{"title": "Chapter 9: Endocrine and Metabolic Disorders", "flashcards": [{"q": "What are the JBDS criteria for DKA resolution?", "a": "pH >7.3, bicarbonate >15 mmol/L, AND blood ketones <0.6 mmol/L (or ketones cleared on urinalysis). All three criteria must be met. Do not stop insulin infusion until eating and drinking and long-acting insulin has been administered (at least 30–60 minutes before stopping VRIII)."}, {"q": "Name four precipitants of DKA.", "a": "Infection (most common — ~40%); missed insulin doses; new-onset type 1 DM; acute illness (MI, pancreatitis, surgery, trauma); pregnancy; drugs (SGLT2 inhibitors — euglycaemic DKA); alcohol excess; pump failure in those on continuous subcutaneous insulin infusion."}, {"q": "What are the biochemical features of primary hypothyroidism?", "a": "Elevated TSH (most sensitive test), low free T4, normal or low free T3. Levothyroxine replacement targets TSH 0.5–2.5 mU/L. Features: weight gain, cold intolerance, bradycardia, constipation, dry skin, periorbital puffiness, depression, prolonged relaxation phase of reflexes, raised cholesterol, macrocytosis."}, {"q": "Define thyroid storm and name three precipitants.", "a": "Thyroid storm (Burch-Wartofsky score ≥45): life-threatening hypermetabolic crisis — hyperpyrexia, tachycardia/arrhythmia, agitation/psychosis, vomiting/diarrhoea, heart failure, jaundice. Precipitants: surgery on a thyrotoxic gland, radioiodine therapy, infection, MI, trauma, iodine-containing contrast/amiodarone. Treatment: propylthiouracil, potassium iodide (after PTU), dexamethasone, propranolol, cooling."}, {"q": "What is the ADA diagnostic criteria for diabetes mellitus?", "a": "Any one of: fasting plasma glucose ≥7.0 mmol/L; 2-hour glucose ≥11.1 mmol/L on OGTT; HbA1c ≥48 mmol/mol (6.5%); random glucose ≥11.1 mmol/L with symptoms. Asymptomatic: requires two separate abnormal results. Confirmed in the presence of diabetic symptoms (polyuria, polydipsia, unexplained weight loss)."}, {"q": "Name three features of Cushing's syndrome.", "a": "Centripetal obesity (buffalo hump, supraclavicular fat pads, moon face); proximal muscle weakness; thin skin with easy bruising and purple striae; hypertension; hyperglycaemia; osteoporosis; hirsutism; psychiatric disturbance (depression, psychosis). Commonest cause: exogenous corticosteroid use. Endogenous: pituitary adenoma (Cushing's disease, 70%), ectopic ACTH, adrenal adenoma."}, {"q": "What is the short Synacthen test (SST) and what result confirms adrenal insufficiency?", "a": "Cosyntropin 250 µg IV given; serum cortisol measured at 0 and 30 minutes. A peak cortisol <450 nmol/L (threshold varies by assay: confirm with local laboratory) at 30 minutes confirms adrenal insufficiency. A rise <200 nmol/L suggests primary adrenal failure. A normal test does not exclude secondary adrenal insufficiency if testing is within 4–6 weeks of a pituitary insult."}, {"q": "What is the significance of a serum calcium >3 mmol/L?", "a": "Hypercalcaemia >3 mmol/L is symptomatic — 'bones, stones, groans, and moans': bone pain (osteoclast activation), renal calculi, nausea/vomiting/constipation/anorexia, and psychiatric symptoms (confusion, depression, psychosis). Life-threatening >3.5 mmol/L requires urgent IV 0.9% NaCl rehydration, then bisphosphonates (pamidronate IV) if malignancy-related. Commonest cause: primary hyperparathyroidism (outpatient), malignancy (inpatient)."}, {"q": "What is metabolic syndrome and name its five diagnostic components?", "a": "A cluster of cardiovascular and metabolic risk factors. Three of five criteria (IDF/AHA/NHLBI 2009): central obesity (waist circumference ethnicity-specific; ≥94 cm men, ≥80 cm women in Europeans); raised triglycerides (≥1.7 mmol/L); low HDL (<1.0 mmol/L men, <1.3 mmol/L women); raised BP (≥130/85); raised fasting glucose (≥5.6 mmol/L or T2DM on treatment)."}, {"q": "What is the mechanism of action of metformin?", "a": "Metformin inhibits mitochondrial complex I (NADH dehydrogenase), reducing hepatic ATP production. This activates AMPK, which suppresses gluconeogenesis and lipogenesis in the liver — the primary glucose-lowering mechanism. Additionally reduces GI glucose absorption and improves peripheral insulin sensitivity. Does not cause hypoglycaemia when used as monotherapy."}], "quiz": [{"q": "What is the most important initial step in managing DKA?", "opts": ["Start insulin infusion immediately", "IV fluid resuscitation with 0.9% NaCl — 1L over first hour, assess for haemodynamic compromise", "Check urine ketones", "Give subcutaneous insulin"], "ans": 1, "exp": "IV fluid resuscitation is the most critical initial step in DKA, addressing dehydration (typically 5–8L deficit), improving renal perfusion, and reducing serum glucose and ketones even before insulin is started. JBDS recommends 1L 0.9% NaCl over first hour; rate adjusted based on haemodynamic assessment. VRIII (variable rate insulin infusion) is started after initial fluids (typically second bag)."}, {"q": "A patient with type 2 diabetes has HbA1c 72 mmol/mol on metformin. What is the preferred second-line agent if they also have established cardiovascular disease?", "opts": ["Sulphonylurea", "GLP-1 receptor agonist or SGLT2 inhibitor with proven cardiovascular benefit (e.g. semaglutide, empagliflozin)", "DPP-4 inhibitor", "Acarbose"], "ans": 1, "exp": "NICE NG28/SIGN guidelines and ADA/EASD 2023 consensus recommend GLP-1RAs (semaglutide, liraglutide) or SGLT2 inhibitors (empagliflozin, dapagliflozin) as preferred second-line agents in T2DM with established ASCVD, heart failure, or CKD due to proven cardiorenal outcomes benefits (EMPA-REG OUTCOME, LEADER, SUSTAIN-6 trials)."}, {"q": "Which test best confirms primary hyperaldosteronism?", "opts": ["Random serum aldosterone", "Aldosterone-to-renin ratio (ARR) followed by confirmatory saline infusion test", "24h urinary sodium", "Serum potassium only"], "ans": 1, "exp": "ARR >30 ng/dL per ng/mL/h (or >800 pmol/L per mU/L in SI units) is a screening threshold for primary hyperaldosteronism (Conn's syndrome). Confirmatory testing (saline infusion test, fludrocortisone suppression test, or oral sodium loading) is required before adrenal imaging and adrenal vein sampling to localise the source (unilateral adenoma vs bilateral hyperplasia)."}, {"q": "What distinguishes Graves' disease from toxic multinodular goitre on thyroid scan?", "opts": ["Both show the same pattern", "Graves': diffuse homogeneous increased uptake; toxic MNG: multiple areas of focal increased uptake with suppression elsewhere", "Graves': cold nodule; toxic MNG: diffuse uptake", "TSH distinguishes them, not scanning"], "ans": 1, "exp": "Technetium pertechnetate or I-123 thyroid scan: Graves' disease shows diffuse, homogeneous increased tracer uptake (stimulated by TSI antibodies throughout all follicular cells). Toxic MNG shows patchy, heterogeneous uptake with multiple 'hot' autonomous nodules and suppression of surrounding thyroid tissue. The pattern directs treatment choice."}, {"q": "What is the triad of multiple endocrine neoplasia type 1 (MEN1)?", "opts": ["Phaeochromocytoma, parathyroid adenoma, medullary thyroid cancer", "Parathyroid adenoma, pituitary tumour, pancreatic islet cell tumour — the '3 Ps' (MEN1/menin gene mutation)", "Parathyroid adenoma, thyroid cancer, adrenal adenoma", "Insulinoma, glucagonoma, VIPoma only"], "ans": 1, "exp": "MEN1 (autosomal dominant, menin gene mutation on chromosome 11q13): Primary hyperparathyroidism (>90% — most common initial manifestation), pituitary adenoma (prolactinoma most common), pancreatic neuroendocrine tumours (gastrinoma most common — Zollinger-Ellison syndrome). Surveillance: annual biochemistry and imaging from adolescence."}, {"q": "A patient develops confusion, weakness, and Na⁺ 128 mmol/L after starting carbamazepine. What is the most likely mechanism?", "opts": ["Cerebral salt wasting", "Syndrome of inappropriate ADH (SIADH) — carbamazepine increases ADH secretion/sensitivity, causing water retention and dilutional hyponatraemia", "Addison's disease", "Hypothyroidism"], "ans": 1, "exp": "Carbamazepine is a common cause of drug-induced SIADH — it potentiates renal ADH action, causing inappropriate water retention. Other drugs: SSRIs, antipsychotics, NSAIDs, opioids, vincristine, cyclophosphamide. SIADH: low plasma osmolality, urine osmolality >100 mOsm/kg, urine Na >20 mmol/L, clinically euvolaemic. Management: fluid restriction ± demeclocycline/tolvaptan."}, {"q": "What is the most common cause of hypercalcaemia in hospitalised patients?", "opts": ["Primary hyperparathyroidism", "Malignancy (bone metastases, PTHrP secretion, myeloma, lymphoma 1,25-dihydroxyvitamin D production)", "Sarcoidosis", "Thiazide diuretics"], "ans": 1, "exp": "Malignancy is the most common cause of hypercalcaemia in hospitalised patients (50–65% of cases). Mechanisms: osteolytic bone metastases (breast, lung, kidney, myeloma); PTHrP production (solid tumours — breast, lung squamous, renal); 1,25-OH-D3 production (lymphoma). Primary hyperparathyroidism is most common in outpatient/community settings."}, {"q": "What is the mechanism of SGLT2 inhibitor-induced euglycaemic DKA?", "opts": ["Direct beta-cell toxicity", "Relative insulin deficiency (from reduced calorie intake, illness, or fasting) + carbohydrate restriction with SGLT2 inhibition promotes ketogenesis while glucosuria masks hyperglycaemia — DKA with near-normal glucose", "Direct stimulation of glucagon", "Inhibition of hepatic glucose production"], "ans": 1, "exp": "SGLT2i-DKA: glucosuria reduces plasma glucose (masking DKA), while relative insulin deficiency (illness, surgery, fasting, or missed insulin in T1DM) promotes lipolysis and ketogenesis. Ketones rise to DKA threshold without typical hyperglycaemia. Risk is higher in T1DM. SGLT2i should be withheld 48–72h before elective surgery and during acute illness/prolonged fasting."}, {"q": "What is the Whipple's triad for insulinoma?", "opts": ["Insulin >200 pmol/L, glucose >3 mmol/L, symptoms relieved by insulin", "Symptoms of hypoglycaemia, documented blood glucose <2.5 mmol/L during symptoms, and relief of symptoms with glucose administration", "Fasting hypoglycaemia, C-peptide elevated, proinsulin elevated", "Hypoglycaemia, tachycardia, diaphoresis only"], "ans": 1, "exp": "Whipple's triad: (1) symptoms consistent with hypoglycaemia; (2) documented low plasma glucose (<2.5 mmol/L) at time of symptoms; (3) relief of symptoms with glucose administration. 72-hour supervised fast confirms the diagnosis (demonstrates inappropriate insulin secretion relative to hypoglycaemia). CT/MRI and endoscopic ultrasound localise the tumour."}, {"q": "What investigation confirms phaeochromocytoma?", "opts": ["Random serum catecholamines", "24-hour urinary catecholamines/metanephrines OR plasma free metanephrines (most sensitive)", "CT abdomen alone", "Serum chromogranin A"], "ans": 1, "exp": "Plasma free metanephrines (sensitivity >95%) or 24h urinary fractionated metanephrines are the biochemical investigation of choice for phaeochromocytoma. Metanephrines are the O-methylated metabolites of adrenaline and noradrenaline; they are continually secreted from the tumour unlike catecholamines. CT/MRI adrenal follows positive biochemistry for anatomical localisation."}, {"q": "What is the preferred test for diagnosing primary adrenal insufficiency (Addison's disease)?", "opts": ["Random serum cortisol alone", "Short Synacthen Test (SST): 250 µg tetracosactide IV/IM; cortisol measured at 0 and 30 (±60) min; peak <450 nmol/L confirms adrenal insufficiency. Paired morning ACTH should be measured simultaneously", "24-hour urinary free cortisol", "Salivary cortisol only"], "ans": 1, "exp": "SST is the gold standard for diagnosing adrenal insufficiency. Peak cortisol <450 nmol/L (laboratory-specific threshold) at 30 min = fail. Elevated ACTH (>300 ng/L) with a failed SST confirms primary adrenal failure (Addison's). Anti-adrenal antibodies (anti-21-hydroxylase) confirm autoimmune Addison's (~80% of cases). Hydrocortisone replacement + fludrocortisone for primary AI; hydrocortisone alone for secondary AI."}, {"q": "What are the clinical features of hyperosmolar hyperglycaemic state (HHS)?", "opts": ["pH <7.3, ketones >3 mmol/L, glucose >11 mmol/L", "Extreme hyperglycaemia (glucose >30 mmol/L), marked hyperosmolality (>320 mOsm/kg), severe dehydration, altered consciousness — but NO significant ketosis or metabolic acidosis; occurs in type 2 diabetes", "Glucose 11–20 mmol/L with ketonuria", "Lactic acidosis with normal glucose"], "ans": 1, "exp": "HHS: plasma glucose >30 mmol/L (often 40–60 mmol/L), osmolality >320 mOsm/kg (calculated: 2×[Na] + glucose + urea), GCS impairment proportional to osmolality. Absent or minimal ketosis (sufficient endogenous insulin to suppress lipolysis). Dehydration typically 8–10L. Management: gradual fluid replacement (0.9% NaCl initially), insulin only after glucose fails to fall with fluids alone, LMWH prophylaxis (high VTE risk), identify precipitant."}, {"q": "What is the mechanism of SIADH and name three causes.", "opts": ["Excessive aldosterone secretion", "Inappropriately elevated ADH (arginine vasopressin) secretion despite low serum osmolality, causing free water retention and dilutional hyponatraemia. Causes: CNS disease (meningitis, SAH, stroke), pulmonary disease (pneumonia, TB, SCLC — ectopic ADH), drugs (SSRIs, carbamazepine, cyclophosphamide, NSAIDs, tricyclics, omeprazole), post-operative state, pain/nausea", "Excessive salt loss in urine", "Psychogenic polydipsia"], "ans": 1, "exp": "SIADH diagnosis (Bartter-Schwartz criteria): plasma osmolality <275 mOsm/kg, urine osmolality >100 mOsm/kg (concentrated urine despite dilute plasma), urine sodium >20 mmol/L, clinical euvolaemia, normal thyroid/adrenal function. Treatment: fluid restriction ±3% NaCl for symptomatic/acute cases; demeclocycline or tolvaptan (V2 receptor antagonist) for chronic SIADH; treat underlying cause."}, {"q": "What is the most accurate test for diagnosing Cushing's syndrome?", "opts": ["Serum morning cortisol", "Late-night salivary cortisol (most sensitive for hypercortisolaemia), 24-hour urinary free cortisol (UFC), or low-dose dexamethasone suppression test (LDDST — cortisol fails to suppress <50 nmol/L at 9 AM after 1 mg dexamethasone at 11 PM)", "Random ACTH", "Single morning serum cortisol"], "ans": 1, "exp": "Screening for Cushing's syndrome requires at least two of: late-night salivary cortisol (×2); 24h UFC (×2); LDDST (1 mg overnight or 2-day 0.5 mg QDS). Each has different sensitivity/specificity. Late-night salivary cortisol is highly sensitive because cortisol has a diurnal nadir at midnight — which is lost in Cushing's syndrome. ACTH-dependent (pituitary or ectopic) vs ACTH-independent (adrenal) is then established using plasma ACTH levels."}, {"q": "What is the treatment for hyperosmolar hyperglycaemic state (HHS)?", "opts": ["Immediate insulin infusion identical to DKA", "Gradual IV 0.9% NaCl replacement (target osmolality fall <3–4 mOsm/kg/h); insulin only when glucose fails to fall ≥5 mmol/L/h with fluids alone (or if ketones >1 mmol/L); LMWH anticoagulation; identify and treat precipitant (infection most common)", "IV bicarbonate infusion", "Rapid fluid replacement to correct all deficit in 12 hours"], "ans": 1, "exp": "Unlike DKA, HHS requires gradual fluid correction to prevent rapid osmolality shifts (cerebral oedema risk). Target rate of osmolality fall: 3–4 mOsm/kg/h. 0.9% NaCl is used initially (even when hypernatraemic — corrects volume first). Insulin is cautiously introduced only after glucose fails to fall with fluids. Potassium replacement as needed. Full fluid deficit corrected over 48–72 hours."}, {"q": "What are the characteristic eye signs of Graves' disease?", "opts": ["Reduced visual acuity from cataracts", "Proptosis/exophthalmos (bilateral, asymmetric), lid lag (von Graefe's sign), lid retraction, chemosis, periorbital oedema, ophthalmoplegia — Graves' ophthalmopathy from TSI-stimulated fibroblast proliferation and GAG deposition in retro-orbital tissues", "Pupillary constriction", "Horner's syndrome"], "ans": 1, "exp": "Graves' ophthalmopathy (TED — thyroid eye disease): caused by cross-reactive antibodies (TRAb) stimulating retroorbital fibroblasts to produce glycosaminoglycans, causing inflammation, proptosis, and restrictive myopathy. Severity graded by NOSPECS/CAS (Clinical Activity Score). Treatment: selenium supplementation for mild CAS; IV glucocorticoids + radiation for moderate-severe; orbital decompression for sight-threatening disease (compressive optic neuropathy)."}, {"q": "What is the mechanism of action of GLP-1 receptor agonists (e.g. semaglutide, liraglutide)?", "opts": ["Inhibit glucose reabsorption in the kidney", "Bind GLP-1 receptors on pancreatic beta cells (glucose-dependent insulin secretion, glucagon suppression), slow gastric emptying, reduce appetite via central hypothalamic receptors — leading to weight loss and HbA1c reduction with low hypoglycaemia risk", "Block intestinal glucose absorption", "Inhibit DPPIV enzyme"], "ans": 1, "exp": "GLP-1 RAs (semaglutide, liraglutide, dulaglutide, exenatide) are incretin mimetics. Their actions: (1) Stimulate insulin secretion glucose-dependently; (2) Suppress glucagon; (3) Delay gastric emptying; (4) Reduce appetite centrally. Benefits beyond glucose lowering: significant weight loss (semaglutide 2.4 mg SC = average 15% body weight reduction in STEP trials), CV protection, renal protection. Side effects: GI (nausea, vomiting), injection site reactions, pancreatitis (rare)."}, {"q": "What are the clinical features of panhypopituitarism?", "opts": ["Only growth hormone deficiency", "Deficiency of all anterior pituitary hormones: GHD (fatigue, reduced muscle mass, central adiposity), ACTH deficiency (central adrenal insufficiency — no hyperpigmentation), TSH deficiency (secondary hypothyroidism), gonadotrophin deficiency (hypogonadism — erectile dysfunction, amenorrhoea), prolactin deficiency (failure of lactation); vasopressin deficiency (cranial DI) if posterior pituitary involved", "Hyperprolactinaemia as the primary feature", "Isolated diabetes insipidus"], "ans": 1, "exp": "Panhypopituitarism results from destruction of the pituitary gland (tumour, surgery, radiation, infarction — Sheehan's syndrome, apoplexy, infiltrative disease). Order of hormonal loss typically: GH and gonadotrophins first, then TSH, then ACTH, then prolactin. Treatment: sequential hormone replacement starting with hydrocortisone (before levothyroxine — thyroid replacement can precipitate adrenal crisis if cortisol insufficient), then levothyroxine, then sex hormones, then GH if indicated."}, {"q": "What is diabetic ketoacidosis (DKA) and what are its three biochemical criteria?", "opts": ["Severe hyperglycaemia with hyperosmolality", "Blood ketones >3 mmol/L (or ++/+++ urine ketones); blood glucose >11 mmol/L (or known diabetes); venous pH <7.3 (or bicarbonate <15 mmol/L). All three must be present — ketosis and acidosis are the defining features, not glucose alone", "Glucose >30 mmol/L without acidosis", "Hyperglycaemia + glycosuria alone"], "ans": 1, "exp": "JBDS-IP 2023 DKA criteria: (1) glucose >11 mmol/L or known DM; (2) blood ketones ≥3 mmol/L OR urine ketones ≥2+ on dipstick; (3) bicarbonate <15 mmol/L OR pH <7.3 (venous). Euglycaemic DKA (glucose <11 mmol/L) occurs in pregnancy and with SGLT2 inhibitors — ketone and pH criteria still met. Management: IV fluids, VRIII, potassium replacement, treat precipitant."}, {"q": "What is the clinical presentation of an adrenal incidentaloma and when should it be investigated further?", "opts": ["All adrenal incidentalomas require immediate surgery", "An adrenal mass discovered incidentally on imaging; investigation warranted for: mass >4 cm, suspicious radiological features (non-homogeneous, >10 HU on unenhanced CT), or evidence of hormonal excess (hypertension, hypokalaemia, Cushingoid features, virilisation)", "Only if symptomatic", "Never requires investigation if <5 cm"], "ans": 1, "exp": "Adrenal incidentaloma evaluation: (1) Radiological characterisation — lipid-rich adenoma: <10 HU unenhanced CT, rapid washout; (2) Biochemical screening: plasma metanephrines (phaeochromocytoma — exclude first as anaesthesia without alpha-blockade is dangerous), 1 mg ODST (subclinical Cushing's), aldosterone/renin if hypertensive. Surgery for confirmed functioning tumours and masses >4 cm or enlarging. Radiology and hormones guided follow-up for non-functioning adenomas."}]}