Insights on Endocrine Disease

Educational Objectives

The goal of this program is to improve identification and treatment of patients with disorders of the thyroid, parathy­roid, pituitary, or adrenal glands. After hearing and assimilating this program, the clinician will be better able to:

Screen patients for thyroid dysfunction and discuss the differential diagnoses associated with hypothyroidism and hyperthyroidism.

Describe the effects of hypopituitarism and hyperpituitarism and detail the causes for each.

Evaluate patients with adrenal incidentalomas.

Assess risk for malignancy associated with thyroid nodules.

Diagnose and treat patients with thyroid cancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgments

Dr. Rushakoff was recorded at Family Medicine Board Review Course, presented by the University of California, San Francisco, School of Medicine, and held July 7-10, 2008, in San Francisco, CA; Dr. Haber was recorded at An Update on Diabetes and Endocrine Disorders for the Practicing Physician, presented by Mount Sinai School of Medicine, and held October 17, 2008, in New York, NY. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Refresher Course on Diseases of the Thyroid, Parathyroid, Pituitary, and Adrenal Glands

Robert J. Rushakoff, MD, Clinical Professor of Medicine, Division of Endocrinology and Metabolism, Univer­sity of California, San Francisco, School of Medicine

Thyroid

Diagnostics: laboratory tests—avoid measuring total thyroid hormones (dependent on level of binding proteins) and triiodothyronine (T₃) uptake (indirect measurement; confusing); measure thyrotropin (TSH) levels to screen for thyroid dysfunction; measure levels of free hormones for diagnosis; imaging—radioactive iodine (¹²³I) uptake use­ful for differential diagnosis of thyrotoxicosis but does not assess thyroid function; iodine turnover and dietary in­take of iodine affect results; ¹²³I scan useful when thyrotoxic nodular disease suspected; however, ¹²³I scan does not assess thyroid function; effect of exogenous estrogen—increases thyroxine-binding globulin, resulting in elevated total thyroxine (T₄); important to know whether patient taking oral contraceptives or on hormone replacement ther­apy

Hyperthyroidism: symptoms—palpitations; nervousness; fatigue; hyperdefecation; sweating; heat intolerance; weight loss; amenorrhea; signs—enlarged thyroid gland; Means-Lerman scratch on auscultation; tremor; tachy­cardia; lid lag and stare; exophthalmos (only in patients with Graves' disease); goiter; onycholysis; palmar ery­thema; dermopathy; primary thyrotoxicosis—TSH absent; T₄ elevated; secondary thyrotoxicosis—pituitary disorder; TSH slightly elevated or inappropriately normal; T₄ elevated; T₃ toxicosis—TSH level normal or low; normal level of T₄; T₃ elevated; more common among patients with nodular disease and older patients with Graves' disease

Causes: Graves' disease (most common); toxic multinodular goiter (typically involves exposure to iodine, eg, ami­odarone); single toxic nodule (typically >3 cm in diameter); subacute thyroiditis (patients typically have history of malaise, neck pain, and viral infection); Jod-Basedow syndrome (iodine-induced)

Differential diagnosis: Graves' disease vs subacute thyroiditis—hormone levels similar; iodine uptake diagnostic (high in Graves' disease; absent in subacute thyroiditis); subacute thyroiditis also associated with elevated sedi­mentation rate; nodular disease—imaging (¹²³I scan) important when distinguishing single from multiple nod­ules; palpation sometimes sufficient

Treatment: Graves' disease—b-blockers used initially to control symptoms; surgery necessary for patients with large thyroid glands and those unable to undergo other therapies; antithyroid drug therapy effective but depen­dent on patient compliance (adverse effects include rash and agranulocy-tosis [rare]); agents include methima­zole and propylthiouracil (PTU; preferred during pregnancy); ¹²³I therapy most common (patients rendered hypothyroid and require T₄ replacement); subacute thyroiditis—self-limited disease; b-blockers to control symptoms; analgesics (typically nonsteroidal anti-inflammatory drugs); toxic state typically resolves within 2 to 3 mo; patients may become transiently hypothyroid (no consensus about whether to treat)

Hypothyroidism: signs and symptoms—fatigue; weight gain; cold intolerance; physical signs (eg, dry skin, puffy face, hoarseness, slow reflexes) relatively rare; patients often asymptomatic; diagnosis—screening important; patients with primary disease have elevated TSH and low levels of T₄; patients with secondary disease (relatively rare) have low T₄ and low or inappropriately normal levels of TSH; subclinical disease—patients have normal levels of T₄ but elevated TSH; clinical significance unclear; upper limit of normal (ULN) level of TSH debated; patients at high risk of developing clinical hypothyroidism in £5 yr

Causes: Hashimoto's disease (most common); iatrogenic (result of treatment for Graves' disease); secondary dis­ease caused by hypothalamic or pituitary disorders

Treatment: T₄—  taken once daily (average dose, 0.125 mg); half-life (t_1/2), 1 wk; T₃  —  dosed tid; bypasses normal conversion of T₄ to T₃; t_1/2, 1 day; desiccated (cow) thyroid gland—variable potency; difficult to monitor; often taken inappropriately; monitoring treatment—goal to achieve normal level of TSH; wait 6 to 8 wk after adjust­ing dose to check level (to achieve steady state); cautions—patient should avoid taking thyroid hormones at same time as calcium, iron, soy, or cholestyramine (reduced absorption); Helicobacter pylori infection and omeprazole therapy also may inhibit absorption; dose adjustment—reduce dose if subclinical hyperthyroidism occurs (associated with decreased bone mineral density [BMD] and atrial arrhythmias in older patients)

Thyroid nodules: assessment requires fine-needle aspiration (FNA); ultrasonography (US) sometimes useful; management—surgery for malignant or suspicious nodules; observation appropriate for benign nodules

Pituitary

Hypopituitarism: growth hormone (GH) levels decrease first, followed by gonadotropins, TSH, then corticotropin (ACTH); etiologies—invasion (eg, tumors); infarction (eg, Sheehan's syndrome); iatrogenic causes (radiation; sur­gery); infiltrative processes; injury

Central hypothyroidism: TSH not reliable for screening or monitoring (levels always low); low level of T₄ impor­tant for diagnosis

Central adrenal insufficiency: renin-aldosterone system remains intact, so potassium levels normal; changes in glo­merular filtration rate and water excretion result in hyponatremia; diagnosis—cosyntropin test; treatment—hydrocortisone 20 to 30 mg/day (two-thirds given in morning; one-third given in afternoon)

Pituitary tumors: prolactinomas most common; 10% of tumors nonfunctioning; presentation—neurologic symp­toms include nerve palsies and changes in visual field (VF); hormonal excess or deficiency may occur; tumors often discovered incidentally; evaluation—assess functionality by measuring hormone levels (eg, T₄, prolactin, cortisol, luteinizing hormone, follicle-stimulating hormone)

Prolactinomas: prolactin levels increase naturally with certain conditions (eg, pregnancy) and activities; pathologic increases usually due to microadenoma (tumors <1 cm in diameter); other causes include pituitary stalk lesions; several classes of drugs (including most antidepressants) increase prolactin levels; presentation—galactorrhea and amenorrhea in women (suspicion increases if both conditions present); in men, symptoms include impotence and decreased libido, and tumors often identified at later stage (ie, macroadenomas; >1 cm in diameter); diagnosis—elevated prolactin (100-200 mg/L suggestive; exclude other causes when elevations more modest); other tumors may interrupt dopamine inhibition and result in increased levels of prolactin; thyroid function and pregnancy tests required to rule out other causes of elevated prolactin; magnetic resonance imaging (MRI) of pi­tuitary diagnostic; treatment—medical therapy with dopamine agonist (eg, bromocriptine, cabergoline); surgery second-line therapy

GH-secreting tumors: typically macroadenomas; 15% also produce prolactin; features—hypertension; hypergly­cemia; proliferation of soft tissues; carpal tunnel syndrome; hypogonadism; VF issues; frontal bossing; acromeg­aly; gigantism occurs if excess GH secreted before puberty; diagnosis—elevated level of insulin-like growth factor-1; treatment—surgery; somatostatin analogue as secondary therapy

Adrenal

Adrenal insufficiency: causes—autoimmune disease; AIDS; metastatic disease; drugs (eg, ketoconazole); gluco­corticoids and anabolic steroids may cause secondary disease; features—often nonspecific (eg, weakness, fatigue, anorexia); increased skin pigmentation (especially around lips and on hands); diagnosis—cosyntropin test (adre­nal function considered normal if cortisol ³18 mg/dL 30-60 min after stimulation); ACTH level helps distinguish primary from secondary disease; treatment—in addition to hydrocortisone, patients with primary disease need mineralocorticoid supplement

Cushing's syndrome: overproduction of adrenal hormones, primarily caused by exogenous steroids; endogenous eti­ologies include Cushing's disease (often due to ACTH secretion by pituitary adenoma) and ectopic syndromes (eg, lung cancer, bronchial carcinoids, adrenal tumors); features—facial features (eg, moon face ); central obesity; hy­pertension; purple striae; papilledema; changes in VFs; virilization in women; others; diagnosis—24-hr urine cor­tisol test; ACTH level (low level suggests adrenal disorder; high level suggests pituitary or ectopic cause)

Primary aldosteronism: accounts for up to 10% of cases of hypertension; results from autonomous production of al­dosterone; may cause hypokalemia; diagnosis—first, replete potassium; measure ratio of plasma aldosterone to re­nin levels (ratio >20 suggestive); follow with confirmatory tests; computed tomography (CT) distinguishes unilateral from bilateral disease; management—resect unilateral disease; medically manage bilateral disease with spironolactone

Pheochromocytoma: rare; signs and symptoms include headache, diaphoresis, palpitations, tremor, and anxiety; 10% of patients normotensive; 10% of cases occur in children; 10% of cases bilateral, 10% malignant, and 10% ex­tra-adrenal; diagnosis—measure 24-hr urinary metanephrine and normetanephrine levels or plasma levels of free metanephrine; adrenal CT or other imaging (eg, ¹³¹I meta-iodobenzylguanidine scintiscan); treatment—surgery

Adrenal incidentaloma: common (seen in »10% of autopsies); assessing functionality—screen for pheochromocy­toma and subclinical Cushing's disease; screen for primary aldosteronism in patients with hypertension; assessing malignancy—size (tumors <3 cm likely benign); density on CT; management—remove functional or large tu­mors; observe small nonfunctional tumors

Parathyroid

Primary hyperparathyroidism: most common cause of hypercalcemia (measure parathyroid hormone [PTH] in all patients with hypercalcemia); commonly results from single adenoma; management—surgery indicated if serum calcium level >1.0 mg/dL above ULN, 24-hr urine calcium measurement >400 mg, creatinine clearance reduced by ³20%, decreased BMD, or age <50 yr; if surgery not indicated, check calcium level twice yearly, serum levels of creatinine once yearly, and BMD at least once every 3 yr

Familial benign hypocalciuric hypercalcemia: mutation in calcium sensor; patients have high serum levels but low urinary levels of calcium and slightly elevated PTH; no treatment necessary

Thyroid Nodules: What to do After Examining the Neck

Richard S. Haber, MD, Professor of Medicine, Mount Sinai School of Medicine, New York, NY

Epidemiology: 4% to 7% of adults have palpable nodules; increased prevalence (4-fold) in women; 5% of nodules malignant; most thyroid cancers associated with low rates of mortality; prevalence of nodules increases with age; thyroid cancer—accounts for »1% of all cancers; incidence increasing (probably due to increased identification), but mortality rates stable (»1000 deaths/yr); benign nodules—colloid nodules (most common); follicular adenoma (neoplasm); nodules also associated with Hashimoto's disease and subacute thyroiditis

Cytology: multinodular goiter—multiple, large, colloid-filled nodules; few cells (appear benign); benign neoplasm—surrounded by capsule; higher density of cells; small follicles with little colloid; thyroid cancer—may appear similar to benign neoplasm under low-power magnification

Thyroid cancer: papillary cancer (up to 90% of cases); follicular carcinoma (»8%); anaplastic carcinoma (1%-2%; most aggressive; typically occurs in older patients); medullary carcinoma (moderately aggressive; produces calcito­nin); thyroid lymphoma (typically occurs in patients with Hashimoto's disease); metastatic carcinoma (very rare; most commonly from renal cell carcinoma)

Radioiodine scans: definition of "hot" nodule—iodine uptake increased in one lobe and greatly reduced in contra­lateral lobe; evaluation—although hot nodules almost always benign, only 5% of nodules hot; scans showing di­minished iodine uptake (ie, "cold") or increased uptake in one lobe but no contralateral suppression (ie, "warm") have little predictive value; thyroid scan reserved for patients with hot nodules (identifiable by suppressed serum levels of TSH)

Risk factors for thyroid cancer: irradiation of head and neck during childhood—from 1930s to 1970s, 1 million children in United States treated with low-dose external beam radiation therapy for benign disease; study found 39% eventually developed thyroid nodules and 11% developed thyroid cancer (more common among women; risk continued for decades); patients require lifetime follow-up; other risk factors—exposure to atmospheric radiation (eg, meltdown at nuclear reactor facility in Chernobyl) during childhood; Graves' disease; Hashimoto's disease; family history of thyroid cancer (but most cases not familial); factors that increase suspicion for malignancy—age <20 yr or >60 yr (with new nodules); rapid growth, hoarseness, or dysphagia (suggests invasion, but most thyroid cancers indolent); hypothyroidism (suggests Hashimoto's disease); hyperthyroidism (patient may have Graves' dis­ease); family history of multinodular goiter, familial colonic polyposis, familial medullary thyroid carcinoma, or multiple endocrine neoplasia type-2 (MEN2) syndrome

Initial evaluation: physical examination—multiple nodules suggest multinodular goiter, but do not rule out cancer; most cancers feel hard when palpated; cancer sometimes associated with palpable cervical lymph nodes; labora­tory tests—serum TSH for all patients; antithyroid antibody test only if Hashimoto's disease suspected; calcitonin only if medullary carcinoma suspected; no role for thyroglobulin

Imaging: US recommended; radioiodine scans only if hyperfunctioning nodule suspected; advantages of US—high echogenicity of thyroid tissue; high resolution; convenience; low cost; detects nonpalpable nodules; visualizes fea­tures (eg, cystic vs solid); aids in measurement of nodule; detects cervical masses (eg, when following patients with thyroid cancer); guides FNA; sonographic features that increase suspicion—hypoechoic; poorly defined, irregular margins; punctate calcifications; anteroposterior diameter greater than transverse diameter

Fine-needle aspiration: most important diagnostic test; simple procedure, performed with small-gauge needle (often requires no anesthetic); cytology identifies most thyroid cancers and enhances selection of surgical patients; predic­tive value—high sensitivity and specificity; nodules characterized as benign, malignant, or suspicious; few false negatives occur because of low incidence of thyroid cancer and high sensitivity of FNA

Suggested Reading

Alexander EK: Does exposure to childhood radiation influence the development of thyroid nodular disease and thy­roid cancer risk? Nat Clin Pract Endocrinol Metab 4:590, 2008; Beshay VE et al: Pituitary tumors: diagnosis, man­agement, and implications for reproduction. Semin Reprod Med 25:388, 2007; Daly AF et al: Update on familial pituitary tumors: from multiple endocrine neoplasia type 1 to familial isolated pituitary adenoma. Horm Res 71 (Suppl 1):105, 2009; Hari Kumar KV et al: Role of thyroid Doppler in differential diagnosis of thyrotoxicosis. En­docr Pract 15:6, 2009; Jin J et al: Incidental thyroid nodule: patterns of diagnosis and rate of malignancy. Am J Surg 197:320, 2009; Lania A et al: Central hypothyroidism and growth hormone treatment: clinical care. J Endocrinol In­vest 31(9 Suppl):66, 2008; Pecori Giraldi F: Recent challenges in the diagnosis of Cushing's syndrome. Horm Res 71 (Suppl 1):123, 2009; Singh PK, Buch HN: Adrenal incidentaloma: evaluation and management. J Clin Pathol 61:1168, 2008; Spence JD: Diagnosis of primary aldosteronism: for medical management, not just surgery. J Hyper­tens 27:204, 2009; Vassilatou E et al: Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol (Oxf) Dec 3, 2008 [Epub ahead of print]; Wirsing N, Hamilton A: How often should you follow up on a patient with newly diagnosed hypothyroidism? J Fam Pract 58:40, 2009.