USMLE Endocrine II

• Any patient with an acute, severe illness may have abnormal thyroid function tests (ie, abnormal thyroid hormone and TSH levels).
• The most common pattern is a fall in total and free T3 levels, with normal levels of T4 and TSH. This condition, often referred to as euthyroid sick syndrome, or "low T3 syndrome," is thought to be a result of decreased peripheral 5'-deiodination of T 4 due to caloric deprivation, elevated glucocorticoid and inflammatory cytokine levels, and inhibitors of 5'monodeiodinase (eg, free fatty acids, certain medications).
• There is a rough correlation between the severity of the underlying, non-thyroidal illness and the fall in T3 levels.
• If the non-thyroidal illness continues, serum T4 and TSH levels may eventually decrease as well.
• Therefore, thyroid function testing is generally not recommended in acutely ill patients.
• Testing should be delayed, if possible, until the patient has returned to baseline health.

• Pathophysiology behind this disease is oxidative stress leading to hemolysis.
• In normal patients, G6PD is responsible for catalyzing the reduction of NADP to NADPH, the first step in the hexose monophosphate shunt. This is the only source of NADPH in red blood cells (RBCs).
• NADPH is necessary to form reduced glutathione, which protects RBCs from oxidative injury.
• In the absence of G6PD and in the presence of oxidizing agents (eg, bacterial toxins, sulfa-containing drugs), hemoglobin becomes oxidized to form methemoglobin, denatured globin, and sulfhemoglobin.
• These molecules form insoluble masses (Heinz bodies) that attach to the RBC membrane, decrease membrane pliability, and promote RBC removal in the spleen's reticuloendothelial system (RES).
• Positive Prussian blue stain indicates the presence of hemosiderin, which is found in the urine during hemolytic episodes.

• Diabetic autonomic neuropathy occurs in >50% of patients with longstanding type 1 or 2 diabetes mellitus and can manifest as disorders of esophageal motility (eg, dysphagia), gastric emptying (eg, gastroparesis), or intestinal function (eg, diarrhea, constipation, incontinence).
• Gastroparesis presents with symptoms of anorexia, nausea, vomiting, early satiety, or postprandial fullness.
• Hypoglycemic episodes can occur with insulin administration prior to meals in patients with impaired gastric emptying or delayed absorption.

• Includes a combination of optimizing diabetes control; dietary modifications with increased fiber intake and small, frequent meals; and medications to improve gastric emptying.
• Metoclopramide has both prokinetic and antiemetic properties and is useful for symptomatic relief of nausea, bloating, and postprandial fullness in patients with diabetic gastroparesis.
• The use of metoclopramide can be associated with a small risk of extrapyramidal side effects (eg, tardive dyskinesia).
• Other alternate therapeutic options include erythromycin (more useful when used intravenously for acute exacerbations) and cisapride (restricted use in the United States due to the risk of cardiac arrhythmias and death).

• Glucagonoma is a rare pancreatic neuroendocrine tumor that usually presents with diabetes mellitus, necrolytic migratory erythema (NME), weight loss, diarrhea, and anemia.
• NME usually presents as erythematous papules or plaques that coalesce to form a large, painful, and inflammatory blister and/or crusting with central clearing.
• NME commonly occurs in the perineum, extremities, and face.
• The diabetes is usually mild in these patients, with normal to slightly high insulin levels, and is controlled with lifestyle changes and oral medications (rarely requiring insulin).
• The normocytic and normochromic anemia may be due to anemia of chronic disease or glucagon's direct effect on erythropoiesis.
• The serum glucagon level more than 500 pg/ml usually confirms the diagnosis in suspected patients.
• Abdominal imaging (computed tomography or magnetic resonance imaging) can localize the tumor and evaluate for metastases.

• During fasting states, glycogen reserves drop dramatically in the first 12 hours, by which time gluconeogenesis starts to play an important role.
• After 24 hours, gluconeogenesis represents the sole source of glucose production.
• The main substrates for gluconeogenesis are gluconeogenic amino acids (from breakdown of muscle protein), lactate (from anaerobic glycolysis), and glycerol 3-phosphate (from triacylglycerol in adipose).
• Alanine is the major gluconeogenic amino acid in the liver, and it is converted into pyruvate by alanine aminotransferase.
• Pyruvate is eventually converted to glucose

• Women normally produce a number of androgens, including testosterone (T), androstenedione (AS), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS).
• AS, DHEA, and T are produced by both the ovaries and the adrenals.
• In contrast, DHEAS is produced predominantly in the adrenal glands.

• Clinical Features: adrenal mass with rapidly progressive (ie, over weeks) hirsutism (excess terminal hair growth) and virilization(eg, vocal deepening, excessive muscular development, clitoromegaly)
• Most androgen-producing adrenal tumors overproduce DHEAS.
• Although DHEA and DHEAS are used as diagnostic markers, they have negligible androgenic activity, and the clinical features are due to the conversion of DHEA and DHEAS to more potent androgens (ie, AS and T). LH would be low due to negative feedback by Testosterone

• Oral estrogen formulations decrease clearance of thyroxine-binding globulin (TBG), leading to elevated TBG levels.
• TBG is synthesized and sialylated in the liver.
• Transdermal estrogen bypasses the liver and does not affect TBG levels.
• Patients with normal thyroid function can readily increase thyroxine production to saturate the increased number of TBG binding sites, but hypothyroid patients are dependent on exogenous thyroid replacement and cannot compensate.
• This results in decreased free thyroxine and increased thyroid-stimulating hormone. As a result, higher dosing of levothyroxine may be required.

• Spironolactone is also a progesterone and androgen receptor antagonist that can cause significant side effects in both men (eg, decreased libido, gynecomastia) and women (eg, breast tenderness, menstrual irregularities).
• Eplerenone is a very selective mineralocorticoid antagonist with a very low affinity for progesterone or androgen receptors. It has fewer endocrine side effects and is an alternate therapy

• Aldosterone increases sodium reabsorption (saves sodium), potassium secretion, and hydrogen secretion in the distal renal tubules.
• The sodium reabsorption also leads to water absorption. However, this is countered in a few days by a spontaneous diuresis that lowers the water and sodium (aldosterone escape).
• This returns the volume status to slightly above normal and results in mild hypernatremia (143-147 mEq/L) without significant peripheral edema.
• The hypokalemia directly increases renal bicarbonate resorption, which, combined with increased hydrogen secretion, results in metabolic alkalosis.

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• Patients with mild primary hyperaldosteronism may not have spontaneous hypokalemia, but they are prone to develop diuretic-induced hypokalemia.
• Severe hypokalemia can cause muscle cramps/weakness.
• Other findings include metabolic alkalosis and mild hypernatremia (1 43-147 mEq/L).
• Patients usually do not have peripheral edema due to spontaneous diuresis (aldosterone escape).

• The best screening test is early-morning plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio.
• However, drugs that significantly alter the PAC/PRA ratio (eg, spironolactone, eplerenone, amiloride, triamterene) should be withdrawn for 4 weeks before testing.
• A PAC/PRA ratio more than 20 with plasma aldosterone more than 15 ng/dL suggests primary hyperaldosteronism and requires further confirmatory adrenal suppression testing.
• Adrenal suppression testing usually involves salt loading and documenting inability to suppress serum aldosterone.
• Patients with positive adrenal suppression testing should then undergo adrenal imaging, usually by computed tomography (CT) scan

• Hyperaldosteronism is most commonly due to bilateral adrenal hyperplasia (50%-60%) or aldosterone-producing adrenal adenoma (40%-50%).
• If CT scan does not reveal a discrete unilateral mass·, adrenal vein sampling is recommended to differentiate between hyperplasia and adenoma.
• Surgery is preferred for adenoma, and medical therapy is preferred for hyperplasia.

• (Increased PRA, Increased PAC, PAC/PRA ratio around 10 )
• Causes:
• • Diuretic use
• • Cirrhosis or congestive heart failure
• • Renovascular hypertension
• • Renin-secreting tumor
• • Malignant hypertension
• • Coarctation of aorta

• MAS is caused by excessive intake of calcium and absorbable alkali (eg, calcium carbonate preparations used in patients with osteoporosis).
• The resulting hypercalcemia causes renal vasoconstriction and decreased glomerular blood flow.
• In addition, inhibition of the Na-K-2Cl cotransporter (due to activation of calcium-sensing receptors in the thick ascending loop) and impaired antidiuretic hormone activity lead to loss of sodium and free water.
• This results in hypovolemia and increased reabsorption of bicarbonate (augmented by the increased intake of alkali).
• In addition to hypercalcemia, metabolic findings in MAS include hypophosphatemia, hypomagnesemia, metabolic alkalosis and acute kidney injury.
• Parathyroid hormone levels are suppressed.

include thiazide diuretics, ACE inhibitors/angiotensin II receptor blockers and nonsteroidal anti inflammatory drugs.

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• • PTH-independent hypercalcemia (suppressed PTH) is usually due to malignancy, vitamin D toxicity, or extra-renal conversion of 25-hydroxyvitamin D to 1 ,25-dihydroxyvitamin D in granulomatous diseases (eg, sarcoidosis).
• • PTH-dependent hypercalcemia (elevated or inappropriately normal PTH) is usually due to primary hyperparathyroidism (PHPT).

• It is the most common cause of PTH-independent hypercalcemia and frequently presents with very high (eg, more than 14 mg/dl), symptomatic (eg, polyuria, constipation, nausea) calcium levels.
• HHM due to secretion of PTH-related protein (PTHrP) by malignant cells is associated with squamous cell (eg, lung, head and neck), renal, bladder, breast, or ovarian carcinomas.
• PTHrP causes increased bone resorption and increased reabsorption of calcium in the distal renal tubule.
• However, PTHrP does not induce the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D to the same extent as PTH does, and so 1,25 dihydroxyvitamin D levels will be low or low-normal.
• Causes of PTH-independent hypercalcemia in malignancy include bony destruction by osteolytic metastasis (eg, breast, non-small cell lung cancer, non-Hodgkin lymphoma, multiple myeloma), increased production of 1 ,25-dihydroxyvitamin D (eg, lymphoma), and increased interleukin-6 levels (eg, multiple myeloma).

• Corrected calcium = measured calcium + 0.8 x (4- albumin)
• Plasma calcium exists in 3 forms: ionized calcium (45%), albumin-bound calcium (40%), and calcium bound to inorganic and organic anions ( 15% ).
• An increased extracellular pH (due to respiratory alkalosis) causes hydrogen ions to dissociate from albumin molecules, thereby freeing up the albumin to bind with calcium. This increase in the affinity of albumin for calcium leads to decreased levels of ionized calcium.
• Ionized calcium is the only physiologically active form, which means that a decrease in ionized calcium can result in the clinical manifestations of hypocalcemia (eg, crampy pain, paresthesias, carpopedal spasm) even though total calcium is unchanged.
• Thus, patients can experience signs and symptoms of hypocalcemia due to respiratory alkalosis likely caused by hyperventilation

• Immobilization is due to increased osteoclastic bone resorption.
• The risk is increased in patients with a pre-existing high rate of bone turnover (eg, younger individuals, Paget disease).
• The onset of hypercalcemia is usually around 4 weeks after immobilization, although patients with chronic renal insufficiency may develop hypercalcemia in as little as 3 days.
• Bisphosphonates inhibit osteoclastic bone resorption and are effective in treating hypercalcemia of immobilization and reducing the associated bone loss.

• HHS is characterized by severe hyperglycemia (frequently more than 1000 mg/dl ) and increased serum osmolality (more than 320 mOsm/kg).
• There is little or no ketonemia or acidosis present, and most patients have pH more than 7.3 and serum bicarbonate more than 20 mEq/L.
• Patients with HHS also frequently develop neurologic symptoms (focal signs, lethargy, blurry vision, and obtundation) due to severe hyperglycemia and elevated serum osmolality.

• Most patients with HHS or DKA have normal or elevated serum potassium levels at initial evaluation. This is due to the combined effects of insulin deficiency and hyperosmolality, which promote the movement of potassium out of cells into the extracellular space.
• Despite normal serum levels, patients with HHS or DKA have a total body potassium deficit (3- 5 mg/kg) due to excessive urinary loss caused by osmotic diuresis induced by hyperglycemia.
• The clinical implication of potassium depletion is that insulin therapy for HHS can abruptly lower serum potassium levels and cause severe hypokalemia.
• In HHS, secretion of ADH by the posterior pituitary is stimulated by the increased plasma osmolality and hypovolemia/hypotension, though patients with chronic hyperglycemia will have a lesser ADH release and antidiuretic response.

• Hypercalcemia with an elevated PTH level, suggests PHPT.
• Normally, elevated plasma calcium suppresses PTH secretion.
• However in PHPT, PTH secretion from autonomously functioning parathyroid adenomas or parathyroid hyperplasia is not suppressed.
• Most patients with PHPT present with mild, asymptomatic hypercalcemia, but potential clinical features include nephrolithiasis, osteoporosis, nausea, constipation, and neuropsychiatric symptoms ("stones, bones, abdominal moans, psychic groans").
• Serum phosphorus is often normal but can be low in moderate-to-severe PHPT.
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• Patient has asymptomatic hypercalcemia, hypophosphatemia, and an elevated parathyroid hormone (PTH) level consistent with primary hyperparathyroidism (PHPT).
• PTH causes increased reabsorption of calcium from the distal tubule, but net urinary calcium excretion is increased due to excess resorption of calcium from bones.
• By contrast, familial hypocalciuric hypercalcemia is characterized by hypercalcemia with an elevated PTH but low urinary calcium excretion (often <100 mg/24 hr).

• Agranulocytosis is the most feared side effect, and is seen in approximately 0.3% of patients treated with
• antithyroid drugs.
• It is caused by immune destruction of granulocytes, and most cases occur within 90 days of treatment. Current recommendations state that once the patient complains of fever and sore throat, the antithyroid drug should be discontinued promptly and the WBC count measured.
• A total WBC count Jess than 1 ,000/cubic mm warrants permanent discontinuation of the drug.
• If the total WBC count is more than 1 ,500 per cubic mm, antithyroid drug toxicity is unlikely to be the cause of the sore throat and fever.

• If left untreated, patients with hyperthyroidism can develop rapid bone loss leading to osteoporosis and increased risk of fracture.
• Direct effects of the thyroid hormones cause increased osteoclastic bone resorption.
• Patients can also develop hypercalcemia and hypercalciuria due to increased bone turnover.
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• More than 99% of the circulating thyroid hormone pool is bound to 3 major transport proteins: TBG, transthyretin, and albumin.
• Only the free (ie, unbound) thyroid hormones are biologically active. Changes in binding protein levels can affect the total circulating pool of thyroid hormones, but if the hypothalamic-pituitary-thyroid axis is intact, free hormone levels are unchanged.
• High levels of estrogen (eg, pregnancy, oral contraceptive pills, hormone replacement therapy) increase the level of TBG by decreasing its catabolism and increasing its synthesis in the liver.
• As the additional TBG binds more thyroid hormone, thyroid hormone production increases to maintain a euthyroid state.
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• General manifestations of hyperthyroidism
• Symptoms:
• • Anxiety & insomnia
• • Palpitations
• • Heat intolerance
• • Increased perspiration
• • Weight loss without decreased appetite
• • Goiter
• Physical examination:
• • Hypertension
• • Tremors involving fingers/hands
• • Hyperreflexia
• • Proximal muscle weakness
• • Lid lag
• • Atrial fibrillation
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• Both toxic adenoma and multinodular goiter have a nodular pattern of uptake; however, in contrast to the focal uptake of radioactive iodine in toxic adenoma, uptake in patients with multinodular goiter shows a patchy distribution.
• Normally, TSH is the major driver for the production of thyroid hormones. However, the hyperplastic cells in toxic adenoma and toxic multinodular goiter overproduce thyroid hormone autonomously without TSH stimulation.
• Some of these patients have activating somatic mutations of the TSH receptors on the hyperplastic follicular cells, leading to TSH-independent activation of adenylyl cyclase.

• Acute thyrotoxic myopathy can present with severe distal or proximal muscle weakness, usually without bulbar or respiratory muscle involvement.
• Chronic hyperthyroid myopathy presents with proximal muscle weakness weeks to months after the onset of hyperthyroidism.
• Objective findings may include muscle atrophy.
• Treatment of hyperthyroidism usually improves the myopathy.

• Graves ophthalmopathy, including proptosis, swelling of the periorbital tissues, and involvement of the extraocular muscles (eg, diplopia, discomfort with ocular movements).
• Graves ophthalmopathy is due to the effects of activated T cells and thyrotropin receptor antibodies (TRAB) on TSH receptors on retro-orbital fibroblasts and adipocytes
• However, titers of TRAB increase significantly following RAI therapy, and RAI can cause worsening of ophthalmopathy.
• For this reason, administration of glucocorticoids with RAI is often advised to prevent complications in patients with mild ophthalmopathy