ENDOCRINOLOGY UPDATE
| THYROID DISORDERS —William A. Norcross, MD, Clinical Professor of Family Medicine, University of California,
San Diego, School of Medicine
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| Hypothyroidism: more common in women and elderly; difficult to determine whether screening for thyroid disease useful
because symptoms (eg, fatigue, depression) common and ubiquitous; hyperlipidemia—elevated low-density lipoprotein
(LDL) with elevated (≥10 mU/L) thyrotropin (TSH; controversy about subclinical hypothyroidism with lower TSH levels);
when diagnosing dyslipidemia, checking thyroid function reasonable; hypothyroidism causes hyponatremia and severe
myositis; drugs that affect thyroid function—lithium causes thyroiditis; dopamine, glucocorticoids, and phenytoin
decrease TSH secretion; metoclopramide, domperidone, and amiodarone increase TSH secretion; central
hypothyroidism—in primary hypothyroidism (failure at thyroid gland), TSH elevated and free thyroxine (T4 ) low; if hypothyroidism
suspected and TSH and free T4 low, consider problem at pituitary gland or hypothalamus; subclinical
hypothyroidism—TSH elevated (5-10 mU/L) and free T4 normal; patient relatively asymptomatic
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| Screening for hypothyroidism: second-generation TSH test—accurate to 0.1 mU/L; most commonly used; in most laboratories,
upper limit of normal ≈5.0 mU/L, but studies found upper limit of normal 2.0 to 2.5 mU/L (95% confidence interval;
means ≈50% of US population would have subclinical hypothyroidism); third-generation TSH test—accurate to
0.01 mU/L; used for diagnosis and monitoring treatment; pituitary takes 3 to 4 mo to adjust to new level of thyroxine, so
rechecking TSH every 3 to 4 mo reasonable (check sooner when restoring thyroid function in child or infant); free T4 —
particularly useful with unexpected TSH results; repeating TSH with free T4 can help diagnose central hypothyroidism);
antithyroid peroxidase and antithyroglobulin antibodies—check after diagnosis of hypothyroidism; positive in patients
with Hashimoto’s thyroiditis (permanently damages thyroid epithelium; outcomes include long-term hypothyroidism in
≈90% of cases)
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| Levothyroxine: treats most hypothyroidism; prohormone with little metabolic activity; cleaved in periphery by 5-deiodinase
to triiodothyronine (T3 ; active form of thyroid hormone); half-life ≈7 days, so giving once daily results in steady
state; generic formulations bioequivalent to brand-name forms; individual patient responses to thyroid hormone—
average replacement dose 1.6 µg/kg per day (no titration needed in young healthy adults); in elderly patients or those
with coronary artery disease (CAD) or heart failure (HF), start low (25 µg daily) and go slow (titrate up every 3-6 wk;
check for symptoms of HF or angina); patient should become clinically and chemically euthyroid; advise patients that
muscular and neuropsychiatric symptoms may take longer to improve; T3 —rarely indicated, but may be needed in older
and chronically ill patients who have no 5-deiodinase activity (do not become euthyroid with increased levothyroxine);
combination of T4 and T3 —not more efficacious in normal healthy people because T4 metabolized to achieve euthyroidism;
once patients euthyroid, recheck every year; CAD—start low, go slow; if patient not on β-blocker, add antianginal
therapy and continue treatment; may increase β-blocker dose (look at pulse rate to judge adequacy of β-blockade), or
treat as though treating unstable angina (evaluation by cardiologist for revascularization); pregnancy—increase levothyroxine
dose by ≈50% and monitor every trimester to maintain euthyroidism; exogenous estrogen—postmenopausal hormones
and oral contraceptives increase production of thyroid-binding globulin (TBG) by liver, resulting in elevated total
T4 (TSH should be normal)
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| Euthyroid patients: liothyronine (T3 ) for treatment of depression refractory to conventional antidepressant therapy; overweight,
depression, hyperlipidemia, and fatigue not indications for additional levothyroxine
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| Thyroid carcinoma: treat with levothyroxine after surgery; when invasive or metastatic, suppress TSH to <0.01 mU/L;
when prognosis good (eg, excision of well-demarcated papillary carcinoma) keep TSH suppressed at more moderate
level
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| Subclinical hypothyroidism: definition—patient has normal free T4 and feels relatively euthyroid; TSH slightly elevated;
prevalence in United States ≈4%; risk for progression to overt hypothyroidism 10% to 20% per year; risk factors—older
age; female sex; higher baseline TSH; presence of antithyroid antibodies; previous therapy for Graves’ disease; patients
may recover spontaneously; benefits of treatment—most patients feel better with levothyroxine replacement, but no evidence
of improved quality of life; improved lipids and cardiac function; discuss gray areas of treatment and options; give
levothyroxine to compliant patients; for patients resistant to taking treatment, follow annually and counsel about symptoms;
use judgment
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| Thyroid nodules: found in 60% to 70% of well population by magnetic resonance imaging (MRI); thyroid nodules in children
and teenagers unusual (cancer until proven otherwise); if patient hypo- or hyperthyroid, nodule less likely due to
cancer; fine needle aspiration biopsy (FNA)—sensitivity and specificity good; if benign, follow clinically; if malignant,
refer patient; if nondiagnostic, repeat with ultrasonography; if suspicious or indeterminate, subtotal thyroidectomy indicated;
if nodule large, try suppression; if small, observe and monitor; after 5 yr, nodule may become malignant; if nodule
grows, repeat FNA
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| Questions and answers: free T3 and T3 uptake testing—free T3 most useful when patient suspected of having thyrotoxicosis
and Graves’ disease, but free T4 normal; patient may have T3 toxicosis (T3 elevated); TSH and free T4 usually sufficient;
asymptomatic patient with moderate thyromegaly and normal TSH without palpable nodule—consider
lymphoma of thyroid and goiter; ask about symptoms associated with goiter (eg, compression of trachea); if goiter small
and developed slowly, follow clinically; if growth appears sudden, recommend biopsy; risk for osteoporosis in presence
of excess levothyroxine—evidence of lower bone density than in euthyroid patients; no clear evidence about incidence
of fracture; decrease levothyroxine dose; do not suppress TSH
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| MORE ABOUT THE THYROID —Robert Rushakoff, MD, Associate Clinical Professor of Medicine, University of California,
San Francisco, School of Medicine
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| Thyroid function testing: total T4 and total T3 ; free T4 and free T3 ; TBG affects total T4 and T3 ; T3 uptake inversely related
to thyroid binding; TSH—0 mU/L indicates primary hyperthyroidism; high levels indicate primary hypothyroidism;
radioactive iodine uptake—amount taken up by thyroid in 8 and 24 hr; useful for differential diagnosis of
thyrotoxicosis; does not provide information about thyroid function; dependent on underlying iodine intake (patients taking
high amount of iodine have low radioactive iodine uptake); radioactive iodine scanning—does not assess thyroid
function; useful for detecting hyperfunctioning nodules
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| Drugs that affect thyroid function: oral contraceptives—increase total T4 and decrease T3 uptake because of increased
TBG; TSH normal; anabolic steroids—decrease serum T4 ; free T4 and TSH normal; increase T3 uptake; patient euthyroid
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| Symptoms and signs of hyperthyroidism: palpitations; nervousness; fatigue; hyperdefecation; sweating; heat intolerance;
weight loss; neck swelling; neck pain; eye changes; decreased menstrual regularity; tachycardia; eyelid lag and stare due
to increased sensitivity to catecholamines; exophthalmos (pathognomonic for Graves’ disease); tremor; thyroid enlargement;
onycholysis; brisk reflexes; dermopathy
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| Thyrotoxicosis: primary—TSH 0 mU/L; free T4 high; secondary—rare; T4 high; TSH normal or slightly high; T3
toxicosis—TSH 0 mU/L and free T4 normal; free T3 may be high; may be seen in Graves’ disease or with single toxic
nodule that produces T3 but has low T4 production; checking thyroid-stimulating immunoglobulin (TSI) usually not necessary;
thyroid antibodies generally not helpful for hyperthyroidism; causes—Graves’ disease; autoimmune disease;
toxic multinodular goiter often seen in older patients (may be precipitated by high-iodine diet); single nodule (Plummer’s
nodule) >3 cm usually identified on physical examination; differential diagnosis—subacute thyroiditis and Graves’ disease
in young patients with history of malaise, neck pain, history of viral infection, and slightly enlarged and tender thyroid;
iodine-induced disease; silent thyroiditis; factitious thyrotoxicosis; less common causes include hypothalamic
disease, molar pregnancy (human chorionic gonadotropin [HCG] level high), and struma ovarii (teratoma)
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| Postpartum thyroiditis: can present as postpartum depression; initial hyperthyroidism followed by hypothyroidism (transient);
most common in patients with underlying autoimmune thyroid disease; management—observation; reasonable to
check TSI during early hypothyroidism to determine whether patient has postpartum thyroiditis or postpartum Graves’ disease;
cannot perform radioactive iodine testing if woman nursing
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| Differentiating Graves’ disease from subacute thyroiditis: TSH low; free T4 high; on physical examination, thyroid
gland “beefy” in Graves’ disease, but hard in thyroiditis; erythrocyte sedimentation rate (ESR) high in subacute thyroiditis;
24-hr radioactive iodine uptake elevated with increased turnover in Graves’ disease (no uptake in subacute thyroiditis)
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| Multinodular goiter: TSH low; free T4 and T3 can be high (same with toxic nodule); 24-hr uptake often unhelpful, but
multinodular goiter palpable on physical examination; imaging studies show multiple hot spots (single hot spot with single
nodule)
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| Treatment: Graves’ disease—1) antithyroid drugs; potential side effect, agranulocytosis; 2) radioactive iodine to ablate
thyroid, then place patient on thyroid hormone; 3) surgery; subacute thyroiditis—viral illness; treat symptoms with β-
blockers; antithyroid medications not useful because patient not producing thyroid hormone; treat pain with nonsteroidal
anti-inflammatory drugs (if severe, prednisone); toxic state resolves in 2 to 3 mo; then patients often have transient hypothyroid
period (determine whether to treat or to observe)
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| Thyroid disease in elderly: studies show no relationship between TSH levels in subclinical hypothyroidism and poor outcomes;
elderly patients who had slightly elevated TSH levels did better than those with normal levels; in newer studies,
low TSH levels (subclinical hyperthyroidism) do not appear associated with poor cardiovascular outcomes, except for increased
risk for atrial fibrillation; recent study showed higher levels of T4 (even in normal range) associated with increased
risk for atrial fibrillation
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| PROBLEMS INVOLVING THE PITUITARY, ADRENAL, AND PARATHYROID GLANDS —Dr. Rushakoff
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| Hypopituitarism: causes—tumors; radiation or surgery; head trauma; idiopathic; management—treat underlying cause;
TSH not good screening test for secondary hypothyroidism because inappropriately low and does not increase; screening
depends on free T4 level; if patient undergoing treatment for hypothyroidism, avoid cardiovascular collapse by making
sure patient does not have adrenal insufficiency before starting thyroid hormone therapy
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| Central adrenal insufficiency: renin aldosterone system intact (no hyperkalemia); use cosyntropin stimulation test
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| Pituitary tumors: microadenomas (<1 cm); macroadenomas (>1 cm); most tumors (60%) prolactinomas, 20% produce
growth hormone (GH), 10% produce corticotropin (ACTH), 10% nonfunctioning; signs and symptoms—endocrinopathy;
nonspecific neurologic symptoms (eg, headache, nerve palsies, visual field deficits); discovery may be incidental;
management—determine whether tumor functional; check TSH, free T4 , prolactin, and ACTH; cosyntropin stimulation
test if deficiency suspected; if excess production of ACTH suspected, obtain 24-hr urine cortisol; check testosterone level
in men; treatment surgery
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| Hyperprolactinemia: causes—pregnancy; lactation; nipple stimulation; exercise; coitus; stress; sleep; beer consumption;
pituitary tumors; pituitary stalk sections; hypothyroidism; estrogen; dopamine antagonists; selective serotonin reuptake
inhibitors (SSRIs); tricyclic antidepressants; verapamil; presentation in women—37% of women with
galactorrhea have prolactinoma; 18% of women with amenorrhea have prolactinoma; 75% of women with galactorrhea
and amenorrhea have prolactinoma (mostly microadenomas); presentation in men—impotence; decreased libido;
macroadenomas; management—check prolactin levels; thyroid tests (severe hypothyroidism can lead to hyperprolactinemia);
treatment—dopamine agonist (eg, bromocriptine, cabergoline); surgery secondary treatment
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| More about pituitary tumors: 80% macroadenomas; often detected many years after onset; may cosecrete prolactin;
rarely due to ectopic GH or GH-releasing hormone production from other tumors (eg, lung cancer); presentation—
hypertension; glucose intolerance; polyps; sweaty palms; carpal tunnel syndrome; hypogonadism; visual field deficits;
acromegaly; gigantism; diagnosis—insulinlike growth factor-1 (IGF-1; somatomedin C) level; treatment—surgery; radiation
therapy; drugs (eg, octreotide)
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| Adrenal disease: causes of primary adrenal failure—autoimmune; metastatic tumor; drugs (eg, ketoconazole); causes of
secondary adrenal failure—glucocorticoids or pituitary disease; symptoms—vague, eg, weakness, fatigue, anorexia,
weight loss, nausea, vomiting, diarrhea, abdominal pain, postural lightheadedness; hyperpigmentation on tongue or nails;
laboratory testing—cosyntropin (Cortrosyn) stimulation test (250 µg intramuscularly [IM] or intravenously [IV]);
check cortisol level 45 to 60 min later (rule out when cortisol >18 µg/dL in absence of adrenal failure); radiologic examination
of adrenal or pituitary gland to distinguish primary from secondary adrenal failure; treatment—hydrocortisone,
20 to 30 mg/day (two-thirds in morning, one-third in afternoon; double dose with stress); for primary adrenal failure,
fludrocortisone (Florinef)
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| Cushing’s syndrome: causes—Cushing’s disease due to ACTH secretion from pituitary adenoma; ectopic ACTH; adrenal
disease; clinical findings—rounded facies; plethora; striae; central obesity; masculinization; diagnosis—high 24-hr
urine cortisol (refer for ACTH and petrosal sinus testing)
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| Primary aldosteronism: accounts for 5% to 10% of hypertension; idiopathic or from adenoma or other rare problem;
features—hypertension; hypokalemia; mild alkalosis; screening—replete potassium; plasma aldosterone-to-renin ratio
(>20 highly suggestive); work-up—computed tomography (CT); resect if unilateral; give spironolactone if bilateral
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| Pheochromocytoma: rare; symptoms—episodic throbbing in head; diaphoresis; palpitations; tremor; weight loss; cold
hands and feet; orthostasis; rule of 10s—10% normotensive; 10% in children; 10% bilateral; 10% malignant; 10% extra-
adrenal; diagnosis—high 24-hr urine metanephrine and normetanephrine or plasma free metanephrine followed by imaging
studies
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| Adrenal incidentalomas: increase with age; determine whether lesion functioning, nonfunctioning, benign, or malignant;
screen for pheochromocytoma and subclinical Cushing’s disease with 24-hr urine cortisol; if patient has hypertension,
look for primary aldosteronism with aldosterone-to-renin ratio; tumor more likely benign if <4 cm and contains fat (suggests
myelolipoma); management—resect if functional; if not functional and <4 cm, repeat imaging at 6, 12, and 24 mo
(resect if changes seen); resect immediately if >4 cm
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| Hypercalcemia: albumin normal; high parathyroid hormone (PTH) indicates primary hyperparathyroidism; causes include
familial hypocalcuric hypercalcemia and lithium therapy; PTH and calcium high, phosphorus low; more often in women
>60 yr of age; generally single adenoma (check for multiple endocrine neoplasia [MEN] types 1 and 2); indications for surgery
(National Institutes of Health)—calcium above upper limits of normal; high 24-hr urine calcium; reduced creatinine
clearance; reduced bone mineral density (>2.5 by T score); patient <50 yr of age; nonsurgical management—follow calcium,
creatinine, and bone mineral density and keep patient hydrated; familial benign hypocalcuric hypercalcemia—
decreased urinary calcium with high PTH and calcium; treatment not needed
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Suggested Reading
Abalovich M et al: Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical
Practice Guideline. J Clin Endocrinol Metab 92:S1, 2007; Benbassat CA et al: Subacute thyroiditis: clinical characteristics
and treatment outcome in fifty-six consecutive patients diagnosed between 1999 and 2005. J Endocrinol Invest 30:631,
2007; Ciccarelli E et al: Diagnosis and drug therapy of prolactinoma. Drugs 51:954, 1996; Lynn WR et al: Tailor treatment
to the patient in thyrotoxicosis. Practitioner 251:37, 39, 41 passim, 2007; Menko FH et al: Familial benign hypercalcaemia.
Study of a large family. Q J Med 52:120, 1983; Metso S et al: Increased long-term cardiovascular morbidity
among patients treated with radioactive iodine for hyperthyroidism. Clin Endocrinol (Oxf), 2007; Papi G et al: Subclinical
hypothyroidism. Curr Opin Endocrinol Diabetes Obes 14:197, 2007; Terzolo M et al: Subclinical Cushing's syndrome in
adrenal incidentaloma. Clin Endocrinol (Oxf) 48:89, 1998; Van Isselt JW et al: The current status of radioiodine therapy
for benign thyroid disorders. Hell J Nucl Med 7:104, 2004; Vitti P et al: Clinical features of patients with Graves' disease
undergoing remission after antithyroid drug treatment. Thyroid 7:369, 1997.
Educational Objectives
| The goal of this program is to improve the management of common endocrine disorders. After hearing and assimilating this
program, the clinician will be better able to:
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 | 1. Identify factors that influence thyroid function, eg, hyperlipidemia and drugs.
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| 2. Use appropriate therapy for the treatment of hypothyroidism.
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| 3. Differentiate Graves’ disease from subacute thyroiditis.
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| 4. List features of Cushing’s syndrome and pituitary tumors.
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| 5. Identify patients with hypercalcemia who may benefit from surgery.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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 reported nothing to disclose.
Acknowledgements
Dr. Norcross spoke in San Diego, CA, at the 50th Annual Postgraduate Symposium Family Medicine Update 2007, presented
August 3-5, 2007, by the San Diego Academy of Family Physicians. Dr. Rushakoff was recorded in San Francisco, CA,
at the Family Medicine Board Review Course, presented July 9-12, 2007, by the University of California, San Francisco,
School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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