,000 IU of vitamin D2 daily may be required. Some patients with steatorrhea respond better to oral 25(OH)D3 (calcifediol), 50–100 mcg/d. All patients receive supplemental oral calcium salts (eg, calcium citrate or calcium carbonate), which are given with meals. Recommended doses of calcium are as follows: calcium citrate (eg, Citracal), 0.4–0.6 g elemental calcium per day, or calcium carbonate (eg, OsCal, Tums), 1–1.5 g elemental calcium per day.

In hypophosphatemic osteomalacia, nutritional deficiencies are corrected, aluminum-containing antacids are discontinued, and patients with renal tubular acidosis are given bicarbonate therapy. In patients with sporadic adult-onset hypophosphatemia, hyperphosphaturia, and low serum 1,25(OH)2D levels, a search is conducted for occult tumors that may be resected; whole-body MRI scanning may be required.

For those with X-linked or idiopathic hypophosphatemia and hyperphosphaturia, oral phosphate supplements

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must be given long-term; calcitriol, 0.25–0.5 mcg/d, is given also to improve the impaired calcium absorption caused by the oral phosphate. Human recombinant growth hormone reduces phosphaturia and may be added to the above regimen.

Bielesz B et al: Renal phosphate loss in hereditary and acquired disorders of bone mineralization. Bone 2004;35:1229.

Hanley DA et al: Vitamin D insufficiency in North America. J Nutr 2005;135:332.

Jan de Beur SM: Tumor-induced osteomalacia. JAMA 2005;294: 1260.

Lyman D: Undiagnosed vitamin D deficiency in the hospitalized patient. Am Fam Physician 2005;71:299.

Pelger RC et al: Severe hypophosphatemic osteomalacia in hormone-refractory prostate cancer metastatic to the skeleton: natural history and pitfalls in management. Bone 2005;36:1.

Paget's Disease of Bone (Osteitis Deformans)

Essentials of Diagnosis

  • Often asymptomatic.

  • Bone pain may be the first symptom.

  • Kyphosis, bowed tibias, large head, deafness, and frequent fractures that vary with location of process.

  • Serum calcium and phosphate normal; alkaline phosphatase elevated; urinary hydroxyproline elevated.

  • Dense, expanded bones on x-ray.

General Considerations

Paget's disease of bone is a common condition manifested by one or more bony lesions having high bone turnover and disorganized osteoid formation. Involved bones become vascular, weak, and deformed. Paget's disease is present in 1–2% of the population of the United States, with a higher prevalence in the elderly and in the Northeast. It is usually discovered incidentally during radiology imaging or because of incidentally discovered elevations in serum alkaline phosphatase. Only 27% of affected individuals are symptomatic at the time of diagnosis. Familial Paget's disease is unusual but is generally more severe than sporadic cases. A rare form occurs in young people.

Clinical Findings

A. Symptoms and Signs

Paget's disease is usually diagnosed in patients over 40 years of age and is often mild and asymptomatic. It can involve just one bone (monostotic) or multiple bones (polyostotic), particularly the skull, femur, tibia, pelvis, and humerus. Pain is the usual first symptom. The bones become soft, leading to bowed tibias, kyphosis, and frequent fractures with slight trauma. If the skull is involved, the patient may report headaches and an increased hat size. Deafness may occur. Increased vascularity over the involved bones causes increased warmth.

B. Laboratory Findings

Serum calcium and phosphorus are normal, but serum alkaline phosphatase is markedly elevated. Urinary hydroxyproline is also elevated in active disease. Serum calcium may be elevated, particularly if the patient is at bed rest.

C. Imaging

The involved bones are expanded and denser than normal on radiographs. Multiple fissure fractures may be seen in the long bones. The initial lesion may be destructive and radiolucent, especially in the skull (“osteoporosis circumscripta”). Technetium pyrophosphate bone scans are helpful in delineating activity of bone lesions even before any radiologic changes are apparent.

Differential Diagnosis

Paget's disease must be differentiated from primary bone lesions such as osteogenic sarcoma, multiple myeloma, and fibrous dysplasia and from secondary bone lesions such as metastatic carcinoma and osteitis fibrosa cystica. Fibrogenesis imperfecta ossium is a rare symmetric disorder that can mimic the features of Paget's disease; alkaline phosphate is likewise elevated. If serum calcium is elevated, hyperparathyroidism may be present in some patients as well.

Complications

Fractures are frequent and occur with minimal trauma. If immobilization takes place and there is an excessive calcium intake, hypercalcemia and kidney stones may develop. Vertebral collapse may lead to spinal cord compression. Osteosarcoma may develop in long-standing lesions. Sarcomatous change is suggested by a marked increase in bone pain, sudden rise in alkaline phosphatase, and appearance of a new lytic lesion. The increased vascularity may give rise to high-output cardiac failure. Arthritis frequently develops in joints adjacent to involved bone.

Extensive skull involvement may cause cranial nerve palsies from impingement of the neural foramina. Ischemic neurologic events may occur as a result of a vascular “steal” phenomenon. Involvement of the auditory region frequently causes hearing loss (mixed sensorineural and conductive) and occasionally tinnitus or vertigo.

Treatment

Asymptomatic patients require no treatment except for those with extensive skull involvement, in whom

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prophylactic treatment may prevent deafness and stroke.

A. Bisphosphonates

Bisphosphonates have become the treatment of choice for Paget's disease. The oral compounds should all be taken with 8 oz of plain water only. Bisphosphonates are usually given cyclically. Therapy is given until a therapeutic response occurs, as evidenced by normalization of the serum alkaline phosphatase. Patients are then given a break from therapy for about 3 months or until the serum alkaline phosphatase becomes elevated again; another cycle is then commenced.

Alendronate, 20–40 mg orally daily (or 70 mg orally once weekly) for 3-month cycles, is also effective. It must be taken in the morning, at least 30–60 minutes before breakfast. Its main side effect is esophagitis, so recumbency after dosing is prohibited, and the drug is contraindicated in patients with a history of esophagitis, esophageal stricture, dysphagia, hiatal hernia, or achalasia.

Tiludronat, 400 mg orally daily for 3 months, is very effective in reducing the activity of bone lesions. It should not be taken within 2 hours of meals, aspirin, indomethacin, calcium, magnesium, or aluminum-containing antacids. Esophagitis is uncommon, so recumbency after dosing is not restricted, and the drug may be taken in the evening as well as during the day. The most common side effects have been gastrointestinal, including abdominal pain in 13% and nausea in 9%.

Risedronate, 30 mg orally daily for 3-month cycles, has been effective in normalizing alkaline phosphatase and eliminating bone pain in the majority of patients. It has been generally well tolerated, but arthralgias and gastrointestinal side effects do occur.

Parenteral bisphosphonates are particularly useful for patients who cannot tolerate oral bisphosphonates. Pamidronate, 60–120 mg intravenously over 2–4 hours, may produce improvements lasting several months. Alkaline phosphatase may continue to drop for 6 months after treatment. (See Treatment of Hypercalcemia.) Zoledronic acid can be given every 6–12 months in doses of 2–4 mg intravenously over 20 minutes. Six months following a single infusion of zoledronic acid, patients had a clinical response rate of 96%, compared with 74% in patients receiving daily oral risedronate. Intravenous zoledronic acid has been demonstrated to be significantly more effective than daily risedronate. Postinfusion fever, fatigue, myalgia, bone pain, and ocular problems occur commonly and may sometimes be severe. Nonhealing jaw ulcers after tooth extraction may occur.

B. Nasal Calcitonin-Salmon

Miacalcin, 200 IU/unit dose spray, is administered as one spray daily, alternating nostrils. It is just as effective as the parenteral preparation and is associated with fewer side effects. Nasal irritation may occur, as may occasional epistaxis. Calcitonin has been used for many years to treat Paget's disease. However, its use has declined dramatically with the introduction of more potent bisphosphonates.

Prognosis

The prognosis in general is good, but sarcomatous changes (in 1–3%) can alter it unfavorably. In general, the prognosis is worse the earlier in life the disease starts. Fractures usually heal well. In the severe forms, marked deformity, intractable pain, and cardiac failure are found. These complications should become rare with prompt bisphosphonate treatment.

Cundy T et al: Recombinant osteoprotegerin for juvenile Paget's disease. N Engl J Med 2005;353:918.

Langston AL et al: Management of Paget's disease of bone. Rheumatology (Oxford) 2004;43:955.

Reid IR et al: Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med 2005; 353:898.

Walsh JP et al: A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone. Bone 2004;34:747.

Diseases of the Adrenal Cortex

Acute Adrenocortical Insufficiency (Adrenal Crisis)

Essentials of Diagnosis

  • Weakness, abdominal pain, fever, confusion, nausea, vomiting, and diarrhea.

  • Low blood pressure, dehydration; skin pigmentation may be increased.

  • Serum potassium high, sodium low, BUN high.

  • Cosyntropin (ACTH1–24) unable to stimulate a normal increase in serum cortisol.

General Considerations

Acute adrenal insufficiency is an emergency caused by insufficient cortisol. Crisis may occur in the course of treatment of chronic insufficiency, or it may be the presenting manifestation of adrenal insufficiency. Acute adrenal crisis is more commonly seen in primary adrenal insufficiency (Addison's disease) than in disorders of the pituitary gland causing secondary adrenocortical hypofunction.

Adrenal crisis may occur in the following situations: (1) following stress, eg, trauma, surgery, infection, or prolonged

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fasting in a patient with latent insufficiency; (2) following sudden withdrawal of adrenocortical hormone in a patient with chronic insufficiency or in a patient with temporary insufficiency due to suppression by exogenous corticosteroidsor megestrol; (3) following bilateral adrenalectomy or removal of a functioning adrenal tumor that had suppressed the other adrenal; (4) following sudden destruction of the pituitary gland (pituitary necrosis), or when thyroid hormone is given to a patient with hypoadrenalism; and (5) following injury to both adrenals by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma.

Clinical Findings

A. Symptoms and Signs

The patient complains of headache, lassitude, nausea and vomiting, abdominal pain, and often diarrhea. Confusion or coma may be present. Fever may be 40.6°C or more. The blood pressure is low. Patients with preexisting type 1 diabetes may present with recurrent hypoglycemia and reduced insulin requirements. Other signs may include cyanosis, dehydration, skin hyperpigmentation, and sparse axillary hair (if hypogonadism is also present). Meningococcemia may be associated with purpura and adrenal insufficiency secondary to adrenal infarction (Waterhouse-Friderichsen syndrome).

B. Laboratory Findings

The eosinophil count may be high. Hyponatremia or hyperkalemia (or both) are usually present. Hypoglycemia is frequent. Hypercalcemia may be present. Blood, sputum, or urine culture may be positive if bacterial infection is the precipitating cause of the crisis.

The diagnosis is made by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given parenterally. (2) Serum is obtained for cortisol between 30 and 60 minutes after cosyntropin is administered. Normally, serum cortisol rises to at least 20 mcg/dL. For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol.

Plasma ACTH is markedly elevated if the patient has primary adrenal disease (generally > 200 pg/mL).

Differential Diagnosis

Acute adrenal insufficiency must be distinguished from other causes of shock (eg, septic, hemorrhagic, cardiogenic). Hyperkalemia is also seen with gastrointestinal bleeding, rhabdomyolysis, hyperkalemic paralysis, and certain drugs (eg, ACE inhibitors, spironolactone). Hyponatremia is seen in many other conditions (eg, hypothyroidism, diuretic use, heart failure, cirrhosis, vomiting, diarrhea, severe illness, or major surgery). Acute adrenal insufficiency must be distinguished from an acute abdomen in which neutrophilia is the rule, whereas adrenal insufficiency is characterized by a relative lymphocytosis and eosinophilia.

More than 90% of serum cortisol is protein bound and low serum levels of binding proteins result in misleadingly low serum cortisol determinations by most assays. Nearly 40% of critically ill patients, with serum albumin < 2.5 g/dL, have low serum total cortisol levels but normal serum free cortisol levels and normal adrenal function.

Treatment

A. Acute Phase

If the diagnosis is suspected, draw a blood sample for cortisol determination and treat with hydrocortisone, 100–300 mg intravenously, and saline immediately, without waiting for the results. Thereafter, give hydrocortisone phosphate or hydrocortisone sodium succinate, 100 mg intravenously immediately, and continue intravenous infusions of 50–100 mg every 6 hours for the first day. Give the same amount every 8 hours on the second day and then adjust the dosage in view of the clinical picture.

Since bacterial infection frequently precipitates acute adrenal crisis, broad-spectrum antibiotics should be administered empirically while waiting for the results of initial cultures. Hypoglycemia should be vigorously treated while serum electrolytes, BUN, and creatinine are monitored.

B. Convalescent Phase

When the patient is able to take food by mouth, give oral hydrocortisone, 10–20 mg every 6 hours, and reduce dosage to maintenance levels as needed. Most patients ultimately require hydrocortisone twice daily (AM, 10–20 mg; PM, 5–10 mg). Mineralocorticoid therapy is not needed when large amounts of hydrocortisone are being given, but as the dose is reduced it is usually necessary to add fludrocortisone acetate, 0.05–0.2 mg daily. Some patients never require fludrocortisone or become edematous at doses of more than 0.05 mg once or twice weekly. Once the crisis has passed, the patient must be evaluated to assess the degree of permanent adrenal insufficiency and to establish the cause if possible.

Prognosis

Rapid treatment will usually be life-saving. However, acute adrenal insufficiency is frequently unrecognized and untreated since its manifestations mimic more common conditions; lack of treatment leads to shock that is unresponsive to volume replacement and vasopressors, resulting in death.

Hamrahian AH et al: Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629.

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Jahangir-Hekmat M et al: Adrenal insufficiency attributable to adrenal hemorrhage: long-term follow-up with reference to glucocorticoid and mineralocorticoid function and replacement. Endocr Pract 2004;10:55.

Chronic Adrenocortical Insufficiency (Addison's Disease)

Essentials of Diagnosis

  • Weakness, easy fatigability, anorexia, weight loss; nausea and vomiting, diarrhea; abdominal pain, muscle and joint pains; amenorrhea.

  • Sparse axillary hair; increased skin pigmentation, especially of creases, pressure areas, and nipples.

  • Hypotension, small heart.

  • Serum sodium may be low; potassium, calcium, and BUN may be elevated; neutropenia, mild anemia, eosinophilia, and relative lymphocytosis may be present.

  • Plasma cortisol levels are low or fail to rise after administration of corticotropin.

  • Plasma ACTH level is elevated.

General Considerations

Addison's disease is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens and causes skin pigmentation that can be subtle or strikingly dark. Volume and sodium depletion and potassium excess eventually occur in primary adrenal failure. In contrast, if chronic adrenal insufficiency is secondary to pituitary failure (atrophy, necrosis, tumor), mineralocorticoid production (controlled by the renin-angiotensin system) persists and hyperkalemia is not present. Furthermore, if ACTH is not elevated, skin pigmentary changes are not encountered.

Etiology

Autoimmune destruction of the adrenals is the most common cause of Addison's disease in the United States (accounting for about 80% of spontaneous cases). It may occur alone or as part of a polyglandular autoimmune (PGA) syndrome. Type 1 PGA is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APCED) syndrome and is caused by a defect in T cell-mediated immunity inherited as an autosomal recessive trait. It usually presents in early childhood with mucocutaneous candidiasis, followed by hypoparathyroidism and dystrophy of the teeth and nails; Addison's disease usually appears by age 15 years. Partial or late expression of the syndrome is common. A varied spectrum of associated diseases may be seen in adulthood, including hypogonadism, hypothyroidism, pernicious anemia, alopecia, vitiligo, hepatitis, malabsorption, and Sjögren's syndrome.

Type 2 PGA usually presents in adulthood with autoimmune adrenal insufficiency (no hypoparathyroidism) that is HLA related. It is associated with autoimmune thyroid disease (usually hypothyroidism, sometimes hyperthyroidism), vitiligo, type 1 diabetes, alopecia areata, or celiac sprue. Autoimmune Addison's disease can also be associated with primary ovarian failure (40% of women before age 50 years), testicular failure (5%), and pernicious anemia (4%). The combination of Addison's disease and hypothyroidism is known as Schmidt's syndrome.

Tuberculosis was formerly a leading cause of Addison's disease. The association is now relatively rare in the United States but common where tuberculosis is more prevalent.

Bilateral adrenal hemorrhage may occur during sepsis, heparin-associated thrombocytopenia or anticoagulation, or with antiphospholipid antibody syndrome. It may occur in association with major surgery or trauma, presenting about 1 week later with pain, fever, and shock. It may also occur spontaneously.

Adrenoleukodystrophy is an X-linked peroxisomal disorder causing accumulation of very long-chain fatty acids in the adrenal cortex, testes, brain, and spinal cord. It may present at any age and accounts for one-third of cases of Addison's disease in boys. Aldosterone deficiency occurs in 9%. Hypogonadism is common. Psychiatric symptoms often include mania, psychosis, or cognitive impairment. Neurologic deterioration may be severe or mild (particularly in heterozygote women), mimics symptoms of multiple sclerosis, and can occur years after the onset of adrenal insufficiency.

Rare causes of adrenal insufficiency include lymphoma, metastatic carcinoma, coccidioidomycosis, histoplasmosis, cytomegalovirus infection (more frequent in patients with AIDS), syphilitic gummas, scleroderma, amyloid disease, and hemochromatosis.

Familial glucocorticoid deficiency is caused by a mutation in the gene encoding the adrenal ACTH receptor. Triple A (Allgrove's) syndrome is characterized by variable expression of the following: adrenal ACTH resistance with cortisol deficiency, achalasia, alacrima, nasal voice, and neuromuscular disease of varying severity (hyperreflexia to spastic paraplegia). Cortisol deficiency usually presents in infancy but may not occur until the third decade of life. Congenital adrenal hypoplasia causes adrenal insufficiency due to absence of the adrenal cortex; patients may also have hypogonadotropic hypogonadism, myopathy, and high-frequency hearing loss. Patients with hereditary defects in adrenal enzymes for cortisol synthesis develop congenital adrenal hyperplasia due to ACTH stimulation. The most common enzyme defect is P-450c21 (21-hydroxylase). Patients with severely defective P-450c21 enzymes manifest deficiency of mineralocorticoids (salt wasting) in addition to deficient cortisol and excessive androgens. Women with milder enzyme defects have adequate cortisol but develop hirsutism in adolescence or adulthood

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and are said to have “late-onset” congenital adrenal hyperplasia. (See Hirsutism section.)

Isolated hypoaldosteronism can be caused by various conditions. Hyporeninemic hypoaldosteronism can be caused by renal tubular acidosis type IV and is commonly seen with diabetic nephropathy, hypertensive nephrosclerosis, tubulointerstitial diseases, and AIDS; patients present with hyperkalemia, hyperchloremia, and metabolic acidosis (see Chapter 21). Hyperreninemic hypoaldosteronism can be seen in patients with myotonic dystrophy, aldosterone synthase deficiency, and congenital adrenal hyperplasia. Some patients with congenital adrenal hyperplasia (CYP17 deficiency) may present in adulthood with hyperkalemia, hypertension, and hypogonadism; cortisol deficiency is also usually present but may not be clinically evident.

Clinical Findings

A. Symptoms and Signs

The symptoms may include weakness and fatigability, weight loss, myalgias, arthralgias, fever, anorexia, nausea and vomiting, anxiety, and mental irritability. Some of these symptoms may be due to high serum levels of IL-6. Pigmentary changes consist of diffuse tanning over nonexposed as well as exposed parts or multiple freckles; hyperpigmentation is especially prominent over the knuckles, elbows, knees, and posterior neck and in palmar creases and nail beds. Nipples and areolas tend to darken. The skin in pressure areas such as the belt or brassiere lines and the buttocks also darkens. New scars are pigmented. Some patients have associated vitiligo (10%). Emotional changes are common. Hypoglycemia, when present, may worsen the patient's weakness and mental functioning, rarely leading to coma. Manifestations of other autoimmune disease (see above) may be present. Patients tend to be hypotensive and orthostatic; about 90% have systolic blood pressures under 110 mm Hg; blood pressure over 130 mm Hg is rare. Other findings may include a small heart, hyperplasia of lymphoid tissues, and scant axillary and pubic hair (especially in women).

Patients with adult-onset adrenoleukodystrophy may present with neuropsychiatric symptoms, sometimes without adrenal insufficiency.

B. Laboratory Findings

The white count usually shows moderate neutropenia, lymphocytosis, and a total eosinophil count over 300/mcL. Among patients with chronic Addison's disease, the serum sodium is usually low (90%) while the potassium is elevated (65%). Patients with diarrhea may not be hyperkalemic. Fasting blood glucose may be low. Hypercalcemia may be present. Young men with idiopathic Addison's disease are screened for adrenoleukodystrophy by determining plasma very long-chain fatty acid levels; affected patients have high levels.

Low plasma cortisol (< 3 mcg/dL) at 8 AM is diagnostic, especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). The diagnosis is made by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given parenterally. (2) Serum is obtained for cortisol between 30 and 60 minutes after cosyntropin is administered. Normally, serum cortisol rises to at least 20 mcg/dL. For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol.

Serum DHEA levels are under 1000 ng/mL in 100% of patients with Addison's disease and a serum DHEA above 1000 ng/mL excludes the diagnosis However, serum DHEA levels below 1000 ng/mL are not helpful, since about 15% of the general population have such low DHEA levels, particularly children and elderly individuals. Antiadrenal antibodies are found in the serum in about 50% of cases of autoimmune Addison's disease. Antibodies to thyroid (45%) and other tissues may be present.

Elevated plasma renin activity indicates the presence of depleted intravascular volume and the need for higher doses of fludrocortisone replacement.

C. Imaging

When Addison's disease is not clearly autoimmune, a chest radiograph is obtained to look for tuberculosis, fungal infection, or cancer as possible causes. CT scan of the abdomen will show small noncalcified adrenals in autoimmune Addison's disease. The adrenals are enlarged in about 85% of cases due to metastatic or granulomatous disease. Calcification is noted in about 50% of cases of tuberculous Addison's disease but is also seen with hemorrhage, fungal infection, pheochromocytoma, and melanoma.

Differential Diagnosis

Addison's disease should be considered in any patient with hypotension or hyperkalemia. Unexplained weight loss, weakness, and anorexia may be mistaken for occult cancer. Nausea, vomiting, diarrhea, and abdominal pain may be misdiagnosed as intrinsic gastrointestinal disease. The hyperpigmentation may be confused with that due to ethnic or racial factors. Weight loss may simulate anorexia nervosa. The neurologic manifestations of Allgrove's syndrome and adrenoleukodystrophy (especially in women) often mimic multiple sclerosis. Hemochromatosis also enters the differential diagnosis of skin hyperpigmentation, but it should be remembered that it may truly be a cause of Addison's disease as well as diabetes mellitus and hypoparathyroidism. Serum ferritin is increased in most cases of hemochromatosis and is a useful screening test. About 17% of patients with AIDS have symptoms of cortisol resistance. AIDS can also cause frank adrenal insufficiency.

Complications

Any of the complications of the underlying disease (eg, tuberculosis) are more likely to occur, and the patient

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is susceptible to intercurrent infections that may precipitate crisis. Associated autoimmune diseases are common (see above).

Treatment

A. Specific Therapy

Replacement therapy should include a combination of corticosteroids and mineralocorticoids. In mild cases, hydrocortisone alone may be adequate.

Hydrocortisone is the drug of choice. Most addisonian patients are well maintained on 15–25 mg of hydrocortisone orally daily in two divided doses, two-thirds in the morning and one-third in the late afternoon or early evening. Some patients respond better to prednisone in a dosage of about 2–3 mg in the morning and 1–2 mg in the evening. Adjustments in dosage are made according to the clinical response. A proper dose usually results in a normal differential white count. Many patients, however, do not obtain sufficient salt-retaining effect and require fludrocortisone supplementation or extra dietary salt.

Fludrocortisone acetate has a potent sodium-retaining effect. The dosage is 0.05–0.3 mg orally daily or every other day. In the presence of postural hypotension, hyponatremia, or hyperkalemia, the dosage is increased. Similarly, in patients with fatigue, elevated plasma renin activity indicates the need for a higher replacement dose of fludrocortisone. If edema, hypokalemia, or hypertension ensues, the dose is decreased.

DHEA is given to some women with adrenal insufficiency. Women taking DHEA 50 mg orally each morning have experienced an improvement in their overall sense of well-being, mood, and sexuality. Because over-the-counter preparations of DHEA have variable potencies, it is best to have the pharmacy formulate this with pharmaceutical-grade DHEA.

B. General Measures

All infections should be treated immediately and vigorously, and the dose of hydrocortisone should be raised appropriately. The dose of corticosteroid should also be raised in case of trauma, surgery, stressful diagnostic procedures, or other forms of stress. The maximum hydrocortisone dose for severe stress is 50 mg intravenously or intramuscularly every 6 hours. Lower doses, oral or parenteral, are used for less severe stress. The dose is reduced back to normal as the stress subsides. Patients are advised to wear a medical alert bracelet or medal reading, “Adrenal insufficiency—takes hydrocortisone.”

For patients with adrenoleukodystrophy, therapy with “Lorenzo's oil” normalizes serum very long-chain fatty acid concentrations but is ineffective clinically. Neurologic manifestations may improve following hematopoietic stem cell transplantation from normal donors.

Prognosis

Patients with Addison's disease can expect a normal life expectancy if their adrenal insufficiency is diagnosed and treated with appropriate replacement doses of corticosteroids and (if required) mineralocorticoids. However, associated conditions can pose additional health risks. For example, patients with adrenoleukodystrophy or Allgrove syndrome may suffer from neurologic disease. Patients with adrenal tuberculosis may have a serious systemic infection that requires treatment. Adrenal crisis can occur in patients who stop their medication or who experience stress such as infection, trauma, or surgery without appropriately higher doses of corticosteroids. Patients who take excessive doses of corticosteroid replacement can develop Cushing's syndrome, which imposes its own risks. Many patients with treated Addison's disease complain of chronic low-grade fatigue. Such fatigue may be due to epinephrine deficiency, which can result from adrenal destruction. Fatigue may also be an indication of suboptimal dosing of medication, electrolyte imbalance, or concurrent problems such as hypothyroidism or diabetes mellitus. However, most patients with Addison's disease are able to live fully active lives.

Alonso N et al: Evaluation of two replacement regimens in primary adrenal insufficiency patients. Effect on clinical symptoms, health-related quality of life and biochemical parameters. J Endocrinol Invest 2004;27:449.

Betterle C et al: Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004;137:225.

Libe R et al: Effects of dehydroepiandrosterone (DHEA) supplementation on hormonal, metabolic and behavioral status in patients with hypoadrenalism. J Endocrinol Invest 2004;27: 736.

Cushing's Syndrome (Hypercortisolism)

Essentials of Diagnosis

  • Central obesity, muscle wasting, thin skin, easy bruisability, psychological changes, hirsutism, purple striae.

  • Osteoporosis, hypertension, poor wound healing.

  • Hyperglycemia, glycosuria, leukocytosis, lymphocytopenia, hypokalemia.

  • Elevated serum cortisol and urinary free cortisol. Lack of normal suppression by dexamethasone.

General Considerations

The term Cushing's “syndrome” refers to the manifestations of excessive corticosteroids, commonly due to supraphysiologic doses of corticosteroid drugs and rarely due to spontaneous production of excessive corticosteroids by the adrenal cortex. Cases of spontaneous Cushing's

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syndrome are rare (2.6 new cases yearly per million population) and have several possible causes.

About 40% of cases are due to Cushing's “disease,” by which is meant the manifestations of hypercortisolism due to ACTH hypersecretion by the pituitary. Cushing's disease is caused by a benign pituitary adenoma that is typically very small (< 5 mm). It is at least three times more frequent in women than men.

About 10% of cases are due to nonpituitary neoplasms (eg, small cell lung carcinoma), which produce excessive amounts of ectopic ACTH. Hypokalemia and hyperpigmentation are commonly found in this group.

About 15% of cases are due to ACTH from a source that cannot be initially located.

About 30% of cases are due to excessive autonomous secretion of cortisol by the adrenals—independently of ACTH, serum levels of which are usually low. Most such cases are due to a unilateral adrenal tumor: Benign adrenal adenomas are generally small and produce mostly cortisol; adrenal carcinomas are usually large when discovered and can produce excessive cortisol as well as androgens, with resultant hirsutism and virilization. ACTH-independent macronodular adrenal hyperplasia can also produce hypercortisolism due to the adrenal cortex cells' abnormal stimulation by hormones such as catecholamines, arginine vasopressin, serotonin, hCG/LH, or gastric inhibitory polypeptide; in the latter case, hypercortisolism may be intermittent and food dependent and serum ACTH may not be completely suppressed. Pigmented bilateral adrenal macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome in children and young adults; it may be an isolated condition or part of the Carney complex.

Clinical Findings

A. Symptoms and Signs

Patients with Cushing's syndrome usually have central obesity with a plethoric “moon face,” “buffalo hump,” supraclavicular fat pads, protuberant abdomen, and thin extremities; oligomenorrhea or amenorrhea (or impotence in the male); weakness, backache, and headache; hypertension; osteoporosis; avascular bone necrosis; and acne and superficial skin infections. Patients may have thirst and polyuria (with or without glycosuria), renal calculi, glaucoma, purple striae (especially around the thighs, breasts, and abdomen), and easy bruisability. Wound healing is impaired. Mental symptoms may range from diminished ability to concentrate to increased lability of mood to frank psychosis. Patients are susceptible to opportunistic infections.

B. Laboratory Findings

Glucose tolerance is impaired as a result of insulin resistance. Polyuria is present as a result of increased free water clearance; diabetes mellitus with glycosuria may worsen it. Patients with Cushing's syndrome often have leukocytosis with relative granulocytosis and lymphopenia. Hypokalemia (but not hypernatremia) may be present, particularly in cases of ectopic ACTH secretion.

Tests for Hypercortisolism

The easiest screening test for hypercortisolism involves giving dexamethasone, 1 mg orally, at 11 PM and collecting serum for cortisol determination at about 8 AM the next morning; a cortisol level under 5 mcg/dL (fluorometric assay) or under 2 mcg/dL (high-performance liquid chromatography [HPLC] assay) excludes Cushing's syndrome with 98% certainty. Antiseizure drugs (eg, phenytoin, phenobarbital, primidone) and rifampin accelerate the metabolism of dexamethasone, in that way causing a false-positive dexamethasone suppression test. Estrogens—during pregnancy or as oral contraceptives or estrogen replacement therapy—may also cause lack of dexamethasone suppressibility.

Patients with an abnormal dexamethasone suppression test require further investigation, which includes a 24-hour urine collection for free cortisol and creatinine. An abnormally high 24-hour urine free cortisol (or free cortisol to creatinine ratio of > 95 mcg cortisol/g creatinine) helps confirm hypercortisolism. A misleadingly high urine free cortisol excretion occurs with high fluid intake. In pregnancy, urine free cortisol is increased, while 17-hydroxycorticosteroids remain normal and diurnal variability of serum cortisol is normal. Carbamazepine and fenofibrate cause false elevations of urine free cortisol when determined by HPLC.

In cases of blatant Cushing's syndrome, no further confirmation of hypercortisolism is necessary. In less certain cases, a 2-day dexamethasone suppression test can also be done by giving dexamethasone, 0.5 mg orally every 6 hours for 48 hours: urine is collected on the second day. Urine free cortisol over 20 mcg/d or urine 17-hydroxycorticosteroid over 4.5 mg/d also helps confirm hypercortisolism.

A midnight serum cortisol level > 7.5 mcg/dL is indicative of Cushing's syndrome and distinguishes it from other conditions associated with a high urine free cortisol (pseudo-Cushing states; see Differential Diagnosis, below). Requirements for this test include being in the same time zone for at least 3 days, being without food for at least 3 hours, and having an indwelling intravenous line established in advance for the blood draw.

Due to the inconvenience of obtaining a midnight blood specimen for serum cortisol, salivary cortisol assays have proved useful. However, the saliva must be collected in special tubes and analyzed only in laboratories that have demonstrated expertise with the assay. Using an enzyme-linked immunosorbent assay, midnight salivary cortisol levels are normally < 0.15 mcg/dL (4.0 nmol/L). Midnight salivary cortisol levels that are consistently > 0.25 mcg/dL (7.0 nmol/L) are nearly diagnostic of endogenous Cushing's syndrome.

Interestingly, hypercortisolism without Cushing's syndrome can occur in several conditions: severe depression,

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anorexia nervosa, alcoholism, and familial cortisol resistance. (See Differential Diagnosis, below.)

Finding the Cause of Hypercortisolism

Once hypercortisolism is confirmed, aplasma ACTH is obtained. It must be collected properly in a plastic tube on ice and processed quickly by a laboratory with a reliable, sensitive assay. A level of ACTH below the normal range (below about 20 pg/mL) indicates a probable adrenal tumor, whereas higher levels are produced by pituitary or ectopic ACTH-secreting tumors.

Localizing Techniques

In ACTH-dependent Cushing's syndrome, MRI of the pituitary demonstrates a pituitary lesion in about 50% of cases. Premature cerebral atrophy is often noted. When the pituitary MRI is normal or shows a tiny irregularity that may be incidental, selective catheterization of the inferior petrosal sinus veins draining the pituitary is performed. ACTH levels in the inferior petrosal sinus that are more than twice the simultaneous peripheral venous ACTH levels are indicative of pituitary Cushing's disease. Inferior petrosal sinus sampling is also done during CRH administration, which ordinarily causes the ACTH levels in the inferior petrosal sinus to be over three times the peripheral ACTH level when the pituitary is the source of ACTH.

When inferior petrosal sinus ACTH concentrations are not above the requisite levels, a search for an ectopic source of ACTH is undertaken.

Location of ectopic sources of ACTH commences with CT scanning of the chest and abdomen, with special attention to the lungs (for carcinoid or small cell carcinomas), the thymus, the pancreas, and the adrenals. In patients with ACTH-dependent Cushing's syndrome, chest masses should not be assumed to be the source of ACTH, since opportunistic infections are common, so it is prudent to biopsy a chest mass to confirm the pathologic diagnosis prior to resection.

CT scanning fails to detect the source of ACTH in about 40% of patients with ectopic ACTH secretion. 111In-octreotide scanning is also useful in detecting occult tumors, but 18FDG-PET scanning is not usually helpful. Some ectopic ACTH-secreting tumors elude discovery, necessitating bilateral adrenalectomy.

In non-ACTH-dependent Cushing's syndrome, a CT scan of the adrenals can localize the adrenal tumor in most cases.

Differential Diagnosis

Alcoholic patients can have hypercortisolism and many clinical manifestations of Cushing's syndrome. Depressed patients also have hypercortisolism that can be nearly impossible to distinguish biochemically from Cushing's syndrome but without clinical signs of Cushing's syndrome. Some adolescents develop violaceous striae on the abdomen, back, and breasts; these are known as “striae distensae” and are not indicative of Cushing's syndrome. Cushing's syndrome can be misdiagnosed as anorexia nervosa (and vice versa) owing to the muscle wasting and extraordinarily high urine free cortisol levels found in anorexia. Patients with severe obesity frequently have an abnormal dexamethasone suppression test, but the urine free cortisol is usually normal, as is diurnal variation of serum cortisol. Patients with familial cortisol resistance have hyperandrogenism, hypertension, and hypercortisolism without actual Cushing's syndrome. In patients with familial partial lipodystrophy type I, central obesity and a moon facies develop, along with thin extremities due to atrophy of subcutaneous fat. However, these patients' muscles are strong and may be hypertrophic, distinguishing this condition from Cushing's syndrome. Patients receiving antiretroviral therapy for HIV-1 infection frequently develop partial lipodystrophy with thin extremities and central obesity with a dorsocervical fat pad (“buffalo hump”) that may mimic Cushing's syndrome.

Complications

Cushing's syndrome, if untreated, produces serious morbidity and even death. The patient may suffer from any of the complications of hypertension or of diabetes. Susceptibility to infections is increased. Compression fractures of the osteoporotic spine and aseptic necrosis of the femoral head may cause marked disability. Nephrolithiasis and psychosis may occur. Following bilateral adrenalectomy for Cushing's disease, a pituitary adenoma may enlarge progressively, causing local destruction (eg, visual field impairment) and hyperpigmentation; this complication is known as Nelson's syndrome.

Treatment

Cushing's disease is best treated by transsphenoidal selective resection of the pituitary adenoma. After pituitary surgery, the rest of the pituitary usually returns to normal function; however, the pituitary corticotrophs remain suppressed and require 6–36 months to recover normal function. Hydrocortisone or prednisone replacement therapy is necessary in the meantime. Patients who do not have a remission (or who have a recurrence) should be treated by bilateral laparoscopic adrenalectomy. Another treatment option for patients with ACTH-secreting pituitary tumors is stereotactic pituitary radiosurgery (gamma knife or cyberknife), which normalizes urine free cortisol in two-thirds of patients within 12 months. Conventional radiation therapy results in a 23% cure rate.

Pituitary radiosurgery can also be used to treat Nelson's syndrome, the progressive enlargement of ACTH-secreting pituitary tumors following bilateral adrenalectomy. Patients who are not surgical candidates may be given a trial of ketoconazole in doses of about 200 mg every 6 hours; liver enzymes must be monitored for progressive elevation.

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Adrenal neoplasms secreting cortisol are resected laparoscopically. The contralateral adrenal is suppressed, so postoperative hydrocortisone replacement is required until recovery occurs. Metastatic adrenal carcinomas may be treated with mitotane; ketoconazole or metyrapone can help suppress hypercortisolism in unresectable adrenal carcinoma.

Ectopic ACTH-secreting tumors should be located, when possible, and surgically resected. If that cannot be done, laparascopic bilateral adrenalectomy is recommended. Medical treatment with ketoconazole or metyrapone (or both) may partially suppress the hypercortisolism; however, metyrapone may exacerbate female virilization. The somatostatin analog octreotide, given parenterally, suppresses ACTH secretion in about one-third of such cases.

Prognosis

Patients with Cushing's syndrome from a benign adrenal adenoma experience a 5-year survival of 95% and a 10-year survival of 90%, following a successful adrenalectomy. Patients with Cushing's disease from a pituitary adenoma experience a similar survival if their pituitary surgery is successful. However, transsphenoidal surgery incurs a failure rate of about 10–20%, often due to the adenoma's ectopic position or invasion of the cavernous sinus. Those patients who have a complete remission after transsphenoidal surgery have about a 15–20% chance of recurrence over the next 10 years. Patients with failed pituitary surgery may require pituitary radiation therapy, which has its own morbidity. Bilateral adrenalectomy is often complicated by infection; recurrence of hypercortisolism may occur as a result of growth of an adrenal remnant stimulated by high levels of ACTH. The prognosis for patients with ectopic ACTH-producing tumors is dependent upon the aggressiveness and stage of the particular tumor. Patients with ACTH of unknown source have a 5-year survival rate of 65% and a 10-year survival rate of 55%. Patients with adrenal carcinoma have a median survival of 7 months.

Findling JW et al: The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. J Clin Endocrinol Metab 2004;89:1222.

Hammer GD et al: Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results. J Clin Endocrinol Metab 2004;89:6348.

Ilias I et al: Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. J Clin Endocrinol Metab 2005;90:4955.

Liu C et al: Cavernous and inferior petrosal sinus sampling in the evaluation of ACTH-dependent Cushing's syndrome. Clin Endocrinol (Oxf) 2004;61:478.

Pacak K et al: The role of [18F]fluordeoxyglucose positron emission tomography and [111In]-diethylenetriaminepentaacetate-D-Phe-pentetreotide scintigraphy in the localization of ectopic adrenocorticotropin-secreting tumors causing Cushing's syndrome. J Clin Endocrinol Metab 2004;89:2214.

Viardot A et al: Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test. J Clin Endocrinol Metab 2005;90:5730.

Woo YS et al: Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas. J Clin Endocrinol Metab 2005;90:4963.

Hirsutism & Virilization

Essentials of Diagnosis

  • Hirsutism, acne, menstrual disorders.

  • Virilization may occur: increased muscularity, androgenic alopecia, deepening of the voice, enlargement of the clitoris.

  • Rarely, a palpable pelvic tumor.

  • Urinary 17-ketosteroids and serum DHEAS and androstenedione elevated in adrenal disorders; variable in others.

  • Serum testosterone is often elevated.

General Considerations

Hirsutism is defined as excessive terminal hair growth that appears in a male pattern in women. Hirsutism is frequently quantitated according to the Ferriman-Gallwey scale, which grades the presence of androgen sensitive hair from 0 (no hair) to 4 (virile) in 9 areas of the body (maximum score = 36). About 5% of reproductive age women are hisute, with Ferriman-Gallwey scores ≥ 8.

Major androgens include testosterone, androstenedione, and DHEAS. In women, circulating testosterone is derived from direct ovarian secretion (60%) and from peripheral conversion from androstenedione (40%). Androstenedione is secreted in about equal amounts by the adrenals and ovaries. DHEAS is secreted exclusively by the adrenals.

Testosterone is the most potent androgen, but 98% circulates in a bound state: About 65% is strongly bound to sex hormone-binding globulin (SHBG), while 33% is weakly bound to albumin. Only free testosterone and a portion of the weakly bound testosterone can enter target cells to exert an androgenic effect. Assays have therefore been devised to measure “total,” “free,” or “free and weakly bound” testosterone.

Testosterone is converted in the skin to dihydrotestosterone, which actually stimulates the hair follicle. Dihydrotestosterone is metabolized to androstanediol glucuronide, which can be measured and is elevated in most cases of hirsutism.

Etiology

Hirsutism may be caused by the following disorders.

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A. Idiopathic or Familial

Most women with hirsutism or androgenic alopecia have no detectable hyperandrogenism. Patients often have a strong familial predisposition to hirsutism that may be considered normal in the context of their genetic background. Such patients may have elevated serum levels of androstenediol glucuronide, a metabolite of dihydrotestosterone that is produced by skin in cosmetically unacceptable amounts.

B. Polycystic Ovary Syndrome (Hyperthecosis, Stein-Leventhal Syndrome)

Polycystic ovary syndrome (PCOS) is a common functional disorder of the ovaries, affecting about 4–6% of premenopausal women in the United States. It accounts for at least 50% of all cases of clinical hirsutism. Patients frequently have amenorrhea or oligomenorrhea with anovulation and obesity. The serum LH:FSH ratio is often greater than 2.0. Both adrenal and ovarian androgen hypersecretion are commonly present. Insulin resistance and obesity are common; fasting insulin levels are elevated in 70% of cases. Women with PCOS have a 35% risk of depression, compared with 10.7% in age-matched controls. Diabetes mellitus is present in about 13% of cases. Hypertension and hyperlipidemia are often present, increasing the risk of cardiovascular disease. Women frequently regain normal menstrual cycles with aging.

C. Steroidogenic Enzyme Defects

Baby girls with “classic” 21-hydroxylase deficiency have ambiguous genitalia and may become virilized unless treated with corticosteroid replacement; about 50% of such patients have clinically evident mineralocorticoid deficiency (salt-wasting) as well.

About 2% of patients with adult-onset hirsutism have been found to have a partial defect in adrenal 21-hydroxylase, whose phenotypic expression is delayed until adolescence or adulthood; such patients do not have salt-wasting. These women are more likely to develop polycystic ovaries and adrenal adenomas.

Some rare patients with hyperandrogenism and hypertension have 11-hydroxylase deficiency. This is distinguished from cortisol resistance by high cortisol serum levels in the latter and by high serum 11-deoxycortisol levels in the former.

Patients with an XY karyotype and a deficiency in 17β-hydroxysteroid dehydrogenase-3 or a deficiency in 5α-reductase-2 may present as phenotypic girls in whom virilization develops at puberty.

D. Neoplastic Disorders

Ovarian tumors are very uncommon causes of hirsutism (0.8%) and include arrhenoblastomas, Sertoli-Leydig cell tumors, dysgerminomas, and hilar cell tumors. Adrenal carcinoma is a rare cause of Cushing's syndrome and hyperandrogenism that can be quite virilizing. Pure androgen-secreting adrenal tumors occur very rarely; about 50% are malignant.

E. Other Rare Causes of Hirsutism

Other rare causes of hirsutism include acromegaly and ACTH-induced Cushing's syndrome. Maternal virilization during pregnancy may occur as a result of a luteoma of pregnancy, hyperreactio luteinalis, or polycystic ovaries. In postmenopausal women, diffuse stromal Leydig cell hyperplasia is a rare cause of hyperandrogenism. Pharmacologic causes include minoxidil, cyclosporine, phenytoin, anabolic steroids, diazoxide, and certain progestins.

Clinical Findings

A. Symptoms and Signs

Modest androgen excess from any source increases sexual hair (chin, upper lip, abdomen, and chest) and increases sebaceous gland activity, producing acne. Menstrual irregularities, anovulation, and amenorrhea are common. If androgen excess is pronounced, defeminization (decrease in breast size, loss of feminine adipose tissue) and virilization (frontal balding, muscularity, clitoromegaly, and deepening of the voice) occur. Virilization implicates the presence of an androgen-producing neoplasm.

Hypertension may be seen in rare patients with Cushing's syndrome, adrenal 11-hydroxylase deficiency, or cortisol resistance syndrome.

A pelvic examination may disclose clitoromegaly or ovarian enlargement that may be cystic or neoplastic.

B. Laboratory Testing and Imaging

Serum androgen testing is mainly useful to screen for rare occult adrenal or ovarian neoplasms. Some general guidelines are presented here, though exceptions are common.

Serum is assayed for total testosterone and free testosterone. Certain assays for free testosterone are not reliable, including the free androgen index, the analog free testosterone assay, and the electrochemical luminescence assay. It is best to specify the assay desired, eg, free testosterone by equilibrium dialysis, calculated free testosterone, or non-sex-hormone-bound testosterone assay.

A serum testosterone level greater than 200 ng/dL or free testosterone greater than 40 ng/dL indicates the need for pelvic examination and ultrasound. If that is negative, an adrenal CT scan is performed.

A serum androstenedione level greater than 1000 ng/dL also implicates an ovarian or adrenal neoplasm.

Patients with milder elevations of serum testosterone or androstenedione usually are treated with an oral contraceptive.

Patients with very elevated serum DHEAS (> 700 mcg/dL) have an adrenal source of androgen. This usually is due to adrenal hyperplasia and rarely to adrenal carcinoma. An adrenal CT scan is performed.

No firm guidelines exist as to which patients (if any) with hyperandrogenism should be screened for

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“late-onset” 21-hydroxylase deficiency. The evaluation requires levels of serum 17-hydroxyprogesterone to be drawn at baseline and at 30–60 minutes after the intramuscular injection of 0.25 mg of cosyntropin (ACTH1–24). This test should ideally be done during the follicular phase of a woman's menstrual cycle. Patients with congenital adrenal hyperplasia will usually have a baseline 17-hydroxyprogesterone level over 300 ng/dL or a stimulated level over 1000 ng/dL. The diagnosis, once made, is interesting academically but not helpful to the patient since corticosteroid treatment is not particularly more effective in this condition than are other treatment modalities (see below).

Patients with any clinical signs of Cushing's syndrome should receive a screening test. (See Cushing's Syndrome.)

Serum levels of FSH and LH are elevated if amenorrhea is due to ovarian failure. An LH:FSH ratio greater than 2.0 is common in patients with PCOS. On abdominal ultrasound, about 33% of normal young women have polycystic ovaries, so the appearance of ovarian cysts on ultrasound is not helpful.

Virilizing tumors of the ovary can usually be detected by pelvic ultrasound or MRI. However, small virilizing ovarian tumors may not be detectable on imaging studies; selective venous sampling for testosterone may be used for diagnosis in such patients.

Treatment

Any underlying cause of hyperandrogenism must be detected and treated if possible. Postmenopausal women with severe hyperandrogenism should undergo laparoscopic bilateral oophorectomy (if CT scan of the adrenals and ovaries is normal), since small hilar cell tumors of the ovary may not be visible on scans. Girls with hyperandrogenism due to classic salt-wasting congenital adrenal hyperplasia may be treated with laparoscopic bilateral adrenalectomy. Any drugs causing hirsutism are stopped. Treatment options for other cases are summarized in the following.

Spironolactone may be taken in doses of 50–100 mg twice daily orally on days 5–25 of the menstrual cycle or daily if used concomitantly with an oral contraceptive. Hyperkalemia or hyponatremia is uncommon.

Cyproterone acetate is a potent antiandrogen with progestational activity. A dose of 2 mg orally is effective. An oral contraceptive is usually prescribed also. Cyproterone is not available in the United States but is available elsewhere as the progestin element in an oral contraceptive (Diane-35: ethinyl estradiol 35 mcg with cyproterone acetate 2 mg). Side effects may include fatigue, nausea, or depression.

Finasteride inhibits 5α-reductase, the enzyme that converts testosterone to active dihydrotestosterone in the skin. Given as 2.5-mg doses orally daily, it provides modest reduction in hirsutism over 6 months—somewhat less than that achieved with spironolactone. Finasteride is ineffective for androgenic alopecia in women. Side effects are rare.

Flutamide inhibits androgen reception uptake and also suppresses serum androgen. It is given orally in a dosage of 250 mg/d for the first year and then 125 mg/d for maintenance. Used with an oral contraceptive, it appears to be more effective than spironolactone in improving hirsutism, acne, and male pattern baldness. Women with congenital adrenal hyperplasia, who take replacement hydrocortisone, experience decreased renal cortisol clearance when treated with flutamide, resulting in lower hydrocortisone dosage requirements; corticosteroid replacement doses should be reduced when flutamide is added for treatment of hirsutism. Hepatotoxicity has been reported but is rare.

Oral contraceptives stimulate menses (if that is desired) and reduce acne vulgaris, but are less effective for hirsutism. Contraceptives containing ethinyl estradiol 0.3 mg with either desogestrel 0.15 mg or levonorgestrel 0.15 mg appear to be equally effective.

Metformin, 500 mg orally three times daily with meals, given to women with PCOS and amenorrhea, tends to restore normal menses and reduce hirsutism. It is contraindicated in renal disease. Gastrointestinal side effects are usually tolerable. Metformin can be taken by nondiabetics without causing hypoglycemia.

Simvastatin, a “statin,” when added to oral contraceptive therapy, has been reported to further decrease serum free testosterone by 16%, besides improving patients' serum lipid profiles.

Local treatment by shaving or depilatories, waxing, electrolysis, or bleaching should be encouraged. Eflornithine (Vaniqua 13.9%) topical cream retards hair growth when applied twice daily to unwanted facial hair; improvement is noted within 4–8 weeks. However, local skin irritation may occur. Hirsutism returns with discontinuation. Laser therapy is an effective treatment for facial hirsutism, particularly for women with dark hair and light skin; complications include skin hypopigmentation (rare) and hyperpigmentation, which occurs in 20% but usually resolves.

Women with androgenic alopecia may be effectively treated with topical minoxidil 2% solution applied twice daily to a dry scalp. Hypertrichosis is an unwanted side effect of topical minoxidil, occurring in 3–5% of treated women; it may affect the forehead, cheeks, upper lip, or chin. Hypertrichosis resolves within 1–6 months after the drug is stopped.

Note: Antiandrogen treatments must be given only to nonpregnant women. Women must be counseled to take oral contraceptives, when indicated, and avoid pregnancy, since use during pregnancy causes malformations and pseudohermaphroditism in male infants.

Azziz R et al: Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 2004; 89:453.

Chang RJ: A practical approach to the diagnosis of polycystic ovary syndrome. Am J Obstet Gynecol 2004;191:713.

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Ganic MA et al: Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-label study. J Clin Endocrinol Metab 2004; 89:2756.

Ortega-Gonzalez C et al: Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:1360.

Palomba S et al: Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90:4068.

Rosenfield RL: Clinical practice. Hirsutism. N Engl J Med 2005; 353:2578.

Souter I et al: The prevalence of androgen excess among patients with minimal unwanted hair growth. Am J Obstet Gynecol 2004;191:1914.

Primary Hyperaldosteronism

Essentials of Diagnosis

  • Hypertension, polyuria, polydipsia, muscular weakness.

  • Hypokalemia, alkalosis.

  • Elevated plasma and urine aldosterone levels and low plasma renin level.

General Considerations

Classic hyperaldosteronism (with hypokalemia) accounts for about 0.7% of cases of hypertension. Milder hyperaldosteronism, without hypokalemia, is more common, with a prevalence of 5–14% among hypertensives. The disorder is more common in women. Primary hyperaldosteronism may be due to unilateral adrenocortical adenoma (Conn's syndrome, 73%) or bilateral cortical hyperplasia (27%), which may be corticosteroid suppressible due to an autosomal-dominant genetic defect allowing ACTH stimulation of aldosterone production.

Clinical Findings

A. Symptoms and Signs

Hypertension, muscular weakness (at times with paralysis simulating periodic paralysis), paresthesias with frank tetany, headache, polyuria, and polydipsia are the main complaints. Hypertension is typically moderate. Some patients have only diastolic hypertension, without other symptoms and signs. Malignant hypertension is rare. Edema is rarely seen in primary hyperaldosteronism.

B. Laboratory Findings

For a patient to be properly tested for hyperaldosteronism, all antihypertensive medications must be discontinued. Calcium channel blockers can normalize aldosterone secretion, thus interfering with the diagnosis. β-Blockers suppress plasma renin activity in patients with essential hypertension. The patient must have a high sodium intake (> 120 mEq/d) during the entire evaluation period; plasma potassium may be low. A 24-hour urine collection is assayed for aldosterone, free cortisol, and creatinine. A low plasma renin activity (< 5 mcg/dL) with 24-hour urine aldosterone over 20 mcg indicates hyperaldosteronism. A urine aldosterone of less than 20 mcg/24 h is seen with rare adrenal or gonadal enzyme defects in the activity of 17α-hydroxylase (associated with ambiguous genitalia or primary amenorrhea) or 11β-hydroxylase (associated with virilization).

The ratio of plasma aldosterone concentration to plasma renin activity has been used to screen for hyperaldosteronism. Unfortunately, this test lacks sensitivity and specificity.

Once hyperaldosteronism is diagnosed, plasma is assayed for 18-hydroxycorticosterone; a level over 85 ng/dL is seen with adrenal neoplasms, whereas levels under 85 ng/dL are nondiagnostic. Additionally, plasma can be assayed for aldosterone at 8 AM while the patient is supine after overnight recumbency and again after 4 hours upright. Patients with an adrenal adenoma usually have a baseline plasma aldosterone level greater than 20 mcg/dL that does not rise. In one study, serum aldosterone levels fell (after 4 hours upright) in 63% of patients with a unilateral aldosteronoma and in no patients with bilateral adrenal hyperplasia. Patients with hyperplasia typically have a baseline plasma aldosterone level less than 20 mcg/dL that rises during upright posture. Exceptions occur.

C. Imaging

If biochemical testing implicates an adrenal aldosterone-secreting adenoma, a thin-section CT scan of the adrenals is obtained. A discrete adrenal adenoma (> 1 cm in diameter with normal contralateral adrenal) is found is 60–80% of such patients. However, about 20% of such “adenomas” are found to be hyperplasia at surgery. A dexamethasone-suppressed 131I-labeled 6β-iodomethyl-19-norcholesterol scan (adrenal scintigraphy) can identify an aldosteronoma but may yield misleading results. Therefore, it is often prudent to supplement CT localization with adrenal vein catheterization for aldosterone.

Differential Diagnosis

The differential diagnosis of hyperaldosteronism includes other causes of hypokalemia (see Chapter 21) in patients with essential hypertension. For example, many hypertensive patients taking diuretics develop hypokalemia even while taking potassium-sparing diuretics or potassium supplements. Chronic depletion of intravascular volume stimulates renin secretion and secondary hyperaldosteronism. Thus, it is important to discontinue diuretics and ensure adequate hydration

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and sodium intake when assessing a patient for primary hyperaldosteronism (see above).

Excessive ingestion of real licorice (black and derived from anise) may produce hypertension and hypokalemia caused by a derivative of its glycyrrhizinic acid inhibiting 11β-hydroxysteroid dehydrogenase, thereby enhancing cortisol's mineralocorticoid effect. Oral contraceptives may increase aldosterone secretion in some patients. Renal vascular disease can cause severe hypertension with hypokalemia; plasma renin activity is high, distinguishing it from primary hyperaldosteronism.

Excessive adrenal secretion of other corticosteroids (besides aldosterone) may also cause hypertension with hypokalemia. This occurs with certain congenital adrenal enzyme disorders such as P-450c11 deficiency (increased deoxycorticosterone with virilization and deficient cortisol) or P-450c17 deficiency (increased deoxycorticosterone, corticosterone, and progesterone but deficient estradiol and testosterone). Primary cortisol resistance can cause hypertension and hypokalemia; renin and aldosterone are suppressed, while plasma levels of cortisol, ACTH, and deoxycorticosterone are high. Liddle's syndrome is an autosomal dominant cause of hypertension and hypokalemia resulting from excessive sodium absorption from the renal tubule; renin and aldosterone levels are low. Thyrotoxicosis and familial periodic paralysis may also present with hypokalemia. Hyperaldosteronism may rarely be due to a malignant ovarian tumor.

Complications

All of the complications of chronic hypertension are encountered in primary hyperaldosteronism. Progressive renal damage is less reversible than hypertension. Following unilateral adrenalectomy for Conn's syndrome, suppression of the contralateral adrenal may result in temporary postoperative hypoaldosteronism, characterized by hyperkalemia and hypotension.

Treatment

Conn's syndrome (unilateral adrenal adenoma secreting aldosterone) is treated by laparoscopic adrenalectomy, though lifelong spironolactone therapy is an option. Bilateral adrenal hyperplasia is best treated with spironolactone; bilateral adrenalectomy corrects the hypokalemia but not the hypertension and should not be performed. Antihypertensive agents may also be necessary. Hyperplasia sometimes responds well to dexamethasone suppression.

Prognosis

The hypertension is reversible in about two-thirds of cases but persists or returns in spite of surgery in the remainder. The prognosis is much improved by early diagnosis and treatment. Only 2% of aldosterone-secreting adrenal tumors are malignant.

The low renin levels found in this condition (and in about 25% of cases of essential hypertension) also imply a relatively good prognosis.

Al Fehaily M et al: Clinical manifestations of aldosteronoma. Surg Clin North Am 2004;84:887.

Seiler L et al: Diagnosis of primary aldosteronism: value of different screening parameters, and influence of antihypertensive medication. Eur J Endocrinol 2004;150:329.

Tiu SC et al: The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab 2005;90:72.

Vasan RS et al: Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004;351: 33.

Young WF et al: Role for adrenal venous sampling in primary aldosteronism. Surgery 2004;136:1227.

Diseases of the Adrenal Medulla

Pheochromocytoma

Essentials of Diagnosis

  • “Attacks” of headache, perspiration, palpitations.

  • Hypertension, frequently sustained but often paroxysmal, especially during surgery or delivery.

  • Attacks of nausea, abdominal pain, chest pain, weakness, dyspnea, tremor, visual disturbance.

  • Anxiety, tremor, or weight loss.

  • Elevated urinary catecholamines or their metabolites. Normal serum T4 and TSH.

General Considerations

Pheochromocytomas are rare, being found in less than 0.3% of hypertensive individuals. The incidence is higher in patients with moderate to severe hypertension. About two new cases per million population are diagnosed annually. However, in autopsy cases, the incidence of pheochromocytoma is 250–1300 cases per million, indicating that most cases are not diagnosed during life. The hypertension is caused by excessive plasma levels of norepinephrine or neuropeptide Y. Patients have disease characterized by paroxysmal or sustained hypertension due to a tumor located in either or both adrenals or anywhere along the sympathetic nervous chain, and rarely in such aberrant locations as the thorax, bladder, or brain. Primary extra-adrenal

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pheochromocytomas are known as “paragangliomas.” Pheochromocytomas are characterized by a rough “rule of tens”: About 10% of cases are not associated with hypertension; 10% of cases are extra-adrenal, and of those about 10% of cases are extra-abdominal (paraganglioma); 10% of cases occur in children. In about 10% of cases, the tumor involves both adrenal glands (bilateral adrenal tumors tend to occur more frequently in familial cases); and about 10% of cases have metastatic disease noted around the time of diagnosis. Initially occult metastases are later discovered in another 5% of cases.

Familial pheochromocytomas are usually bilateral (70% of cases) and may be associated with the following: calcitonin-secreting medullary thyroid carcinoma and hyperparathyroidism (MEN type 2), medullary thyroid carcinoma and the syndrome of multiple mucosal neuromas (MEN type 2B), neurofibromatosis (Recklinghausen's disease), and islet cell tumors (rare).

Pheochromocytomas develop in about 20% of patients with von Hippel-Lindau disease (hemangiomas of the retina, cerebellum, brainstem, and spinal cord; pancreatic cysts; renal cysts, adenomas, and carcinomas); inheritance is autosomal dominant.

Familial paragangliomas arise in patients harboring pathologic sequence variants in the succinate dehydrogenase gene subunits: SDHB, SDHC, and SDHD. Multiple paragangliomas typically arise at an early age and are often malignant.

Only about 10% of affected patients have a family history of pheochromocytoma or paraganglioma. However, family histories are unreliable and phenotypic penetrance is variable. About 20–30% of these patients harbor germline mutations, making such patients prone to development of additional tumors.

Clinical Findings

A. Symptoms and Signs

Pheochromocytomas can be lethal unless they are diagnosed and treated appropriately. They typically cause attacks of severe headache (80% of patients), perspiration (70% of patients), and palpitations (60% of patients); other symptoms may include anxiety (50% of patients), a sense of impending doom, or tremor (40% of patients). Vasomotor changes during an attack cause mottled cyanosis and facial pallor; as the attack subsides, facial flushing may occur as a result of reflex vasodilation. Other findings may include tachycardia, precordial or abdominal pain, vomiting, increasing nervousness and irritability, increased appetite, and loss of weight. Anginal attacks may occur. Physical findings usually include hypertension (90% of patients), which may be sustained (20% of patients), sustained with paroxysms (50% of patients), or paroxysmal only (25% of patients). There may be cardiac enlargement and cardiomyopathy, postural tachycardia (change of more than 20 beats/min) and postural hypotension, and mild elevation of basal body temperature. Retinal hemorrhage or cerebrovascular hemorrhage occurs occasionally.

Catastrophic hypertensive crisis and fatal cardiac arrhythmias can occur spontaneously or may be triggered by intravenous contrast dye or glucagon injection, needle biopsy of the mass, anesthesia, and surgical procedures.

The manifestations of pheochromocytoma are quite varied and mimic other conditions. Some patients are normotensive and asymptomatic. In addition to the above symptoms, some patients can present with psychosis or confusion, seizures, hyperglycemia, bradycardia, hypotension, constipation, paresthesias, or Raynaud's phenomenon. Other patients may have pulmonary edema and heart failure due to cardiomyopathy. Epinephrine secretion may cause episodic tachyarrhythmias, hypotension, or syncope. Some patients may be entirely asymptomatic despite high serum levels of catecholamines. Others may present with abdominal discomfort from a large hemorrhagic pheochromocytoma, or with pain from metastatic disease.

In addition to catecholamines and their metabolites, pheochromocytomas secrete a wide range of other peptides that can sometimes cause symptoms of Cushing's syndrome (ACTH), erythrocytosis (erythropoietin), or hypercalcemia (PTHrP).

B. Laboratory Findings

Hypermetabolism is present; thyroid function tests are normal, including serum T4, FT4, T3, and TSH. Hyperglycemia is present in about 35% of patients but is usually mild. Leukocytosis is common. The ESR is sometimes elevated. Plasma renin activity may be increased by catecholamines.

C. Special Tests

The most sensitive test for secretory pheochromocytoma is plasma fractionated free metanephrines; false-positive results are fairly common. Assay of urinary catecholamines and metanephrines (total and fractionated) and creatinine detects most pheochromocytomas, especially when samples are obtained during or immediately following an episodic attack. A 24-hour urine specimen is usually obtained, although an overnight or shorter collection may be used; patients with pheochromocytomas generally have more that 2.2 mcg of total metanephrine per milligram of creatinine, and more than 135 mcg total catecholamines per gram creatinine. Urinary assay for total metanephrines is about 97% sensitive for detecting functioning pheochromocytomas. Urinary assay for vanillylmandelic acid (VMA) is about 89% sensitive and is not usually required.

Testing for catecholamines and metanephrines should be done using high-performance liquid chromatography with electrochemical detection (HPLC-ECD); this minimizes false test results. Nevertheless, some drugs and foods can interfere with certain assays, and stresses can also cause misleading elevations in catecholamine excretion (Table 26-15). About 10% of

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hypertensive patients have a misleadingly elevated level of one or more tests.

Table 26-15. Factors potentially causing misleading catecholamine or metanephrine results: high-performance liquid chromatography with electrochemical detection (HPLC-ECD).

Drugs Foods Conditions
Acetaminophen2 Bananas1 Amyotrophic lateral sclerosis1
Aldomet2 Caffeine1  
Amphetamines1 Coffee2 Brain lesions1
Bronchodilators1 Peppers2 Carcinoid1
Buspirone2 Eclampsia1
Captopril2 Emotion, severe1
Cocaine1 Exercise, vigorous1
Cimetidine2 Guillain-Barré syndrome1
Codeine2  
Decongestants1 Hypoglycemia1
Ephedrine1 Lead poisoning1
Fenfluramine3 Myocardial infarct, acute1
Isoproterenol1  
Levodopa2 Pain, severe1
Labetalol1,2 Porphyria, acute1
Mandelamine2 Psychosis, acute1
Metoclopramide2 Quadriplegia1
Nitroglycerin1 Renal failure3
Viloxazine2  
1Increases catecholamine excretion.
2May cause confounding peaks on HPLC chromatograms.
3Decreases catecholamine excretion.

Direct assay of epinephrine and norepinephrine in blood and urine during or following an attack is a sensitive test for pheochromocytoma associated with paroxysmal hypertension. Plasma free metanephrine concentrations may also be used. Proper, quiet collection of plasma specimens is essential.

Serum chromogranin A is elevated in 90% of patients with pheochromocytoma and the levels correlate with tumor size, being higher in patients with metastatic disease. Serum chromogranin A levels can be misleadingly elevated in patients with azotemia or hypergastrinemia, and in those treated with corticosteroids or proton pump inhibitors. Serum may also be assayed for neuron-specific enolase; high levels implicate a malignant pheochromocytoma, while normal levels are nonspecific.

Pharmacologic provocative and suppressive tests that evaluate the rise or fall in blood pressure are usually not required or recommended.

Genetic testing should ideally be performed on all patients with pheochromocytoma or paraganglioma. Testing for VHL, ret protooncogene, and SDHB/SDHD mutations is advisable. Family members may then be screened for the specific gene mutation.

D. Imaging

1. CT and MRI scanning

Imaging should not usually replace biochemical testing, since incidental adrenal adenomas are common (2–4% of scans) and can be misleading. When a pheochromocytoma is suspected because of biochemical testing or a genetic condition predisposing to pheochromocytoma, a CT scan of the abdomen is performed, with thin sections through the adrenals. A noncontrast CT should be followed by a CT scan using nonionic contrast, which reduces the risk catecholamine release from a pheochromocytoma. Glucagon should not be used during scanning, since it can provoke hypertensive crisis; similarly, intravenous contrast can precipitate hypertensive crisis, particularly in patients whose hypertension is uncontrolled.

MRI scanning has the advantage of not requiring intravenous contrast dye; its lack of radiation makes it the imaging of choice during pregnancy and childhood. On T2-weighted MRI, adrenal tumors that are hyperintense relative to liver have an increased likelihood of being pheochromocytomas. Both CT and MRI scanning have a sensitivity of about 90% for adrenal pheochromocytoma and a sensitivity of 95% for adrenal tumors over 0.5 cm in diameter. However, both CT and MRI are less sensitive for detecting recurrent tumors, metastases, and extra-adrenal paragangliomas. If no adrenal tumor is found, the scan is extended to include the entire abdomen, pelvis, and chest.

2. Nuclear imaging

A whole-body [123I]m-Iodobenzylguanidine ([123I]mIBG) scan can localize tumors with a sensitivity of 85% and a specificity of 99%. It is less sensitive for MEN 2A- or MEN 2B-related pheochromocytomas. Preoperative [123I]mIBG scanning is not usually required to confirm that a unilateral adrenal mass is a pheochromocytoma in a patient with classic clinical and biochemical presentation. Preoperative whole-body [123I]mIBG scanning can be useful when the CT scan cannot locate a suspected pheochromocytoma, making a paraganglioma more likely; it can also be useful when the CT scan is ambiguous for pheochromocytoma. It is prudent to perform a whole-body [123I]mIBG scan about 3 months postoperatively to determine if metastatic or recurrent tumor is present. Drugs that reduce [123I]mIBG uptake should be avoided, including tricyclic antidepressants and cyclobenzaprine (6 weeks), amphetamines, nasal decongestants, phenothiazines, haloperidol, diet pills, labetalol, and cocaine (2 weeks).

Somatostatin receptor imaging using 111In-labeled octreotide is only 25% sensitive for detecting an adrenal pheochromocytoma. However, 111In-labeled octreotide scanning is quite sensitive for detecting extra-adrenal pheochromocytomas (paragangliomas) and metastatic pheochromocytomas, sometimes locating tumors that were missed by [123I]mIBG scanning.

PET scanning usually detects tumors using 18F-labeled deoxyglucose or 18F-labeled dopamine, and may demonstrate tumors that are not visible on [123I]mIBG scanning. Combining PET scan with

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noncontrast CT produces a PET/CT fusion scan with exceptional sensitivity.

Differential Diagnosis

Tachycardia, tremor, palpitation, and hypermetabolism may give rise to confusion with thyrotoxicosis. Pheochromocytoma may also be misdiagnosed as essential hypertension, myocarditis, glomerulonephritis or other renal lesions, toxemia of pregnancy, eclampsia, and psychoneurosis (anxiety attack). It can sometimes be mistaken for an acute abdomen.

Other conditions that have manifestations similar to those of pheochromocytoma include acute intermittent porphyria, hypogonadal vascular instability (hot flushes), cocaine or amphetamine use, clonidine withdrawal, hypertensive crisis caused by foods containing tyramine (eg, cheeses) in patients taking monoamine oxidase inhibitor antidepressants, labile hypertension, and unstable angina. Patients with erythromelalgia can have hypertensive crises; their episodic painful flushing and leg swelling are relieved by cold, distinguishing this condition from pheochromocytoma. Pheochromocytomas can cause chest pain and electrocardiographic changes that mimic acute cardiac ischemia. Renal artery stenosis can cause severe hypertension and may coexist with pheochromocytoma.

False-positive testing for catecholamines and metabolites occurs in about 10% of hypertensives, but levels are usually less than 50% above normal and typically normalize with repeat testing.

Complications

All of the complications of severe hypertension may be encountered. Additionally, a catecholamine-induced cardiomyopathy may develop. Sudden death may occur due to cardiac arrhythmia. Acute respiratory distress syndrome has been reported. Hypertensive crises with sudden blindness or cerebrovascular accidents are not uncommon. Paroxysms may be precipitated by sudden movement, by manipulation during or after pregnancy, by emotional stress or trauma, or during surgical removal of the tumor. Decongestant medications, fluoxetine, and other SSRIs may induce hypertensive paroxysms. Cardiomyopathy may develop. Occasionally, the initial manifestation of pheochromocytoma may be hypotension or even shock.

After removal of the tumor, a state of severe hypotension and shock (resistant to epinephrine and norepinephrine) may ensue with precipitation of renal failure or myocardial infarction. Hypotension and shock may occur from spontaneous infarction or hemorrhage of the tumor.

On rare occasions, a patient dies as a result of the complications of diagnostic tests or during surgery. During surgery, pheochromocytoma cells may be seeded within the peritoneum, resulting in multifocal recurrent tumors.

Treatment

Laparoscopic removal of the tumor or tumors is the treatment of choice. Very large and invasive tumors are treated with open laparotomy. Patients with small familial or bilateral pheochromocytomas may undergo selective resection of the tumors, sparing the adrenal cortex; however, there is a recurrence rate of 10% over 10 years. Preoperative administration of α-adrenergic-blocking drugs has made pheochromocytoma surgery much safer in recent years. Phenoxybenzamine is given initially in a dosage of 10 mg orally every 12 hours, increasing gradually—about every 3 days—until hypertension is controlled. The usual maintenance dose is 40–120 mg daily. Optimal α-blockade is achieved when supine arterial pressure is below 160/90 mm Hg and standing arterial pressure is above 80/45 mm Hg. Calcium channel blockers such as sustained-release nifedipine or nicardipine are also effective, are better tolerated than α-blockers, and may be coadministered with α-blockers. Labetalol therapy is avoided, since it has been associated with more postoperative hypotension, causes interference in some urinary catecholamine assays, and reduces [123I]mIBG scanning sensitivity.

After appropriate antihypertensive therapy, propranolol (10–40 mg four times orally daily), can be used to control tachycardia and other arrhythmias. Blood pressure control should be maintained for a minimum of 4–7 days or until optimal cardiac status is established. The ECG should be monitored until it becomes stable. (It may take a week or even months to correct electrocardiographic changes in patients with catecholamine myocarditis, and it may be prudent to defer surgery until then in such cases.) Patients must be very closely monitored during surgery to promptly detect sudden changes in blood pressure or cardiac arrhythmias.

Hypertensive crisis can be managed initially with oral nifedipine 10 mg (chewed pierced capsule). Intraoperative severe hypertension is managed with continuous intravenous nicardipine (a short-acting calcium channel blocker), 2–6 mcg/kg/min, or nitroprusside, 0.5–10 mcg/kg/min. Prolonged nitroprusside administration can cause cyanide toxicity. Tachyarrhythmia is treated with intravenous atenolol (1 mg boluses), esmolol, or lidocaine.

Autotransfusion of 1–2 units of blood at 12 hours preoperatively plus generous intraoperative volume replacement reduces the risk of postresection hypotension caused by desensitization of the vascular α1-receptors. Shock may therefore occur following removal of the pheochromocytoma. It is treated with intravenous saline or colloid and high doses of intravenous norepinephrine. Intravenous 5% dextrose is infused postoperatively to prevent hypoglycemia.

Because there may be multiple or metastatic tumors, it is essential to recheck urinary catecholamine levels postoperatively (at least 2 weeks after surgery). It is also prudent to perform a whole-body [123I]mIBG scan about 3 months postoperatively, since previously undetected metastases may become visible. Thereafter, blood pressure and symptoms must be rechecked regularly

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for life; urinary catecholamines and metanephrines are also rechecked regularly, at least every 6 months for 5 years, and immediately if hypertension or symptoms recur or if metastases are evident.

For inoperable or metastatic tumors, metyrosine may be added to reduce catecholamine synthesis. Metyrosine is a competitive blocker in the synthesis of catecholamines that is also useful; the initial dosage is 250 mg four times daily, increased daily by increments of 250–500 mg to a maximum of 4 g/d. Metyrosine causes central nervous system side effects and crystalluria; hydration must be ensured. Metastatic pheochromocytomas may be treated with combination chemotherapy (eg, cyclophosphamide, vincristine, and dacarbazine) or with high doses of [131I]mIBG.

Prognosis

The prognosis depends on how early the diagnosis is made. The malignancy of a pheochromocytoma cannot be determined by histologic examination. A tumor is considered malignant if metastases are present; this may take many years to become clinically evident. Therefore, lifetime surveillance is required. Malignancy is more likely for paragangliomas and for large pheochromocytomas (> 7 cm in diameter). The prognosis is good for patients with smaller, benign pheochromocytomas that are resected before causing cardiovascular damage. Hypertension usually resolves after successful surgery, but may persist or return in 25% of patients despite successful surgery. Although this may be essential hypertension, biochemical reevaluation is then required, looking for a second or metastatic pheochromocytoma.

Before the advent of blocking agents, the surgical mortality rate was as high as 30%, but this has rapidly decreased. A team approach—endocrinologist, anesthesiologist, and surgeon—is critically important. With optimal management, the surgical mortality rate is less than 3%.

Patients with metastatic pheochromocytoma and paraganglioma have a 5-year survival rate of 44% after surgery; patients who have their primary tumor resected and subsequently receive high-dose [131I]mIBG therapy have been reported to have a 5-year survival rate of 75%. Patients with a heavy and increasing tumor burden and distant metastases have a worse prognosis; patients with multiple pulmonary metastases have limited survival. Those with metastases limited to the abdomen have a better prognosis. Some patients have an indolent malignancy and experience a prolonged survival.

Ilias I et al: Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 2004;89:479.

Kercher KW et al: Laparoscopic curative resection of pheochromocytomas. Ann Surg 2005;241:919.

Khorram-Manesh A et al: Mortality associated with pheochromocytoma in a large Swedish cohort. Eur J Surg Oncol 2004; 30:556.

Lenders JW et al: Phaeochromocytoma. Lancet 2005;366:665.

Neumann HP et al: Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943.

Rose B et al: High-dose 131I-metaiodobenzylguanadine therapy for 12 patients with malignant pheochromocytoma. Cancer 2003;98:239.

Pancreatic & Duodenal Neuroendocrine Tumors*

Islet Cell Tumors

Essentials of Diagnosis

  • Half the tumors are nonsecretory; weight loss, abdominal pain, or jaundice may be presenting signs.

  • Secretory tumors cause a variety of manifestations depending upon the hormones secreted.

General Considerations

The pancreatic islets are composed of several types of cells, each with distinct chemical and microscopic features: the A cells (20%) secrete glucagon, the B cells (70%) secrete insulin, and the D cells (5%) secrete somatostatin or gastrin. F cells secrete “pancreatic polypeptide.” Each type of cell may give rise to benign or malignant neoplasms that may be multiple and usually present with a clinical syndrome related to hypersecretion of a native or ectopic hormonal product. The endocrine diagnosis of a particular pancreatic islet neoplasm depends on first suspecting it from its clinical manifestations. Many tumors secrete two or more different hormones.

Insulinomas are usually (about 82%) benign and secrete excessive amounts of insulin (as well as proinsulin and C-peptide), which causes hypoglycemia. The tumors may be multiple, especially in familial MEN 1—about 12% of cases (see Chapter 27).

Gastrinomas secrete excessive quantities of the hormone gastrin (as well as “big” gastrin), which stimulates the stomach to hypersecrete acid, thereby causing hyperplastic gastric rugae and peptic ulceration (Zollinger-Ellison syndrome). Most gastrinomas are benign, but some are malignant and metastasize to the liver. Gastrinomas are typically found in the duodenum (49%), pancreas (24%), or lymph nodes (11%).

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Presenting symptoms and signs include abdominal pain (75%), diarrhea (73%), heartburn (44%), bleeding (25%), or weight loss (17%). Endoscopy usually discovers prominent gastric folds (94%). Sporadic Zollinger-Ellison syndrome is rarely suspected at the onset of symptoms; typically, there is a 5-year delay in diagnosis. About 22% of patients have MEN 1. MEN 1 usually presents in patients who are younger; hyperparathyroidism may occur from 14 years preceding the Zollinger-Ellison diagnosis to 38 years afterward. (See Multiple Endocrine Neoplasia, below.) Therapy with high doses of proton pump inhibitors (quadruple usual doses) is usually effective. Surgery is not usually performed because of the low cure rates, particularly in patients with MEN 1. Note that serum gastrin levels tend to be high in any patient who is taking a proton pump inhibitor; hypercalcemia also stimulates gastrin release.

The 5-, 10-, and 20-year survival rates with MEN 1 are 94%, 75%, and 58%, respectively, while the survival rates for sporadic Zollinger-Ellison syndrome are 62%, 50%, and 31%, respectively. (See Chapter 14.)

Glucagonomas are usually malignant; weight loss and liver metastases are ordinarily present by the time of diagnosis. They usually secrete other hormones besides glucagon, often gastrin. Other initial symptoms often include diarrhea, nausea, peptic ulcer, or necrolytic migratory erythema. About 35% of patients ultimately develop diabetes. The median survival is 2.8 years after diagnosis.

Somatostatinomas are very rare and are associated with weight loss, diabetes mellitus, malabsorption, and hypochlorhydria.

Other rare tumors secrete excessive amounts of vasoactive intestinal polypeptide (VIP), a substance that causes profuse watery diarrhea (Verner-Morrison syndrome). Treatment with octreotide improves the symptoms but does not halt tumor growth. Symptomatic improvement with calcitonin treatment has also been reported.

Islet cell tumors can secrete ectopic hormones in addition to native hormones, often in combinations producing a variety of clinical syndromes. They may secrete ACTH, producing Cushing's syndrome. Secretion of serotonin can produce an atypical carcinoid syndrome manifested by pain, diarrhea, and weight loss; skin flushing occurs in only 39% of patients. Pancreatic carcinoid tumors grow slowly but usually metastasize to local and distant sites, particularly to other endocrine organs.

Islet cell tumors may be part of the syndrome of multiple endocrine adenomatosis type I (with pituitary and parathyroid adenomas).

Localization of noninsulinoma pancreatic islet cell tumors and their metastases is best done with somatostatin receptor scintigraphy (SRS); SRS detects about 75% of noninsulinomas. CT and MRI are also useful. Insulinomas can usually be located preoperatively by endoscopic ultrasonography. For insulinomas, preoperative localization studies are less successful and have the following sensitivities: ultrasonography 25%, CT 25%, endoscopic ultrasonography 27%, transhepatic portal vein sampling 40%, arteriography 45%, intraoperative palpation 55%, and intraoperative pancreatic ultrasound 75%. Nearly all insulinomas can be successfully located at surgery by intraoperative palpation and ultrasound. An abdominal CT scan is usually obtained, but extensive preoperative localization procedures, especially with invasive methods, are not required. Tumors may be located in the pancreatic head or neck (57%), body (15%), or tail (19%) or in the duodenum (9%).

Direct resection of the tumor (or tumors), which often spreads locally, is the primary form of therapy for all types of islet cell neoplasm except Zollinger-Ellison syndrome, where use of high doses of a proton pump inhibitor is the therapy of choice. Insulinomas are resected. However, in MEN 1, insulinomas are rarely cured, so surgery is reserved for dominant masses in such cases. Palliation of functioning malignant disease often requires both antihormonal and anticancer chemotherapy. The use of streptozocin, doxorubicin, and asparaginase, especially for malignant insulinoma, has produced some encouraging results, though these drugs are quite toxic. The hypoglycemia of insulinoma may be counteracted by verapamil or diazoxide. Octreotide LAR is useful in the therapy of islet cell tumors with the exception of insulinoma; monthly subcutaneous injections of 20–30 mg are required.

The prognosis in these neoplasms is variable. The surgical complication rate is about 40%, with patients commonly developing fistulas and infections. Extensive pancreatic resection may cause diabetes mellitus. The overall 5-year survival is higher with functional tumors (77%) than with nonfunctional ones (55%) and higher with benign tumors (91%) than with malignant ones (55%).

Footnote

*Diabetes mellitus and hyperglycemia are discussed in Chapter 27.

Finlayson E et al: Surgical treatment of insulinomas. Surg Clin North Am 2004;84:775.

Hirshberg B et al: Malignant insulinoma: spectrum of unusual clinical features. Cancer 2005;104:264.

Norton JA et al: Resolved and unresolved controversies in the surgical management of patients with Zollinger-Ellison syndrome. Ann Surg 2004;240:757.

Warner RR: Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology 2005;128:1668.

Diseases of the Testes

Male Hypogonadism

Essentials of Diagnosis

  • Diminished libido and erections.

  • Decreased growth of body hair.

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  • Testes may be small or normal in size. Serum testosterone is usually decreased.

  • Serum gonadotropins (LH and FSH) are decreased in hypogonadotropic hypogonadism; they are increased in testicular failure (hypergonadotropic hypogonadism).

General Considerations

Male hypogonadism is caused by deficient testosterone secretion by the testes. It may be classified according to whether it is due to (1) insufficient gonadotropin secretion by the pituitary (hypogonadotropic) or (2) pathology in the testes themselves (hypergonadotropic) (Table 26-16). The evaluation for hypogonadism begins with a serum testosterone or free testosterone measurement. A low serum testosterone is evaluated with serum LH and FSH levels. Patients with low gonadotropins are further evaluated for other pituitary abnormalities, including hyperprolactinemia.

Etiology

A. Hypogonadotropic Hypogonadism

A deficiency in FSH and LH may be isolated or associated with other pituitary hormonal abnormalities. (See Hypopituitarism.) Patients must be evaluated for signs of Cushing's syndrome or adrenal insufficiency, growth hormone excess or deficiency, and thyroid hormone excess or deficiency.

Table 26-16. Causes of male hypogonadism.

Hypogonadotropic (Low or Normal LH) Hypergonadotropic (High LH)
Alcohol Antitumor chemotherapy
Chronic illness Bilateral anorchia
Congenital syndromes Idiopathic
Constitutional delay Klinefelter's syndrome
Cushing's syndrome Leprosy
Drugs Lymphoma
Estrogen-secreting tumors (testicular, adrenal) Male climacteric
Mumps
GnRH agonist (leuprolide) Myotonic dystrophy
Hemochromatosis Noonan's syndrome
Hypopituitarism Orchitis
Hypothyroidism Radiation therapy
Idiopathic Sertoli cell-only syndrome
Kallmann's syndrome Testicular trauma
Ketoconazole Tuberculosis
17-Ketosteroid reductase deficiency Uremia
Malnourishment
Marijuana
Obesity (BMI > 40)
Prader-Willi syndrome
Prior androgens
Spironolactone
GnRH = gonadotropin-releasing hormone; BMI = body mass index.

Acquired hypogonadotropic hypogonadism may be due to pituitary or hypothalamic factors but may be idiopathic. Hyperprolactinemia (see Table 26-4) may also induce hypogonadism.

Hypogonadotropic hypogonadism can develop in men receiving GnRH agonist therapy for prostate cancer and can persist following cessation of therapy.

B. Hypergonadotropic Hypogonadism

A failure in testicular secretion of testosterone causes a rise in LH. If testicular Sertoli cell function is deficient, FSH will be elevated. Conditions that can cause testicular failure include viral infection (eg, mumps), irradiation, cancer chemotherapy, autoimmunity, myotonic dystrophy, uremia, XY gonadal dysgenesis, partial 17-ketosteroid reductase deficiency, Klinefelter's syndrome, and male climacteric.

Klinefelter's syndrome (seminiferous tubule dysgenesis) is a common cause of male hypogonadism that is due to the expression of an abnormal karyotype, classically 47,XXY. Other forms are common, eg, 46,XY/47,XXY mosaicism, 48,XXYY, 48,XXXY, or 46,XX males.

The manifestations of Klinefelter's syndrome are variable. Testes feel normal during childhood, but during adolescence they usually become firm, fibrotic, small, and nontender to palpation. Although puberty occurs at the normal time, the degree of virilization is variable. About 85% of patients have some gynecomastia at puberty.

Other common findings include tall stature and abnormal body proportions that are unusual for hypogonadal men (height greater than arm span; crown-pubis length greater than pubis-floor). Patients with multiple X or Y chromosomes are more apt to have mental deficiency and other abnormalities such as clinodactyly or synostosis. They may also exhibit problems with coordination and social skills. Other problems include a higher incidence of breast cancer, chronic pulmonary disease, varicosities of the legs, and diabetes mellitus (8% of patients); impaired glucose tolerance occurs in an additional 19% of patients.

Most men (about 95%) have azoospermia, but men with 46,XY/47,XXY mosaicism may be fertile. The diagnosis is confirmed by karyotyping or by determining the presence of RNA for X-inactive-specific transcriptase (XIST) in peripheral blood leukocytes by polymerase chain reaction.

The serum testosterone is low, and FSH and LH are elevated. Sometimes the serum testosterone is normal, but serum free testosterone is usually low.

All causes of gynecomastia (see Table 26-1) must be differentiated from Klinefelter's syndrome.

C. Androgen Insensitivity

Partial resistance to testosterone is a rare condition in which phenotypic males have variable degrees of apparent

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hypogonadism, hypospadias, cryptorchism, and gynecomastia. Serum testosterone levels are normal.

Clinical Findings

A. Symptoms and Signs

Hypogonadism that is congenital or acquired during childhood presents as delayed puberty. Men with acquired hypogonadism have variable manifestations. Most men experience decreased libido. Others complain of erectile dysfunction, hot sweats, fatigue, or depression. Their presenting complaint may also be infertility, gynecomastia, headache, fracture, or other symptoms related to the cause or result of the hypogonadism. The patient's history often gives a clue to the cause (Table 26-16).

Physical signs associated with hypogonadism may include decreased body, axillary, beard, or pubic hair; such diminished sexual hair growth is not reliably present except after years of severe hypogonadism. Men in whom hypogonadism develops tend to lose muscle mass and gain weight due to an increase in subcutaneous fat. Examination should include measurements of arm span and height. Testicular size should be assessed with an orchidometer (normal volume is about 10–25 mL; normal length is usually over 6 cm). Testicular size may decrease but usually remains within the normal range in men with postpubertal hypogonadotropic hypogonadism, but it may be diminished with testicular injury or Klinefelter's syndrome. The testes must also be carefully palpated for masses, since Leydig cell tumors may secrete estrogen and present with hypogonadism. The testicles must be carefully examined for evidence of trauma, infiltrative lesions (eg, lymphoma), or ongoing infection (eg, leprosy, tuberculosis).

B. Laboratory Findings

The hemoglobin and hematocrit may be slightly below the male range due to hypogonadism.

To evaluate a man for hypogonadism, the morning serum total testosterone concentration is determined. Normal ranges for serum testosterone have been derived from nonfasting morning blood specimens, which tend to be the highest of the day. Later in the day, serum testosterone levels can be 25–50% lower. Therefore, a serum testosterone drawn fasting or late in the day may be misleadingly below the “normal range.” Serum testosterone levels in men are highest at age 20–30 years and slightly lower at age 30–40 years; testosterone falls gradually but progressively after age 40 years. Elderly men have higher levels of SHBG, with consequently lower levels of free testosterone. Newer automated chemiluminescent assays measure serum total testosterone less accurately than older radioimmunoassays. Chemiluminescent kit assays tend to suffer interference from hyperlipidemia and also generally underestimate serum testosterone levels. Very low serum testosterone levels, measured by chemiluminescent assay, accurately diagnose severe male hypogonadism; however, mildly low serum testosterone levels should be viewed skeptically and repeated, along with an assay for free testosterone (see below).

Only about 2% of serum testosterone circulates free from protein binding. About 98% of serum testosterone is bound to either SHBG or albumin. Serum testosterone is tightly bound to SHBG and not available to tissues, whereas testosterone is weakly bound to albumin and is bioavailable to tissues. Assays that measure both free testosterone and non-SHBG testosterone are described as assays for “free and weakly bound testosterone.” Testing for serum free testosterone is especially important for detecting hypogonadism in elderly men, who generally have high levels of SHBG. Different assay methodologies for free testosterone are in use. Assays using equilibrium dialysis, calculated free testosterone, and non-SHBG-bound testosterone are reasonably accurate. However, the free androgen index, direct radioimmunoassay, and analog free testosterone assays are inaccurate.

In patients with low or borderline-low serum testosterone levels, serum LH and FSH should be measured. LH and FSH tend to be high in patients with hypergonadotropic hypogonadism but low or inappropriately normal in men with hypogonadotropic hypogonadism. Testosterone stimulates erythropoiesis in men, causing the normal red blood count range to be higher in men than in women; mild anemia is common in men with hypogonadism, with red blood counts below the normal male range. For men with long-standing male hypogonadism, bone densitometry is recommended. Men with severe osteoporosis may require treatment with bisphosphonates and vitamin D, in addition to testosterone replacement therapy. (See Osteoporosis section.)

1. Hypogonadotropic hypogonadism

Men with hypogonadotropic hypogonadism have low serum testosterone

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levels without a compensatory increase in gonadotropins. A serum PRL determination is obtained but may be elevated for many reasons (see Table 26-4). Men with gynecomastia may be screened for partial 17-ketosteroid reductase deficiency with serum determinations for androstenedione and estrone, which are elevated in this condition. X-linked congenital adrenal hypoplasia is a rare condition in which a DAX-1 gene mutation causes hypogonadotropic hypogonadism and azoospermia, which usually presents in adolescence; the associated primary adrenal insufficiency usually presents in childhood, but it may remain undiagnosed into adulthood. The serum estradiol level may be elevated in patients with cirrhosis and in rare cases of estrogen-secreting tumors (testicular Leydig cell tumor or adrenal carcinoma). Men with no discernible definite cause for hypogonadotropic hypogonadism should be screened for hemochromatosis and have an MRI of the pituitary and hypothalamic region to look for a tumor or other lesion. (See Hypopituitarism.)

2. Hypergonadotropic hypogonadism

Men with hypergonadotropic hypogonadism have low serum testosterone levels with a compensatory increase in gonadotropins. Klinefelter's syndrome can be confirmed by karyotyping or by measurement of leukocyte XIST. Testicular biopsy is usually reserved for younger patients in whom the reason for primary hypogonadism is unclear.

Treatment

Testosterone replacement is ordinarily commenced once the diagnosis of hypogonadism is confirmed and the cause determined. It is prudent to screen older men for prostate cancer before testosterone therapy is begun. Testosterone helps reverse sexual dysfunction and muscle atrophy. Men with Klinefelter's syndrome have a reduced risk of developing verbal fluency problems if testosterone therapy is begun at the time of normal puberty.

Topical testosterone gel has become the preferred method for administering testosterone. Topical 1% testosterone gel is commercially available as Androgel or Testim (2.5-g and 5-g packets); Androgel is odorless, while Testim has a musky odor. The starting dose is 5 g (50 mg testosterone) applied once daily to clean, dry skin of the shoulders, upper arms, or abdomen. The skin serves as a reservoir that slowly releases about 10% of the testosterone into the blood; serum testosterone levels reach a steady state in 1–3 days. The gel should not be applied to the genitals. The entire contents of a packet are squeezed onto the palm and then immediately applied. The hands should be washed and the application site allowed to dry for 3–5 minutes before dressing. A shirt must be worn during contact with women or children to prevent transfer of testosterone to them. The serum testosterone level should be determined about 14 days after starting therapy; if the level remains below normal or the clinical response is inadequate, the dose may be increased to 7.5 g or 10 g.

Testosterone transdermal systems (skin patches) are available in two formulations for application to nongenital skin. The testosterone may be mixed with the adhesive (eg, Testoderm II, 5 mg/d) with a new patch applied daily to a different site; this system leaves a sticky residue but causes little skin irritation. A different patch uses testosterone in a reservoir system applied to skin (eg, Androderm); this system adheres more tightly to the skin but may cause more skin irritation. Both produce reliable serum levels of testosterone that are somewhat lower that those achieved with injections. The patch systems also suffer from being rather inconvenient and expensive.

Hypogonadism may also be treated with parenteral testosterone (enanthate or cypionate). The usual dose is about 300 mg intramuscularly every 3 weeks or 200 mg every 2 weeks. The preparation is oil based and is usually given in the gluteal area. The dose is adjusted according to the patient's response.

Oral androgen preparations include methyltestosterone and fluoxymesterone. These oral preparations have rarely caused liver tumors or peliosis hepatis with long-term use. Cholestatic jaundice occurs in 1–2% of patients but usually remits after the medication is discontinued. The oral androgens are not as effective as parenteral testosterone.

Men with mosaic Klinefelter's syndrome (eg, 46,XY/47,XXY) may be fertile. However, men with nonmosaic Klinefelter's syndrome (eg, 47,XXY) are usually azoospermic; fertility may be achieved by testicular sperm retrieval and in vitro intracytoplasmic sperm injection (ICSI) into an ovum.

Men with hypogonadotropic hypogonadism must receive further evaluation and specific treatment (see Hypopituitarism).

Testosterone replacement therapy may cause a minimal reduction in serum HDL levels and has no effect on LDL levels; testosterone therapy has never been demonstrated to increase the incidence of cardiovascular disease, myocardial infarction, or stroke.

Testosterone therapy can aggravate benign prostatic hypertrophy (BPH). However, aggravation of voiding problems is uncommon. In men with BPH, finasteride may be coadministered with testosterone to reduce prostate size. The incidence of prostate cancer does not appear to be increased by testosterone therapy. However, testosterone therapy is contraindicated in the presence of active prostate cancer. It is prudent to monitor serum prostate-specific antigen (PSA) levels before and during testosterone therapy. Hypogonadal men who have had a prostatectomy for low-grade prostate cancer, and who have remained in complete remission for several years, may have testosterone therapy given cautiously while monitoring sensitive serum PSA levels.

Erythrocytosis develops in some men who are treated with testosterone. Erythrocytosis is more common with intramuscular injections of testosterone enanthate than with transcutaneous testosterone. It is particularly common in men receiving intramuscular testosterone enanthate in doses of 200 mg intramuscularly every 2 weeks. However, no increase in the incidence of thromboembolic events has been reported.

Testosterone therapy tends to aggravate sleep apnea in older men, likely through central nervous system effects. Surveillance for sleep apnea is recommended during testosterone therapy and a formal evaluation with nocturnal pulse oximetry recording is recommended for all high-risk patients. A man's risk for sleep apnea may be approximated by determining an “adjusted neck circumference” with the following algorithm: Measure the neck circumference in centimeters; add 4 cm if the patient is hypertensive; add 3 cm if the patient snores; add 3 cm if the patient chokes or gasps most nights. Adjusted neck circumference: < 43 = low risk; 43–48 = moderate risk; > 48 = high risk.

Men who are treated with testosterone frequently experience some increase in acne, which is usually mild and tolerated; topical antiacne therapy or a reduction in testosterone replacement dosage may be required. During the initiation of testosterone replacement

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therapy, gynecomastia develops in some men, which usually is mild and tends to resolve spontaneously; switching from testosterone injections to testosterone transdermal gel may help this condition.

Prognosis of Male Hypogonadism

If hypogonadism is due to a pituitary lesion, the prognosis is that of the primary disease (eg, tumor, necrosis). The prognosis for restoration of virility is good if testosterone is given.

Bojesen A et al: Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004;89:3830.

Greenstein A et al: Does sildenafil combined with testosterone gel improve erectile dysfunction in hypogonadal men in whom testosterone supplement therapy alone failed? J Urol 2005; 173:530.

Lanfranco F et al: Klinefelter's syndrome. Lancet 2004;364:273.

Matsumoto AM et al: Serum testosterone assays—accuracy matters. J Clin Endocrinol Metab 2004;89:529.

Rhoden EL et al: Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350: 482.

Wang C et al: Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2004;89:534.

Testicular Tumors in Adults (See also Chapter 23)

About 95% of testicular tumors are germ cell tumors (seminomas or nonseminomas). Seminomas do not produce α-fetoprotein, but about 5–10% produce some hCG. Nonseminomas, on the other hand, produce increased serum levels of one or both of these markers in about 90% of cases. Men with liver disease may have misleadingly high levels of α-fetoprotein. Most germ cell tumors are sensitive to cisplatin-based combined chemotherapy. Sperm banking is advised.

About 5% of testicular tumors are Leydig or Sertoli cell tumors. Leydig cell tumors tend to produce estrogen (75%) and cause gynecomastia and impotence on that basis; they may sometimes produce androgens that can cause pseudoprecocious puberty in boys. Sertoli cell tumors may also produce estrogen (30%) with feminization; gynecomastia may be due to hCG secretion (25%).

Some testicular tumors may be small and nonpalpable yet may secrete sufficient amounts of hCG or estrogen to cause gynecomastia or impotence. Testicular ultrasound may help reveal small tumors.

After unilateral orchiectomy for testicular cancer, an elevated FSH level prior to further treatment indicates a patient at higher risk for cancer in the remaining testis.

Garner MJ et al: Epidemiology of testicular cancer: an overview. Int J Cancer 2005;116:331.

Hussain A: Germ cell tumors. Curr Opin Oncol 2005;17:268.

Huyghe E et al: Fertility after testicular cancer treatments: results of a large multicenter study. Cancer 2004;100:732.

Oosterhuis JW et al: Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer 2005;5:210.

Amenorrhea & Menopause (See also Chapter 17)

Primary Amenorrhea

Menarche ordinarily occurs between ages 11 and 15 years (average in the United States: 12.7 years). The failure of any menses to appear is termed primary amenorrhea, and evaluation is commenced (1) at age 14 years if neither menarche nor breast development has occurred or if height is in the lowest 3%, or (2) at age 16 years if menarche has not occurred.

Etiology of Primary Amenorrhea

The causes of primary amenorrhea include hypothalamic-pituitary causes, hyperandrogenism, ovarian causes, pseudohermaphroditism, uterine causes, and pregnancy.

A. Hypothalamic-Pituitary Causes (with Low or Normal FSH)

A genetic deficiency of GnRH and gonadotropins may be isolated or associated with other pituitary deficiencies or diminished olfaction (Kallmann's syndrome). Hypothalamic lesions, particularly craniopharyngioma, may be present. Pituitary tumors may be nonsecreting or may secrete PRL or GH. Cushing's syndrome may be caused by corticosteroid treatment, a cortisol-secreting adrenal tumor, or an ACTH-secreting pituitary tumor. Hypothyroidism can delay adolescence. Head trauma or encephalitis can cause gonadotropin deficiency. Primary amenorrhea may also be caused by constitutional delay of adolescence, organic illness, vigorous exercise (eg, ballet dancing, running), stressful life events, dieting, or anorexia nervosa; however, these conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. (See section on Hypopituitarism.)

B. Hyperandrogenism (with Low or Normal FSH)

Excess testosterone may be secreted by adrenal tumors or by adrenal hyperplasia caused by steroidogenic enzyme defects such as P-450c21 deficiency (salt-wasting) or P-450c11 deficiency (hypertension). Ovarian tumors or polycystic ovaries may also secrete excess testosterone. Androgenic steroids may also cause this syndrome.

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C. Ovarian Causes (with High FSH)

Gonadal dysgenesis (Turner's syndrome and variants; see below) is a frequent cause of primary amenorrhea. Ovarian failure due to autoimmunity is a common cause. Rare deficiencies in certain ovarian steroidogenic enzymes are causes of primary hypogonadism without virilization: 3β-hydroxysteroid dehydrogenase deficiency (adrenal insufficiency with low serum 17-hydroxyprogesterone) and P-450c17 deficiency (hypertension and hypokalemia with high serum 17-hydroxyprogesterone). A whole-body deficiency in P-450 aromatose (P-450arom) activity produces female hypogonadism associated with polycystic ovaries, tall stature, osteoporosis, and virilization.

D. Pseudohermaphroditism (with High LH)

An enzymatic defect in testosterone synthesis may present as a sexually immature phenotypic girl with primary amenorrhea. Complete androgen resistance (testicular feminization) presents as a phenotypic young woman without sexual hair but with normal breast development and primary amenorrhea. In both cases, the uterus is absent and testes are intra-abdominal or cryptorchid. Intra-abdominal testes are surgically resected. Such patients are treated as normal but infertile, hypogonadal women.

E. Uterine Causes (with Normal FSH)

Congenital absence or malformation of the uterus may be responsible for primary amenorrhea, as may an unresponsive or atrophic endometrium. An imperforate hymen is occasionally the reason for the absence of visible menses.

F. Pregnancy (with High hCG)

Pregnancy may be the cause of primary amenorrhea even when the patient denies ever having had sexual intercourse.

Clinical Findings

A. Symptoms and Signs

Patients with primary amenorrhea require a thorough history and physical examination to look for signs of the conditions noted above. Headaches or visual field abnormalities implicate a hypothalamic or pituitary tumor. Signs of pregnancy may be present. Blood pressure abnormalities, acne, and hirsutism should be noted. Short stature may be seen with an associated growth hormone or thyroid hormone deficiency. Short stature with manifestations of gonadal dysgenesis indicates Turner's syndrome (see below). Olfaction testing screens for Kallmann's syndrome. Obesity and short stature may be signs of Cushing's syndrome. Tall stature may be due to eunuchoidism or gigantism. Hirsutism or virilization suggests excessive testosterone.

An external pelvic examination plus a rectal examination should be performed to assess hymenal patency and the presence of a uterus.

B. Laboratory Findings

The initial endocrine evaluation should include serum determinations of FSH, LH, PRL, testosterone, TSH, FT4, and hCG (pregnancy test). Patients who are virilized or hypertensive require serum electrolyte determinations and further hormonal evaluation. Girls with low-normal FSH and LH—especially those with high PRL levels—are evaluated by MRI of the hypothalamus and pituitary. Girls who have a normal uterus and high FSH without the classic features of Turner's syndrome may require a karyotype to diagnose X chromosome mosaicism.

Treatment

Treatment of primary amenorrhea is directed at the underlying cause. Girls with permanent hypogonadism are treated with estrogen replacement therapy (see below).

Torstveit MK et al: Participation in leanness sports but not training volume is associated with menstrual dysfunction: a national survey of 1276 elite athletes and controls. Br J Sports Med 2005;39:141.

Warren MP et al: The genetics, diagnosis and treatment of amenorrhea. Minerva Ginecol 2004;56:437.

Secondary Amenorrhea & Menopause

Secondary amenorrhea is defined as the absence of menses for 3 consecutive months in women who have passed menarche. Menopause is defined as the terminal episode of naturally occurring menses; it is a retrospective diagnosis, usually made after 6 months of amenorrhea.

Etiology

The causes of secondary amenorrhea include pregnancy, hypothalamic-pituitary causes, hyperandrogenism, uterine causes, premature ovarian failure, and menopause.

A. Pregnancy (High hCG)

Pregnancy is the most common cause for secondary amenorrhea in women of childbearing age. The differential diagnosis includes rare ectopic secretion of hCG by a choriocarcinoma or bronchogenic carcinoma.

B. Hypothalamic-Pituitary Causes (with Low or Normal FSH)

The hypothalamus must release GnRH in a pulsatile manner for the pituitary to secrete gonadotropins. GnRH pulses occurring more than once per hour favor LH secretion, while less frequent pulses favor FSH secretion. In normal ovulatory cycles, GnRH pulses in the follicular phase are rapid and favor LH synthesis and ovulation; ovarian luteal progesterone is then secreted that slows GnRH pulses, causing FSH

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secretion during the luteal phase. Most women with hypothalamic amenorrhea have a persistently low frequency of GnRH pulses.

Secondary “hypothalamic” amenorrhea may be caused by stressful life events such as school examinations or leaving home. Such women usually have a history of normal sexual development and irregular menses since menarche. Amenorrhea may also be the result of strict dieting, vigorous exercise, organic illness, or anorexia nervosa. Intrathecal infusion of opioids causes amenorrhea in most women. These conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. Young women in whom the results of evaluation and progestin withdrawal test are normal have noncyclic secretion of gonadotropins resulting in anovulation. Such women typically recover spontaneously but should have regular evaluations and a progestin withdrawal test about every 3 months to detect loss of estrogen effect.

PRL elevation due to any cause (see section on hyperprolactinemia) may cause amenorrhea. Pituitary tumors or other lesions may cause hypopituitarism. Corticosteroid excess of any cause suppresses gonadotropins.

C. Hyperandrogenism (with Low-Normal FSH)

Elevated serum levels of testosterone can cause hirsutism, virilization, and amenorrhea. In PCOS, GnRH pulses are persistently rapid, favoring LH synthesis with excessive androgen secretion; reduced FSH secretion impairs follicular maturation. Progesterone administration can slow the GnRH pulses, thus favoring FSH secretion that induces follicular maturation. Rare causes include adrenal P-450c21 deficiency, ovarian or adrenal malignancies, ectopic ACTH secretion by a malignancy, and Cushing's disease. Anabolic steroids also cause amenorrhea.

D. Uterine Causes (with Normal FSH)

Infection of the uterus commonly occurs following delivery or D&C but may occur spontaneously. Endometritis due to tuberculosis or schistosomiasis should be suspected in endemic areas. Endometrial scarring may result, causing amenorrhea (Asherman's syndrome). Such women typically continue to have monthly premenstrual symptoms. The vaginal estrogen effect is normal. Diagnosis and treatment are best done by direct hysteroscopic inspection of the endometrium and lysis of adhesions. A small Foley catheter is left in the uterus for 1 week while antibiotics are given. The catheter is then replaced by an intrauterine device (IUD) for about 2 months. Cyclic estrogen and progestin are given to build up the endometrial lining. After such treatment, menses usually resume and fertility is possible, but spontaneous abortions and other pregnancy complications occur commonly.

E. Premature Ovarian Failure (with High FSH)

This refers to primary hypogonadism that occurs before age 40 years. It affects about 1% of women. About 30% of such cases are due to autoimmunity against the ovary. About 8% of cases are due to X chromosome mosaicism. Other causes include surgical bilateral oophorectomy, radiation therapy for pelvic malignancy, and chemotherapy. Women who have undergone hysterectomy are prone to premature ovarian failure even though the ovaries were left intact. Myotonic dystrophy, galactosemia, and mumps oophoritis are additional causes. Other cases may be familial or idiopathic. Ovarian failure is usually irreversible. Treatment consists of estrogen replacement therapy plus a progestin if the uterus is present.

F. Menopause (with High FSH)

“Climacteric” is defined as the period of natural physiologic decline in ovarian function, generally occurring over about 10 years. By about age 40 years, the remaining ovarian follicles are those that are the least sensitive to gonadotropins. Increasing titers of FSH are required to stimulate estradiol secretion. Estradiol levels may actually rise during early climacteric. Frequent anovulation tends to cause menometrorrhagia (dysfunctional uterine bleeding). Fertility declines progressively. Psychological symptoms may include depression and irritability. Women may experience fatigue, insomnia, headache, diminished libido, or rheumatologic symptoms. Vasomotor instability (hot flushes) is experienced by 80% of women, lasting seconds to many minutes. Hot flushes with drenching sweats may be most severe at night or may be triggered by emotional stress. Some women continue to menstruate for many months despite symptoms of estrogen deficiency. Estrogen supplementation provides symptomatic relief.

The normal age for menopause in the United States ranges between 48 and 55 years, with an average of about 51.5 years. Serum estradiol levels fall and the remaining estrogen after menopause is estrone, derived mainly from peripheral aromatization of adrenal androstenedione. Such peripheral production of estrone is enhanced by obesity and liver disease. Individual differences in estrone levels partly explain why the symptoms noted above may be minimal in some women but severe in others. The acute symptoms of estrogen deficiency noted above tend to decline in severity within several years after menopause. However, about 35% of women have symptoms for more than 5 years. The late manifestations of estrogen deficiency include urogenital atrophy with vaginal dryness and dyspareunia; dysuria, frequency, and incontinence may occur. Increased bone osteoclastic activity increases the risk for osteoporosis and fractures. The skin becomes more wrinkled. Increases in the LDL:HDL cholesterol ratio cause an increased risk for arteriosclerosis.

Clinical Findings

A. Symptoms and Signs

All women with amenorrhea require a complete history and physical examination. Nausea and breast engorgement are typical signs of early pregnancy. Hot

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flushes are common in ovarian failure. Headache or visual field abnormalities are seen with pituitary or hypothalamic tumors. Complaints of thirst and polyuria require evaluation; diabetes insipidus implicates a hypothalamic lesion. Goiter may be due to hyperthyroidism. Weight loss, diarrhea, or skin darkening may indicate adrenal insufficiency. Weight loss with a distorted body image implicates anorexia nervosa. The breasts are examined carefully for galactorrhea, a common sign of hyperprolactinemia. Hirsutism or virilization may be a sign of hyperandrogenism. Manifestations of hypercortisolism (eg, weakness, psychiatric changes, hypertension, central obesity, hirsutism, thin skin, ecchymoses) may indicate alcoholism or Cushing's syndrome. Signs of acromegaly or gigantism may also indicate a pituitary tumor. Signs of systemic illness (eg, cirrhosis, renal failure) should be appreciated. Various drugs may elevate PRL and cause amenorrhea (see section on Hyperprolactinemia). Needle tracks may indicate heroin or amphetamine abuse.

A careful pelvic examination is always required to check for uterine or adnexal enlargement and to obtain a Papanicolaou smear and a vaginal smear for assessment of estrogen effect. Various life stresses, vigorous exercise, and “crash” dieting all predispose to amenorrhea; however, such factors should not be assumed to account for amenorrhea without a complete workup to screen for other causes.

B. Laboratory Findings

Since pregnancy is the most common cause of amenorrhea, women of childbearing age are immediately screened with a serum or urine hCG (pregnancy test). An elevated hCG overwhelmingly indicates pregnancy; false-positive testing may occur very rarely with ectopic hCG secretion (eg, choriocarcinoma or bronchogenic carcinoma). Women without an elevated hCG receive further laboratory evaluation including serum PRL, FSH, LH, TSH, and plasma potassium. Hyperprolactinemia or hypopituitarism (without obvious cause; see section on Hypopituitarism) should prompt an MRI study of the pituitary region. Routine testing for renal and hepatic function (eg, BUN, serum creatinine, bilirubin, alkaline phosphatase, and alanine aminotransferase) is also performed. A serum testosterone level is obtained in hirsute or virilized women. Patients with manifestations of hypercortisolism receive a 1-mg overnight dexamethasone suppression test for initial screening (see section on Cushing's syndrome). Nonpregnant women without any laboratory abnormality may receive a 10-day course of a progestin (eg, medroxyprogesterone acetate, 10 mg/d); absence of withdrawal menses typically indicates a lack of estrogen or a uterine abnormality.

Treatment

Therapy of hypogonadism generally consists of hormone replacement therapy (see below). The doses of estrogen required for symptomatic relief from vasomotor symptoms are sometimes higher than typical physiologic replacement doses. Slow, deep breathing can also ameliorate hot flushes. Tamoxifen and raloxifene offer bone protection but aggravate hot flushes. Treatment or prevention of postmenopausal osteoporosis with bisphosphonates such as alendronate, risedronate, or intravenous zoledronic acid (see section on Osteoporosis) is another therapeutic option. Women with low serum testosterone levels may experience hypoactive sexual desire disorder (HSDD) that may respond to low-dose testosterone replacement.

Estrogen Replacement Therapy

The Women's Health Initiative (WHI) monitored 16,606 postmenopausal women in the United States in a prospective, double-blinded, placebo-controlled study of postmenopausal HRT. A control group of women taking a daily placebo was compared to (1) women receiving daily conventional-dose oral combined HRT (conjugated equine estrogens [CEE] 0.625 mg/d with medroxyprogesterone acetate [MPA] 2.5 mg/d) and (2) women, having had a hysterectomy, receiving only CEE 0.625 mg/d.

The WHI risk-benefit findings (described below) have dramatically changed postmenopausal HRT. To reduce the risks of HRT, lower-dose estrogen regimens are now preferred over conventional-dose therapy. Estrogen preparations other than CEE are increasingly favored. Transdermal and vaginal estrogen preparations are now widely preferred over oral estrogen replacement. Also, the potential adverse effects of progestins are now recognized, such that women taking very low-dose estrogen replacement may receive progestin therapy only periodically, if at all. For moderate to high-dose estrogen therapy, progestins are being used in lower doses. Also, clinicians are now tending to prescribe progestins other than MPA. A progestin-eluting intrauterine device prevents endometrial hyperplasia while avoiding systemic progestin exposure.

Oral estrogen preparations include CEEs (0.3, 0.45, 0.625, 0.9, and 1.25 mg), ethinyl estradiol (20 and 50 mcg), estradiol (0.5, 1, 1.5, and 2 mg), estropipate (0.75, 1.5, 3, and 6 mg), plant-derived esterified estrogens (eg, Menest, Estratab, 0.3, 0.625, and 2.5 mg), and synthetic estrogens (eg, Cenestin, 0.3, 0.625, 0.9, and 1.25 mg).

Oral estrogen plus progestin preparations include CEE with MPA (Prempro 0.3/1.5, 0.45/1.5, 0.625/2.5, and 0.625/5), CEE for 14 days cycled with CEE plus MPA for 14 days (Premphase 0.625, 0.625/5), estradiol with norethindrone acetate (Activella 1/0.5), ethinyl estradiol with norethindrone acetate (Femhrt 1/5, 5 mcg/1 mg/tablet), and estradiol with norgestimate (Ortho-Prefest, sequences of estradiol 1 mg/d for 3 days, alternating with a combination of 1 mg estradiol/0.09 mg norgestimate daily for 3 days). Oral contraceptives can also be used for combined HRT.

Transdermal estradiol: Estradiol can be delivered systemically with different transdermal systems.

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1. Transdermal systems with estradiol mixed with adhesive: These systems tend to cause minimal skin irritation. Of the following preparations, the Vivelle-Dot patches are the smallest and least obtrusive. Available preparations include Esclim, Vivelle, and Vivelle-Dot (0.025, 0.0375, 0.05, 0.075, or 0.1 mg/d), replaced twice weekly; Alora (0.025, 0.05, 0.075, or 0.1 mg/d), replaced twice weekly; Climara (0.025, 0.0375, 0.05, 0.06, 0.075, or 0.1 mg/d), replaced weekly; FemPatch (0.025 mg/d), replaced weekly; and Menostar (0.014 mg/d), replaced weekly. This type of estradiol skin patch can be cut in half and applied to the skin without proportionately greater loss of potency.

2. Transdermal systems with estradiol in a drug reservoir: These systems cause significant skin irritation in some women. Available preparations include Estraderm (0.05 or 0.1 mg/d), replaced twice weekly.

3. Transdermal systems with estradiol (E) and norethindrone acetate (NA) mixed with adhesive: Available preparations include Combipatch (0.05 mg/d E and 0.14 mg/d NA or 0.05 mg/d E and 0.25 mg/d NA), replaced twice weekly. The addition of a progestin increases the likelihood of side effects compared with therapy with estrogen alone.

4. Transdermal estradiol gel (EstroGel, 0.6%) is available in a metered-dose dispenser that delivers 1.25 g estradiol per actuation. The gel is applied to one arm from the wrist to the shoulder daily after bathing. To avoid spreading the estradiol to others, the hands should be washed and precautions taken to avoid prolonged skin contact with children.

Vaginal estrogen: Urogenital atrophy commonly develops in postmenopausal women and can cause dryness of the vagina, genital itching, burning, and dyspareunia. Urinary symptoms can include urgency and dysuria. Vaginal estrogen is intended to deliver estrogen directly to local tissues in an effort to reduce these symptoms, while minimizing systemic estrogen exposure. Some estrogen is absorbed systemically and can relieve menopausal symptoms. Systemically absorbed estrogen avoids first-pass liver metabolism, causing less hypertriglyceridemia and prothrombotic effects than oral estrogen. Manufacturers recommend that these preparations be used for only 3–6 months in women with an intact uterus, since vaginal estrogen can cause endometrial proliferation. However, most clinicians use them for longer periods. Vaginal estrogen can be administered in three different ways:

1. Estrogen vaginal creams: These creams are administered intravaginally with a measured-dose applicator daily for 2 weeks for atrophic vaginitis, then administered one to three times weekly. Available preparations include conjugated equine estrogens (Premarin, 0.626 mg/g cream), 0.25–0.5 g cream vaginally; dienestrol (Ortho Dienestrol, 10 mg/g cream), 0.25–0.5 g cream vaginally; estradiol (Estrace, 0.1 mg/g cream), 1 g cream vaginally; and estropipate (Ogen, 1.5 mg/g cream), 0.25–0.5 g vaginally.

2. Estradiol vaginal tablets: These tablets are sold prepackaged in a disposable applicator and can be administered deep intravaginally daily for 2 weeks for atrophic vaginitis, then twice weekly. The tablets dissolve into a gel that gradually releases estradiol. Available preparations include vaginal estradiol tablets (Vagifem, 25 mcg/tablet).

3. Estradiol vaginal rings: These rings are inserted manually into the upper third of the vagina, worn continuously, and replaced every 90 days. Only a small amount of the released estradiol enters the systemic circulation. Vaginal rings do not usually interfere with sexual intercourse. If a ring is removed or descends into the introitus, it may be washed in warm water and reinserted. Available preparations include Estring (2 mg estradiol/ring, releasing 0.0075 mg/d) and Femring (12.4 mg estradiol/ring, releasing 0.05 mg/d, or 24.8 mg estradiol/ring, releasing 0.10 mg/d).

Oral progestins: For a woman with an intact uterus, long-term conventional-dose unopposed systemic estrogen therapy can cause endometrial hyperplasia, which typically results in dysfunctional uterine bleeding (DUB) and can rarely lead to endometrial cancer. Progestin therapy transforms proliferative into secretory endometrium, causing a menses when given intermittently or no bleeding when given continuously.

The type of progestin preparation, its dosage, and the timing of administration may be tailored to the given situation. Progestins may be given daily, monthly, or at longer intervals. When given episodically, progestins are usually administered for 7–14 day periods. Progestins are available in different formulations: Micronized progesterone (Prometrium, 100 mg/capsule), medroxyprogesterone acetate (Provera, Amen, Cycrin; 2.5, 5.0, and 10 mg/scored tablet), norethindrone acetate (Aygestin, 5 mg/tablet), and norethindrone (Micronor, Nor-QD; 0.35 mg/tablet).

Topical progesterone (20–50 mg/d) may reduce hot flushes in women who are intolerant to oral hormone replacement therapy. It may be applied to the upper arms, thighs, or inner wrists daily. It may be compounded as micronized progesterone 250 mg/mL in a transdermal gel. Its effects upon the breast and endometrium are unknown.

Progesterone-releasing IUDs: Progesterone-releasing intrauterine devices can be useful for women receiving estrogen replacement therapy, since they can reduce the incidence of DUB and endometrial carcinoma without exposing women to the significant risks of systemic progestins.

Benefits of estrogen replacement therapy: Estrogen replacement without progestin (unopposed): Surprisingly, the WHI study found that postmenopausal women who received conventional-dose estrogen-only therapy had a reduced risk for breast cancer (seven fewer cases/year per 10,000 women) compared with a placebo group. The WHI study also found that women who received estrogen therapy experienced a reduced number of hip fractures (six fewer fractures/year per 10,000 women) compared with placebo. Unopposed estrogen therapy had no discernible effect

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upon the risk for heart attacks, colorectal cancer, or overall mortality.

Women receiving unopposed conventional-dose daily conjugated estrogen and medroxyprogesterone acetate (0.625 mg and 2.5 mg, respectively), for an average of 5.6 years, experienced a lower risk of developing diabetes (3.5%) versus those taking a placebo (4.2%).

Serum levels of atherogenic lipoprotein(a) are reduced by estrogen replacement with or without daily or cycled progestins. Improvement in serum HDL cholesterol is greatest with unopposed estrogen but is also seen with the addition of a progestin.

Estrogen replacement improves or eliminates postmenopausal hot flushes and diaphoretic episodes. Vaginal moisture is improved. Libido is enhanced in some women. Sleep disturbances are common in menopause and can be reversed with estrogen replacement. Sex hormone replacement may also improve the body pain and reduced physical function experienced by some women at the time of menopause.

Perimenopause-related depression is improved by unopposed estrogen replacement; the addition of a progestin may negate this effect. Estrogen replacement, when initiated at the time of menopause or oophorectomy, has been reported to help protect cognitive function, particularly verbal memory, whereas estrogen replacement that is begun many years after menopause confers little or no benefit on cognition. Estrogen therapy does not appear to reduce the risk of Alzheimer's dementia.

Unopposed estrogen replacement improves glycemic control in women with type 2 diabetes mellitus. Estrogen replacement does not prevent facial skin wrinkling; however, it may improve facial skin moisture and thickness, reducing seborrhea and atrophy.

Risks of estrogen replacement therapy: The risks of estrogen replacement depend on the dose. Conventional doses (eg, oral conjugated estrogens ≥ 0.625 mg/d or transdermal estradiol ≥ 0.05 mg/d) carry higher risks than lower doses (eg, oral conjugated estrogens, ≤ 0.3 mg/d or transdermal estradiol ≤ 0.025 mg/d). Route of administration also affects risks, since oral estrogens pass through the liver and increase hepatic production of clotting factors (thereby increasing the risks of thrombotic stroke), whereas transdermal or vaginal administration of estrogen does not significantly increase clotting proclivity. The risks for HRT also depend on whether estrogen is administered alone (unopposed HRT) or with a progestin (combined HRT).

Estrogen replacement without progestin (unopposed HRT): Conventional-dose unopposed estrogen replacement increases the risk of endometrial hyperplasia and DUB, which often prompts patients to stop the estrogen. Lower-dose unopposed estrogen has a much lower risk of DUB. Recurrent dysfunctional bleeding necessitates a pelvic examination and possibly an endometrial biopsy.

Unopposed estrogen in conventional doses may increase the risk for endometrial carcinoma, although the absolute risk remains low. A Cochrane Database Review found no increased risk of endometrial carcinoma in a review of 30 randomized controlled trials. Therefore, lower-dose unopposed estrogen replacement confers a negligible risk for endometrial cancer.

Long-term conventional-dose unopposed estrogen increases the mortality risk from ovarian cancer, although the absolute risk is small. The annual age-adjusted ovarian cancer death rates for women taking estrogen replacement for ≥ 10 years are 64:100,000 for current users, 38:100,000 for former users, and 26:100,000 for women who had never taken estrogen. Lower-dose estrogen replacement is believed to confer a negligible increased risk for ovarian cancer.

The WHI study has reported that conventional doses of unopposed oral estrogen do not increase the risk of breast cancer; in fact, somewhat fewer breast cancers were found in women taking estrogen alone, compared with placebo. However, the WHI trial was stopped in 2002 because of an increased risk of stroke among women taking conjugated oral estrogens in doses of 0.625 mg daily; the risk was about 44 strokes per 10,000 person-years versus about 32 per 10,000 person-years in women taking placebo. Transdermal or transvaginal estrogen is not expected to increase the risk of stroke.

Conventional-dose oral estrogen replacement increases the risk of deep venous thrombosis. It can cause hypertriglyceridemia, particularly in women with preexistent hyperlipidemia, rarely resulting in pancreatitis. Postmenopausal estrogen therapy also slightly increases the risk of gallstones and cholecystitis. Oral estrogens reduce the effectiveness of growth hormone replacement. These side effects can be reduced or avoided by using nonoral estrogen replacement.

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Elderly women, receiving long-term conventional-dose estrogen replacement, experience an increased risk of urinary incontinence. Some women complain of estrogen-induced edema or mastalgia. Estrogen replacement has been reported to lower the seizure threshold in some women with epilepsy. Untreated large pituitary prolactinomas may enlarge if exposed to estrogen.

Estrogen replacement with a progestin (combined HRT): The WHI study found that women who received long-term conventional oral doses of combined HRT (conjugated estrogens 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d) had an increased risk of deep venous thrombosis (3.5 per 1000 person-years) compared with women receiving placebo (1.7 per 1000 person-years).

Conventional-dose oral combined HRT results in an increased risk for myocardial infarction (24% or six additional heart attacks per 10,000 women), mostly in women with high-risk LDL levels or preexistent coronary disease. Most of the risk for myocardial infarction occurs in the first year of therapy. This increased risk is attributable to the progestin component, since the estrogen-only arm of the WHI study found no increased risk of myocardial infarction.

Long-term conventional-dose oral combined HRT increases breast density and increases the risk for abnormal mammograms (9.4% versus 5.4% for placebo). There is also a higher risk for breast cancer (8 cases per 10,000 women/year versus 6.5 cases per 10,000 women/year for placebo); no increased risk of breast cancer has been found with estrogen-only HRT. This increased risk for breast cancer appears to mostly affect relatively thin women with a BMI < 24.4. The Iowa Women's Health Study reported an increase in breast cancer with HRT only in women consuming more than 1 oz of alcohol weekly. No accelerated risk of breast cancer has been seen in users of HRT who have benign breast disease or a family history of breast cancer.

The Women's Health Initiative Mental Study (WHIMS) followed the effect of combined conventional-dose oral HRT on cognitive function in women 65–79 years old. HRT did not protect these older women from cognitive decline. In fact, they experienced an increased risk for severe dementia at a rate of 23 more cases/year for every 10,000 women over age 65 years.

In the WHI study, women receiving conventional-dose combined oral HRT experienced an increased risk of stroke (31 strokes per 10,000 women/year versus 26 strokes per 10,000 women/year for placebo). Stroke risk was also increased by hypertension, diabetes, and smoking.

Women taking combined estrogen-progestin replacement do not experience an increased risk of ovarian cancer. They do experience an increased risk of developing asthma.

Progestins may cause moodiness, particularly in women with a history of premenstrual dysphoric disorder. Cycled progestins may trigger migraines in certain women. Many other adverse reactions have been reported, including breast tenderness, alopecia, and fluid retention. Contraindications to the use of progestins include thromboembolic disorders, liver disease, breast cancer, and pregnancy.

Androgen replacement: Women who have undergone a bilateral oophorectomy almost invariably have low serum androgens. Women with panhypopituitarism tend to have particularly low androgen levels. However, after natural menopause, the ovaries and adrenals continue to secrete testosterone, such that postmenopausal women are not always androgen deficient. Androgen deficiency contributes to hot flushes, loss of libido and sexual hair, muscle atrophy, and osteoporosis. Selected women may be treated with low-dose methyltestosterone, which is available in combination with conjugated estrogens (eg, Estratest). Tablets contain either 1.25 mg conjugated estrogens with 2.5 mg methyltestosterone or 0.625 mg conjugated estrogens with 1.25 mg methyltestosterone. Estratest is usually started at the lowest strength every 2 days, alternating days with standard estrogen replacement (see above). It should be given cyclically at the lowest dose that controls symptoms. At small doses, side effects of androgens are usually minimal but may include nausea, polycythemia, emotional changes, paresthesias, electrolyte disturbances, and potentiation of anticoagulant therapy. Reduction in HDL cholesterol may negate the beneficial effect on cardiovascular mortality conferred by estrogen replacement therapy. Cholestatic jaundice and elevation of liver enzymes occur rarely. Hepatocellular neoplasms and peliosis hepatis, rare complications of oral androgens at higher doses, have not been reported with lower doses. Side effects of excess androgen treatment include hirsutism and virilization. Androgens should not be given to women with liver disease or during pregnancy or breast-feeding.

Selective estrogen receptor modulators (SERMs) (eg, raloxifene; Evista) are an alternative to estrogen replacement for hypogonadal women at risk for osteoporosis who prefer not to take estrogens because of their contraindications (eg, breast or uterine cancer) or side effects. Raloxifene does not reduce hot flushes, vaginal dryness, skin wrinkling, or breast atrophy; it does not improve cognition. However, in doses of 60 mg/d orally, it inhibits bone loss without stimulating effects upon the breasts or endometrium. Because raloxifene may slightly increase the risk of venous thromboembolism, it should not be used by women at prolonged bed rest or by those prone to thrombosis. In contrast with the use of estrogen replacement therapy, concomitant progesterone therapy is not needed, and raloxifene does not increase the risk of development of breast cancer. Tibolone (Livial) is an SERM whose metabolites have mixed estrogenic, progestogenic, and weak androgenic activity. It is comparable to HRT for the treatment of climacteric-related complaints. It does not appear to significantly stimulate proliferation of breast or endometrial tissue. It depresses both serum triglycerides and HDL cholesterol. Long-term studies are lacking. It is not available in the United States.

Phytoestrogens are substances found in plants that bind to estrogen receptors. Phytoestrogens, found in soy and red clover extracts, do not appear to significantly improve menopausal hot flushes, cognitive function, bone density, or plasma lipids.

Testosterone replacement therapy in women: Low serum testosterone levels develop in women following bilateral oophorectomy and also later in menopause. Serum testosterone levels are extremely low in women with panhypopituitarism. Low serum testosterone levels are a major cause of HSDD and may also cause fatigue, a diminished sense of well-being, and a dulled enthusiasm for life. Testosterone replacement may increase sexual activity and desire in women with HSDD.

Testosterone replacement may be given orally as methyltestosterone, compounded in capsules and taken orally in doses of 1.25–2.5 mg daily. At these doses, methyltestosterone has not been associated with peliosis hepatis. Testosterone can also be compounded as a cream containing 1 mg/mL, with 1 mL applied to the low abdomen daily. A testosterone skin patch is being developed for women that will deliver testosterone

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transdermally 0.3 mg/d and will be changed twice weekly. Women receiving testosterone therapy must be monitored for the appearance of any acne or hirsutism, and serum testosterone levels are determined periodically if women feel that they are benefitting and long-term testosterone therapy is instituted.

Anderson GL et al: Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:701.

Barnabei VM et al; Women's Health Initiative Investigators: Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol 2005;105(5 Pt 1):1063.

Cushman M et al; Women's Health Initiative Investigators: Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573.

Evans ML et al: Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol 2005;105:161.

Johnson SR et al: Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol 2005; 105:779.

Lethaby A et al: Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004;(3):CD000402.

Reed SD et al: Dose of progestin in postmenopausal-combined hormone therapy and risk of endometrial cancer. Am J Obstet Gynecol 2004;191:1146.

Sherwin BB: Estrogen and memory in women: how can we reconcile the findings? Horm Behav 2005;47:371.

Simon J et al: Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005;90:5226.

Wise PM et al: Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women's health initiative. Endocr Rev 2005;26:308.

Turner's Syndrome (Gonadal Dysgenesis)

Turner's syndrome is a chromosomal disorder associated with primary hypogonadism, short stature, and other phenotypic anomalies. It is a common cause of primary amenorrhea and early ovarian failure. Patients with the classic syndrome lack one of the two X chromosomes and have a 45,XO karyotype.

Typical Turner's Syndrome (45,XO Gonadal Dysgenesis)

Features of Turner's syndrome (Table 26-17) are variable and may be subtle in girls with mosaicism. Typical manifestations in adulthood include short stature, hypogonadism, webbed neck, high-arched palate, wide-spaced nipples, hypertension, and renal abnormalities. Emotional disorders are common. 45,XO accounts for about 50% of cases. Less than 3% of these zygotes survive to term, with the incidence of Turner's syndrome being about 2:10,000 female newborns.

Table 26-17. Manifestations of Turner's syndrome.

Short stature
Distinctive facial features
   Ptosis
   Micrognathia
   Low-set ears
   Epicanthal folds
Sexual infantilism due to gonadal dysgenesis with primary amenorrhea (80%)
Early ovarian failure with secondary amenorrhea (20%)
Webbed neck (40%)
Low hairline
High-arched palate
Cubitus valgus
Short fourth metacarpals (50%)
Lymphedema of hands and feet (30%)
Hypoplastic widely spaced nipples
Hyperconvex nails
Pigmented nevi
Keloid formation (eg, surgical scars or after ear piercing)
Recurrent otitis media
Renal abnormalities (60%)
   Horseshoe kidney
   Hydronephrosis
Hypertension (idiopathic or due to coarctation or renal disease)
Gastrointestinal bleeding from intestinal telangiectases (rare)
Impaired space-form recognition, direction sense, and mathematical reasoning
Cardiovascular anomalies
   Coarctation of the aorta (10–20%)
   Aortic stenosis
   Bicuspid aortic valve
   Aortic dissection due to coarctation and cystic medial necrosis of the aorta
Associated conditions
   Obesity
   Diabetes mellitus (types 1 and 2)
   Dyslipidemia
   Hyperuricemia
   Hashimoto's thyroiditis
   Achlorhydria
   Cataracts, corneal opacities
   Neuroblastoma (1%)
   Rheumatoid arthritis
   Inflammatory bowel disease

Girls with Turner's syndrome may be diagnosed at birth, since they tend to be small and may exhibit severe lymphedema. Evaluation for childhood short stature often leads to the diagnosis. Growth hormone and somatomedin levels are normal. Hypogonadism presents as “delayed adolescence” (primary amenorrhea, 80%) or early ovarian failure (20%); girls with 45,XO

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Turner (blood karyotyping) who enter puberty are typically found to have mosaicism if other tissues are karyotyped. Hypogonadism is confirmed in girls who have high serum levels of FSH and LH. A blood karyotype showing 45,XO (or X chromosome abnormalities or mosaicism) establishes the diagnosis.

Treatment of short stature with daily injections of growth hormone (0.1 unit/kg/d) plus an androgen (eg, oxandrolone) for at least 4 years before epiphysial fusion increases final height by a mean of about 10.3 cm over the mean predicted height of 144.2 cm. Such growth hormone treatment rarely causes pseudotumor cerebri. After age 12 years, estrogen therapy is begun with low doses of conjugated estrogens (0.3 mg) or ethinyl estradiol (5 mcg) given on days 1–21 per month. When growth stops, HRT is begun with estrogen and progestin; transdermal estrogen may be used to initiate pubertal development.

Women with Turner's syndrome have a reduced life expectancy due in part to their increased risk for diabetes mellitus (types 1 and 2), hypertension, dyslipidemia, and osteoporosis. Diagnostic vigilance and aggressive treatment of these conditions reduce the risk of aortic aneurysm dissection, ischemic heart disease, stroke, and fracture. Patients are prone to keloid formation after surgery or ear piercing. Yearly ocular examinations and periodic thyroid evaluations are recommended. It is advisable to evaluate all patients with Turner's syndrome with an ultrasound, CT, or MRI examination of the chest and abdomen, looking for cardiac, aortic, and renal abnormalities. Patients with a prominent webbed neck also tend to have a bicuspid aortic valve and aortic coarctation. Aortic aneurysms are common, as are cases of unilateral renal agenesis.

Turner's Syndrome Variants

A. 46,X (Abnormal X) Karyotype

An abnormality or deletion of certain genes on the short arm of the X chromosome causes short stature and other signs of Turner's syndrome; some gonadal function and even fertility are possible. Transmission of Turner's syndrome from mother to daughter can occur. There may be an increased risk of trisomy 21 in the conceptuses of women with Turner's syndrome. Abnormalities or deletions of other genes located on both the long and short arms of the X chromosome can produce gonadal dysgenesis with few other somatic features.

B. 45,XO/46,XX Mosaicism

This karyotype results in a modified form of Turner's syndrome. Such girls tend to be taller and may have more gonadal function and fewer other manifestations of Turner's syndrome.

C. Other Variants

45,XO/46,XY mosaicism can produce some manifestations of Turner's syndrome. Patients may have ambiguous genitalia or male infertility with an otherwise normal phenotype. Germ cell tumors, such as gonadoblastomas and seminomas, develop in about 10% of patients with 45,XO/46,XY mosaicism; most such tumors are benign.

El-Mansoury M et al: Hypothyroidism is common in Turner syndrome: results of a five-year follow-up. J Clin Endocrinol Metab 2005;90:2131.

Cardoso G et al: Current and lifetime psychiatric illness in women with Turner syndrome. Gynecol Endocrinol 2004;19:313.

Gravholt CH: Epidemiological, endocrine and metabolic features of Turner syndrome. Eur J Endocrinol 2004;151:657.

Ho VB et al: Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004;110:1694.

Hogler W et al: Importance of estrogen on bone health in Turner syndrome: a cross-sectional and longitudinal study using dual-energy X-ray absorptiometry. J Clin Endocrinol Metab 2004;89:193.

Ostberg JE et al: A comparison of echocardiography and magnetic resonance imaging in cardiovascular screening of adults with Turner syndrome. J Clin Endocrinol Metab 2004;89:5966.

Soriano-Guillen L et al: Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone. J Clin Endocrinol Metab 2005;90:5197.

Sybert VP et al: Turner's syndrome. N Engl J Med 2004;351: 1227.

Multiple Endocrine Neoplasia

Syndromes of MEN are inherited as autosomal dominant traits and cause a predisposition to the development of tumors in different tissues, particularly involving endocrine glands (see Table 26-11).

Men 1 (Wermer's Syndrome)

MEN 1 is a familial autosomal dominant multiglandular syndrome, with a prevalence of 2–10 per 100,000 people. The presentation of MEN 1 is quite variable, even in the same kindred. Parathyroid, enteropancreatic, and pituitary tumors can be present in one individual, though not necessarily at the same time. Nonendocrine tumors also occur, such as subcutaneous lipomas, facial angiofibromas, and collagenomas. In some affected individuals, tumors may start developing in childhood, whereas in others, tumors develop late in adult life.

About 90% of patients with MEN 1 gave germline mutations that are inherited as an autosomal dominant trait. Patients with MEN 1 usually have detectable mutations in the 10 exons of the menin gene, located

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on the long arm of chromosome 11 (11q13). MEN 1 gene testing is available at a few centers and is able to detect the specific mutation in 60–95% of cases. If no mutation is detected, genetic linkage analysis can be done if there are several affected members in the kindred. Gene testing permits the rest of the kindred to be tested for the specific gene defect and allows informed genetic counseling.

With close endocrine surveillance of affected individuals, the initial biochemical manifestations (usually hypercalcemia) can often be detected as early as age 14–18 years in patients with a MEN 1 gene mutation, although clinical manifestations do not usually present until the third or fourth decade.

Hyperparathyroidism is the first clinical manifestation of MEN 1 in two-thirds of affected patients, but it may present at any time of life. Patients with the MEN 1 mutation have a > 90% lifetime risk of developing hyperparathyroidism. Hyperparathyroidism presents with hypercalcemia, caused by hyperplasia or adenomas of several parathyroid glands. The hyperparathyroidism of MEN 1 is notoriously difficult to treat surgically, due to multiple gland involvement and the frequency of supernumerary glands and ectopic parathyroid tissue. Typically, three and one-half glands are resected, leaving one-half of the most normal-appearing gland intact. Also, during neck surgery, a thymectomy is performed to resect any intrathymic parathyroid glands or occult thymic carcinoid tumors. Nevertheless, the surgical failure rate is about 38%, and there is a recurrence rate of about 16%, with hypercalcemia often recurring many years after neck surgery. Aggressive parathyroid resection can cause permanent hypoparathyroidism. Patients with persistent or recurrent hyperparathyroidism should avoid oral calcium supplements and thiazide diuretics; oral therapy with calcimimetic drug, such as cinacalcet, is effective but expensive. The diagnosis and treatment of hyperparathyroidism is described earlier in this chapter.

Enteropancreatic tumors occur in about 75% of patients with MEN 1. Nonsecretory neuroendocrine tumors occur and do not secrete hormones; they tend to be large and very aggressive. Gastrinomas occur in about 35% of patients with MEN 1; they secrete gastrin, thereby causing severe gastric hyperacidity (Zollinger-Ellison syndrome) with peptic ulcer disease or diarrhea. Concurrent hypercalcemia, due to hyperparathyroidism (see above), stimulates gastrin and gastric acid secretion; control of the hypercalcemia often reduces gastric acid secretion and serum gastrin levels. These gastrinomas tend to be small, multiple, and ectopic; they are frequently found outside the pancreas, usually in the duodenum. Gastrinomas of MEN 1 can metastasize to the liver; but in patients with MEN 1, depending upon the kindred, hepatic metastases tend to be less aggressive than those from sporadic gastrinomas. Treatment of patients with gastrinomas in MEN 1 is usually conservative, utilizing long-term high-dose proton pump inhibitor therapy and control of hypercalcemia; surgery is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum. Zollinger-Ellison syndrome is also discussed in Chapter 14.

Insulinomas cause hyperinsulinism and fasting hypoglycemia. They occur in about 15% of patients with MEN 1. Surgery is usually attempted, but the tumors can be small, multiple, and difficult to detect. The diagnosis and treatment of insulinomas are described in Chapter 27. Glucagonomas (1.6%) secrete glucagon and cause diabetes and migratory necrolytic erythema. VIPomas (1%) secrete VIP and cause profuse watery diarrhea, hypokalemia, and achlorhydria (WDHA, Verner-Morrison syndrome). Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea, and cholelithiasis.

Pituitary adenomas occur in about 42% of patients with MEN 1. They are more common in women (50%) than men (31%) and are the presenting tumor in 17% of patients with MEN 1. These tumors tend to be more aggressive macroadenomas (> 1 cm diameter, 85%) compared to sporadic pituitary tumors (42%). Of MEN 1-associated pituitary tumors, about 62% secrete PRL, 8% secrete GH, 13% secrete both PRL and GH, and 13% are nonsecretory; only 4% secrete ACTH and cause Cushing's disease. The diagnosis and treatment of pituitary tumors and Cushing's disease were described earlier in this chapter. These pituitary tumors can produce local pressure effects and hypopituitarism.

Adrenal adenomas or hyperplasia occurs in about 37% of patients with MEN 1 and 50% are bilateral. They are generally benign and nonfunctional. In one series, one out of 12 of these patients developed a feminizing adrenal carcinoma. These adrenal lesions are pituitary independent.

Nonendocrine tumors occur commonly in MEN 1. Small facial angiofibromas and subcutaneous lipomas are common. Collagenomas can present as firm dermal nodules. Malignant melanomas have been reported.

The differential diagnosis of MEN 1 includes sporadic or familial tumors of the pituitary, parathyroids, or pancreatic islets. Hypercalcemia (from any cause) may cause gastrointestinal symptoms and increased gastrin levels, simulating a gastrinoma. Routine suppression of gastric acid secretion with H2-blockers or proton pump inhibitors causes a physiologic increase in serum gastrin that can be mistaken for a gastrinoma. H2-blockers and metoclopramide cause hyperprolactinemia, simulating a pituitary prolactinoma.

Variants of MEN 1 also occur. Kindreds with MEN 1 Burin variant have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors.

Men 2A (Sipple's Syndrome)

MEN 2A is a rare familial multiglandular syndrome that is inherited as an autosomal dominant trait. Patients with MEN 2A should have genetic testing for a ret protooncogene (RET) mutation. Their first-degree relatives may then be tested for the specific RET mutation. Patients with MEN 2A may have medullary thyroid carcinoma (> 90%); hyperparathyroidism

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(20–50%), due to hyperplasia or multiple adenomas in over 70% of cases; pheochromocytomas (20–35%), which are often bilateral; or Hirschsprung's disease. The medullary thyroid carcinoma is of mild to moderate aggressiveness. Children harboring an MEN 2A RET gene mutation are advised to have a prophylactic total thyroidectomy by age 6 years.

Siblings or children of patients with MEN 2A should have genetic testing to determine if they have a mutation of the ret protooncogene (RET) on chromosome 10cen-10q11.2; this identifies about 95% of affected individuals. Each kindred has a certain ret codon mutation that correlates with the particular variation in the MEN 2 syndrome, such as the age of onset and aggressiveness of medullary thyroid cancer. The specific mutation as well as case histories of family members should guide the timing for prophylactic thyroidectomy. Before any surgical procedure, MEN 2 carriers should be screened for pheochromocytoma. There is incomplete penetrance, and about 30% of those with such mutations never manifest endocrine tumors.

Patients may be screened for medullary thyroid carcinoma with a serum calcitonin drawn after 3 days of omeprazole, 20 mg orally twice daily; calcitonin levels rise in the presence of medullary thyroid carcinoma to above 80 pg/mL in women or above 190 pg/mL in men.

Men 2B

MEN 2B is a familial, autosomal dominant multiglandular syndrome that is caused by a mutation of the ret protooncogene (RET) on chromosome 10. MEN 2B is characterized by mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue, Marfan-like habitus (75%), adrenal pheochromocytomas (60%) that are rarely malignant and often bilateral, and medullary thyroid carcinoma (80%). Patients also have intestinal abnormalities (75%) such as intestinal ganglioneuromas, skeletal abnormalities (87%), and delayed puberty (43%). Medullary thyroid carcinoma is aggressive and presents early in life. Therefore, infants having a parent with MEN 2B receive genetic screening; those carrying the RET mutation undergo a prophylactic total thyroidectomy by age 6 months.

Gertner ME et al: Multiple endocrine neoplasia type 2. Curr Treat Options Oncol 2004;5:315.

Lairmore TC et al: Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN 1). Ann Surg 2004;239:637.

Lambert LA et al: Surgical treatment of hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Arch Surg 2005;140:374.

Levy-Bohbot N et al; Groupe des Tumeurs Endocrines: Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol 2004;28:1075.

Malone JP et al: Hyperparathyroidism and multiple endocrine neoplasia. Otolaryngol Clin North Am 2004;37:715.

Skinner MA et al: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005;353:1105.

Clinical Use of corticosteroids

Mechanisms of Action

Cortisol is a steroid hormone that is normally secreted by the adrenal cortex in response to ACTH. It exerts its action by binding to nuclear receptors, which then act upon chromatin to regulate gene expression, producing effects throughout the body.

Relative Potencies

Hydrocortisone and cortisone acetate, like cortisol, have mineralocorticoid effects that become excessive at higher doses. Other synthetic corticosteroids such as prednisone, dexamethasone, and deflazacort (an oxazoline derivative of prednisolone) have minimal mineralocorticoid activity. The potencies relative to hydrocortisone are listed in Table 26-18. Anticonvulsant drugs (eg, phenytoin, carbamazepine, phenobarbital) accelerate the metabolism of corticosteroids other than hydrocortisone, making them significantly less potent. Megestrol, a synthetic progestin, has slight corticosteroid activity that becomes significant when administered in high doses for appetite stimulation.

Table 26-18. Systemic versus topical activity of corticosteroids.1

  Systemic Activity Topical Activity
Prednisone 4–5 1–2
Fluprednisolone 8–10 10
Triamcinolone 5 1
Triamcinolone acetonide 5 40
Dexamethasone 30–120 10
Betamethasone 30 5–10
Betamethasone valerate 50–150
Methylprednisolone 5 5
Fluocinolone acetonide 40–100
Flurandrenolone acetonide 20–50
Fluorometholone 1–2 40
Deflazacort 3–4
1Hydrocortisone = 1 in potency.

Table 26-19. Management of patients receiving systemic corticosteroids.

  • Do not administer corticosteroids unless absolutely indicated or more conservative measures have failed.
  • Keep dosage and duration of administration to the minimum required for adequate treatment.
  • Screen for tuberculosis before treatment with a purified protein derivative (PPD) test or chest x-ray.
  • Screen for diabetes mellitus before treatment and at each physician visit. Teach the patient about the symptoms of hyperglycemia and to test urine weekly for glucose.
  • Screen for hypertension before treatment and at each physician visit.
  • Screen for glaucoma and cataracts before treatment, 3 months into treatment, and then at least yearly.
  • Prepare the patient and family for possible adverse effects on mood, memory, and cognitive function. Inform them about other possible side effects, particularly weight gain, osteoporosis, and aseptic necrosis of bone.
  • Institute a vigorous physical exercise and isometric regimen tailored to each patient's disabilities.
  • Administer calcium (1 g elemental calcium) and vitamin D3, 400–800 IU orally daily. Check spot morning urines, and alter dosage to keep urine calcium concentration below 30 mg/dL. If the patient is receiving thiazide diuretics, check for hypercalcemia, and administer only 500 mg elemental calcium daily. Consider a bisphosphonate such as alendronate (5–10 mg orally daily or 70 mg orally weekly) or periodic intravenous infusions of pamidronate or zoledronic acid.
  • Avoid prolonged bed rest that will accelerate muscle weakness and bone mineral loss. Ambulate early after fractures.
  • Treat hypogonadism in women or men.
  • Avoid elective surgery, if possible. Vitamin A in a daily dose of 20,000 units orally for 1 week may improve wound healing, but it is not prescribed in pregnancy.
  • Avoid activities that could cause falls or other trauma.
  • Watch for fungal or yeast infections of skin, nails, mouth, vagina, and rectum, and treat appropriately.
  • Ulcer prophylaxis: Administer oral corticosteroids with meals. If administered with nonsteroidals, consider prophylaxis with omeprazole, 20–40 mg/d. Corticosteroids alone do not need prophylaxis with H2-blockers or omeprazole. Avoid large doses of antacids containing aluminum hydroxide (many popular brands); aluminum hydroxide binds phosphate and may cause a hypophosphatemic osteomalacia that can compound corticosteroid osteoporosis.
  • Treat infections aggressively. Consider unusual pathogens.
  • Weigh daily. Use dietary measures to avoid obesity and optimize nutrition.
  • Measure height frequently. This serves to document the degree of axial spine demineralization and compression.
  • Treat edema as indicated.
  • Monitor plasma potassium for hypokalemia. Treat as indicated.
  • Obtain bone densitometry before treatment and then periodically. Treat osteoporosis.
  • Counsel to avoid smoking and excessive ethanol consumption.
  • With dosage reduction, watch for signs of adrenal insufficiency or corticosteroid withdrawal syndrome.

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Adverse Effects

Prolonged treatment with systemic corticosteroids causes a variety of adverse effects that can be life-threatening. Patients should be thoroughly informed of the major possible side effects of treatment such as insomnia, personality change, weight gain, muscle weakness, polyuria, kidney stones, diabetes mellitus, sex hormone suppression, occasional amenorrhea in women, candidiasis and opportunistic infections, osteoporosis with fractures, or aseptic necrosis of bones, particularly of the hips, which may become manifest many months after even brief treatment (see section on Cushing's syndrome). Alendronate, 5–10 mg orally daily, prevents the development of osteoporosis among patients receiving prolonged courses of corticosteroids. For convenience, alendronate (70 mg) or risedronate (35 mg) may be taken orally once weekly. Ibandronate, 150 mg orally, may be taken once monthly. For patients who are unable to tolerate oral bisphosphonates (due to esophagitis, hiatal hernia, or gastritis), periodic intravenous infusions of pamidronate, 60–90 mg, or zoledronic acid, 2–4 mg, should also be effective. It is wise to follow an organized treatment plan such as the one outlined in Table 26-19.

Buttgereit F et al: Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet 2005;365:801.

Gluck O et al: Recognizing and treating glucocorticoid-induced osteoporosis in patients with pulmonary diseases. Chest 2004;125:1859.

Rhen T et al: Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 2005;353:1711.