Endocrinology and Metabolism Flashcards

A 34-year-old woman with type 1 diabetes presents with recurrent hypoglycemia despite decreasing her insulin doses. She reports fatigue, salt cravings, and a 10-pound weight loss over 3 months. Morning cortisol is 3.2 mcg/dL. Which finding would most strongly support autoimmune polyglandular syndrome type 2 (APS-2) rather than isolated primary adrenal insufficiency?

Answer: Elevated TSH with low free T4

APS-2 (Schmidt syndrome) is defined by the co-occurrence of primary adrenal insufficiency with autoimmune thyroid disease (Hashimoto's or Graves') and/or type 1 diabetes. An elevated TSH with low free T4 (primary hypothyroidism) in a patient with type 1 diabetes and adrenal insufficiency confirms APS-2. Positive 21-hydroxylase antibodies confirm autoimmune etiology of the adrenal insufficiency but are present in isolated Addison's as well. Hyperkalemia/hyponatremia and low ACTH stimulation response are features of primary adrenal insufficiency regardless of whether it is isolated or part of APS-2.

A 52-year-old man undergoes surgical resection of a 3 cm pancreatic neuroendocrine tumor. Post-operatively, he develops persistent hypoglycemia with glucose nadir of 38 mg/dL during a 72-hour fast. Insulin level is 18 µU/mL, C-peptide is 4.2 ng/mL, and proinsulin is 22 pmol/L (normal <5). Urine sulfonylurea screen is negative. Which additional test would most definitively differentiate nesidioblastosis from occult insulinoma recurrence?

Answer: Selective arterial calcium stimulation with hepatic venous sampling

Selective arterial calcium stimulation with hepatic venous sampling (ASVS) is the gold standard for localizing focal insulin hypersecretion. In nesidioblastosis (diffuse beta-cell hyperplasia), calcium stimulation causes a diffuse, non-localizing insulin response from multiple arterial territories. In a focal insulinoma, a stepwise dominant response is seen from the specific artery supplying that region. 68Ga-DOTATATE is ideal for somatostatin receptor-positive NETs but insulinomas often have low SSTR2 expression. Endoscopic ultrasound may miss small recurrences. Glucagon stimulation tests cannot differentiate focal from diffuse disease.

A 28-year-old woman presents with amenorrhea, galactorrhea, and a serum prolactin of 340 ng/mL. MRI reveals a 1.8 cm pituitary macroadenoma. She is started on cabergoline 0.5 mg twice weekly. After 6 months, prolactin normalizes and the tumor shrinks 60%, but she reports new-onset compulsive gambling and hypersexuality. What is the most appropriate next step?

Answer: Discontinue cabergoline and initiate bromocriptine

Impulse control disorders (ICDs) — including pathological gambling, hypersexuality, binge eating, and compulsive shopping — are a recognized class effect of dopamine agonists, particularly cabergoline, due to stimulation of mesolimbic D3/D4 receptors. When ICDs develop, cabergoline should be discontinued. Bromocriptine has a lower affinity for extrastriatal dopamine receptors and a substantially lower risk of ICD and is the preferred alternative. Simply reducing cabergoline may not eliminate the risk and may compromise tumor control. Surgery is indicated for dopamine agonist resistance or intolerance, not as the first step when an alternative agonist is available. Adding an SSRI does not address the dopaminergic mechanism driving the ICD.

A 45-year-old man with a history of neck irradiation for Hodgkin lymphoma at age 20 is found to have a 1.2 cm thyroid nodule. Fine-needle aspiration returns Bethesda IV (follicular neoplasm). Molecular testing shows a PAX8-PPARγ rearrangement. Which statement most accurately characterizes the significance of this molecular finding?

Answer: It is highly specific for follicular thyroid carcinoma and supports proceeding directly to total thyroidectomy

PAX8-PPARγ rearrangement is found in approximately 30–40% of follicular thyroid carcinomas (FTC) and only rarely in follicular adenomas. Unlike BRAF V600E (which is diagnostic of malignancy in PTC), PAX8-PPARγ is not 100% specific but significantly increases the probability of malignancy in a Bethesda IV nodule, typically guiding surgeons toward total thyroidectomy rather than diagnostic lobectomy alone. It is not a feature of PTC and does not mandate central neck dissection, which is reserved for PTC with high-risk features. The presence of this rearrangement does not confirm benignity. While some FTCs show radioiodine resistance, this is not the primary clinical implication of PAX8-PPARγ — the malignancy risk stratification is.

A 38-year-old woman is evaluated for osteoporosis with a T-score of -2.9 at the lumbar spine. She has no fractures. Labs reveal calcium 10.9 mg/dL, phosphorus 2.0 mg/dL, PTH 88 pg/mL (normal 15–65), and 24-hour urine calcium of 95 mg/24h (low). Vitamin D is normal. Genetic testing shows a heterozygous inactivating mutation in CaSR (calcium-sensing receptor). Which management is most appropriate?

Answer: Parathyroidectomy is contraindicated; treat osteoporosis with bisphosphonates

This patient has Familial Hypocalciuric Hypercalcemia (FHH) due to a heterozygous loss-of-function CaSR mutation. The hallmark is hypercalcemia with inappropriately normal/elevated PTH and markedly low urine calcium excretion (typically <100 mg/24h, calcium-to-creatinine clearance ratio <0.01). Parathyroidectomy does NOT cure FHH — the set-point abnormality is in peripheral tissues (kidney, parathyroid), not a discrete adenoma. Surgery leaves patients hypercalcemic and risks permanent hypoparathyroidism. Cinacalcet may modestly lower calcium in FHH but is not routinely indicated except in the rare homozygous neonatal form. Sestamibi would be misleading, as there is no adenoma. Treating the complication (osteoporosis with bisphosphonates) without curative surgery is appropriate management.

A 55-year-old man with type 2 diabetes on metformin, empagliflozin, and insulin glargine presents with nausea, vomiting, and abdominal pain. Glucose is 198 mg/dL, bicarbonate 11 mEq/L, pH 7.19, anion gap 24, beta-hydroxybutyrate 4.8 mmol/L, and urine ketones 3+. Which factor most directly explains why euglycemic diabetic ketoacidosis (euDKA) occurs with SGLT2 inhibitors?

Answer: SGLT2 inhibition increases renal glucose excretion, lowering plasma glucose while glucagon-mediated ketogenesis is simultaneously upregulated

SGLT2 inhibitors cause euDKA through a two-pronged mechanism: (1) they increase urinary glucose excretion, which lowers plasma glucose and reduces the insulin-to-glucagon ratio (lower glucose → less insulin secretion → relative glucagon excess); (2) SGLT2 inhibitors directly increase glucagon secretion via an alpha-cell mechanism, driving ketogenesis from free fatty acids. The result is ketoacidosis without significant hyperglycemia. SGLT2 inhibitors do not directly inhibit beta-cell insulin secretion. They do not interfere with ketone measurement assays. While volume depletion and stress hormones can contribute, the primary mechanism is the glucose-lowering effect uncoupling the usual signal that suppresses ketogenesis, combined with direct glucagonotropic effects.