Endocrinology and Metabolism Flashcards

A 34-year-old woman with a history of lithium therapy for bipolar disorder presents with polyuria, polydipsia, and a serum sodium of 148 mEq/L. Her urine osmolality after 8 hours of water deprivation is 185 mOsm/kg. After administration of desmopressin (DDAVP), urine osmolality rises to 210 mOsm/kg. Which pathophysiologic mechanism best explains this blunted response to exogenous ADH?

Answer: Downregulation of aquaporin-2 channels in the collecting duct due to impaired cAMP-mediated signaling

Lithium causes nephrogenic diabetes insipidus by entering principal cells via ENaC channels and inhibiting adenylyl cyclase, reducing cAMP generation downstream of the V2 receptor. This impairs PKA-mediated phosphorylation and insertion of aquaporin-2 (AQP2) water channels into the apical membrane. The post-DDAVP rise in urine osmolality from 185 to 210 mOsm/kg (< 50% increase) confirms nephrogenic DI — partial response occurs because some residual AQP2 expression remains. Lithium does not destroy pituitary neurons, does not competitively antagonize V2 receptors, and COX-2 upregulation is not the primary mechanism of concentrating defect.

A 52-year-old man undergoes selective inferior petrosal sinus sampling (IPSS) for suspected Cushing's disease. Basal central-to-peripheral ACTH ratio is 1.8. After CRH stimulation, the ratio rises to 2.4 on the right side and 1.6 on the left. MRI of the pituitary is unremarkable. What is the most appropriate next step in management?

Answer: Proceed with right-sided selective transsphenoidal exploration targeting the right hemipituitary

An IPSS central-to-peripheral ACTH ratio ≥ 2 basal or ≥ 3 post-CRH confirms pituitary-source Cushing's disease with ~95% sensitivity and specificity. Here the post-CRH ratio is 2.4 on the right (≥ 2 is sufficient for lateralization when ≥ 3 threshold is not reached, though many centers use ≥ 1.4 lateralization ratio). Since pituitary source is confirmed (post-CRH ratio 2.4 > 2.0) and lateralization favors the right, right-sided hemipituitary exploration is appropriate even with a negative MRI — approximately 40–60% of corticotroph adenomas are MRI-occult. Ectopic ACTH is excluded by the central-to-peripheral gradient. Repeating biochemical confirmation is unnecessary after IPSS confirmation. Repeating IPSS is not indicated when the procedure was technically successful.

A 28-year-old woman presents with a 6-month history of amenorrhea, galactorrhea, and a serum prolactin of 340 ng/mL. MRI reveals a 14 mm pituitary macroadenoma. She is started on cabergoline 0.5 mg twice weekly. After 6 months of therapy, her prolactin normalizes and repeat MRI shows > 50% tumor reduction. She asks about discontinuing therapy to attempt pregnancy. Which statement best characterizes the risk of tumor growth during pregnancy if cabergoline is stopped?

Answer: Risk of symptomatic tumor enlargement during pregnancy is approximately 20–30% for macroadenomas not surgically treated prior to conception

For prolactinomas, the risk of clinically significant tumor enlargement during pregnancy depends on adenoma size and prior treatment. Macroadenomas (≥ 10 mm) that have not been surgically debulked carry a ~20–30% risk of symptomatic growth during pregnancy when dopamine agonists are discontinued, due to estrogen-driven lactotroph proliferation. This compares to < 3% for microadenomas. The 50% reduction in tumor size on cabergoline is favorable but does not eliminate risk for a macroadenoma. Estrogen does not suppress corticotrophs (it stimulates lactotrophs). Tumor reduction on dopamine agonist therapy does not reclassify a macroadenoma. Rebound hyperprolactinemia upon withdrawal does not universally exceed baseline and is not the primary mechanism of tumor growth risk.

A 61-year-old man with type 2 diabetes and an eGFR of 28 mL/min/1.73m² presents for medication review. His HbA1c is 8.9%. Current medications include metformin 1000 mg BID, glipizide 10 mg BID, and linagliptin 5 mg daily. His blood pressure is 148/92 mmHg and urine albumin-to-creatinine ratio is 620 mg/g. Which change to his diabetes regimen has the strongest evidence for reducing risk of kidney disease progression at this stage?

Answer: Discontinue metformin and linagliptin; initiate an SGLT2 inhibitor titrated to the lowest approved dose for kidney protection

At eGFR 28, metformin is contraindicated (hold at eGFR 200 is appropriate per EMPA-KIDNEY trial data (eGFR 20–45 enrolled), making option C more complete and mechanistically accurate.

A 44-year-old woman is found to have a serum calcium of 11.6 mg/dL on routine labs. PTH is 78 pg/mL (normal 15–65). 24-hour urine calcium is 95 mg/24h (reference > 200 mg for hypercalcemia). Her calcium-to-creatinine clearance ratio (CCCR) is 0.008. She has no symptoms and her DEXA scan shows Z-score of −1.0 at the lumbar spine. Her sister was recently diagnosed with the same condition. What is the most appropriate management?

Answer: Reassure and monitor without intervention; refer for genetic testing for CaSR or AP2S1 mutation

This presentation is classic for Familial Hypocalciuric Hypercalcemia (FHH), an autosomal dominant condition caused by loss-of-function mutations in the calcium-sensing receptor (CaSR) gene, or less commonly AP2S1 or GNA11. Key features: mild-moderate hypercalcemia, inappropriately normal-to-elevated PTH, markedly low 24-hour urine calcium (< 100 mg/day), and CCCR < 0.01 (the diagnostic threshold). Family history of similar calcium levels strongly supports FHH. FHH is benign — parathyroidectomy does not normalize calcium and is not indicated. Cinacalcet may lower calcium temporarily but is not standard of care for FHH. Genetic testing confirms the diagnosis and prevents unnecessary surgical intervention. DEXA Z-score of −1.0 does not meet criteria for parathyroidectomy even if primary hyperparathyroidism were confirmed.

A 38-year-old woman with Graves' disease has been on methimazole 10 mg daily for 18 months. Her free T4 and TSH are now normal. She is eager to pursue definitive therapy. She is 10 weeks pregnant. Her TRAb titer is 4.2 IU/L (reference < 1.75). Which statement best guides clinical decision-making regarding fetal and neonatal thyroid risk?

Answer: Elevated maternal TRAb at > 3× upper limit of normal in the third trimester predicts fetal/neonatal hyperthyroidism and warrants fetal surveillance with Doppler thyroid vascularity and fetal heart rate monitoring

TRAb (TSH receptor antibodies) are IgG immunoglobulins that cross the placenta from the first trimester onward and can stimulate the fetal thyroid (which becomes responsive to TSH at ~20 weeks). Maternal TRAb > 3× ULN (here 4.2 vs ULN 1.75, ratio ~2.4 — borderline) in the second and especially third trimester identifies fetuses at risk for fetal and neonatal hyperthyroidism. Guidelines (ATA, ETA) recommend fetal surveillance (Doppler thyroid vascularity, fetal heart rate, growth) in women with elevated TRAb. TRAb does cross the placenta from the first trimester. Neonatal Graves' disease risk is primarily predicted by TRAb titer, not free T4. Regarding drug choice: PTU is preferred in the FIRST trimester (lower teratogenic risk), and methimazole is generally acceptable after 16 weeks — the instruction to switch PTU for the remainder of pregnancy is incorrect; PTU has its own risk profile (hepatotoxicity) and the switch timing guidance is the reverse of current recommendations.