Endocrine Flashcards

Question

DM Ix, PE and diagnostic criteria

Answer 1

Diagnostic criteria (must know!) American Diabetic Association (ADA) criteria: any one • HbA1c ≥ 6.5% • Fasting plasma glucose ≥ 7.0 mmol/L • 2-hour post OGTT plasma glucose ≥11.1 mmol/L • Random plasma glucose ≥11.1 mmol/L (in the presence of classical hyperglycemic symptoms) FamMed: Asymptomatic + 2 abnormal readings OR Symptomatic + 1 abnormal reading *Fasting blood glucose 5.6-7 = impaired fasting glycaemia * OGTT plasma glucose 7.8-11.1 = impaired glucose intolerance Fasting plasma glucose - ≥7.0 - Fasting ≥8h 2-hour post-oral glucose tolerance test (OGTT) plasma glucose - ≥11.1 - Pre-procedure: 3 days of normal diet & activity, fast overnight - Procedure: at 9am, drink 75g anhydrous glucose in 300mL water in 10min (free water intake in between) - Measurement: check plasma glucose at baseline & 120min - (C/I if initial glucose is very high: life-threatening hyperglycemia) HbA1c - ≥6.5% - Glycated haemoglobin that persists throughout the life of the RBC —> mean BG level over the lifespan of RBC (~120 days) Falsely high if rapid RBC turnover (e.g. pregnancy, haemolytic anaemia, thalassaemia major) Inaccurate in CKD: hemodialysis, EPO treatment Alternatives: fructosamine, glycated albumin, 1,5-anhydroglucitol, continuous glucose monitoring (CGM) Physical examination in diabetes 1. Underlying secondary causes - Cushingoid features - Features of acromegaly 2. Signs of DM complications - Measure BP, postural BP, BMI, urine dipstix - Skin: ulcers, acanthosis nigricans, necrobiosis lipoidica diabeticorum Foot: - Ulcers, deformities, amputation, fungal infection - Pes cavus, sensory loss [neuropathy] - Capillary refill, atrophic changes, pulses [PVD] - Ankle edema [nephropathy] Neuro: - Muscle atrophy, small hand muscle wasting, power [neuropathy] Cardiac: - Heart failure signs [CAD], carotid bruit, murmurs Abdomen: - Lipodystrophy due to insulin injection

Answer 2

Management overview • Treatment targets: Individualised glycaemic control o HbA1c < 7% in general – stricter (6.5%) for young / short DM Hx, less stringent for elderly / advanced DM o BP < 130/80 o Lipids: HDL >1.0 (M) or >1.3 (F), LDL <1.8 (<1.4 if Hx of CAD), TG < 1.7 • Stat with 3-6 months of lifestyle modifications (decreased HbA1c by 1-2%) o Diet (complex carbohydrates, low fat, small frequent meals) o Aerobic exercise o Smoking cessation, limit alcohol intake • Pharmacotherapy (refer to next page) • Manage associated conditions: HT, hyperlipidaemia, obesity • Screen & manage complications (see separate section)

Answer 3

- globe subluxation - exposure keratitis - compressive optic neuropathy - glaucoma

Answer 4

1. Metformin - start: 500mg BD / 850mg daily (Nax: 850mg tds) - MoA: Biguanides: decrease hepatic glucose production, increase insulin sensitivity - oral, taken after or with food - pros: weight neutral, used in pregnancy, few hypoglycaemia - cons: GI (metallic taste, diarrhoea, vitamin b12 deficiency—> numbness, poor memory), Metformin induced lactic acidosis (Mx: stop Metformin, Actrapid prn, NaHCO3 prn, haemodialysis prn) - C/I: renal imoair( C/I if GFR<30, half dose if GFR 30-45), risk of lactic acidosis: Hx, CT contrast , increased LFT, sepsis 2. Sulphonylurea e.g. glicazide, glipizide - MoA: increase insulin secretion - oral : 15-30 mins before meal - pros: rapid - cons: hypoglycaemia, weight gain with increase appetite - C/I: GFR<30 3. DPP4 inhibitor e.g. linagliptin - MoA: increase incretin—> increase insulin secretion after meal - oral - pros: weight neutral, few hypoglycaemia - cons: pancreatitis, pancreatic CA/ CHF 4. GLP1 agonist e.g. liraglutide, semaglutide - MoA: increase insulin secretion after meal - SC injection weekly - pros: weight loss, cardio protective, few hypoglycaemia - cons: GI upset, pancreatitis, medullary thyroidal CA - C/I: renal impairment , pancreatic disease, Hx of MTC/MEN2, Hx of gallstone 5. Thiazolidonedione e.g. pioglitazone - MoA: increase insulin sensitivity - oral - pros: useful in fatty liver, renal impairment - cons: fluid retention, weight gain, increased fracture risk, possible CA bladder, worsen macular edema - C/I: CHF, liver impairment, Hx of CA bladder 6. SGLT2 inhibitor e.g. empaglifozin - MoA: block SGLT2 in proximal tubule —> decrease renal glucose reabsorption - oral - pros: few hypoglycaemia, weight loss, cardio protective , benefit in CkD, decrease BP 3-5mmHg - cons: GU infection (vulvovaginal candidiasis, urosepsis, UTI), euglycaic DKA, postural hypotension - C/I: T1DM, T2DM with GFR<30 Summary (First line = metformin) • Clinical CV disease: SGLT2 inhibitor or liraglutide (GLP-1 agonist with proven CV benefits) • HF or CKD: empagliflozin (proven CV & renal benefits) • ESRF (eGFR <30): linagliptin / alogliptin (*excreted through liver), selected sulphonylureas (e.g. glipizide, gliclazide), GLP-1 agonist, insulin o C/I to metformin (lactic acidosis), SGLT2i (dehydration), most sulphonylureas, other DPP4i, pioglitazone (fluid retention) • None of above: depends on whether prefer weight loss (GLP1RA/ SGLT2i) or minimal hypoglycaemia (SGLT2i/ GLPRA, DPP4i/ TZD)

Answer 5

• decreased HbA1c by 1.5-3.5% • First-line if initial HbA1c high • Side effects o Weight gain o Hypoglycaemia: monitor BG o Lipodystrophy, lipohypertrophy: rotate injection site Types of insulin Types of preparations: • Basal supplement: intermediate / long-acting insulin (e.g. NPH, glargine, determir, degludec) • Pre-meal bolus: rapid-acting / short-acting insulin (e.g. lispro, aspart, regular) • Pre-mixed: combination 1. Rapid acting Insulin - Aspart (Novorapid) / Insulin Lispro (Humalog) - Prandial - onset 10min - duration: 3h - admin: 15 min before meal 2. Short acting (regular) - Regular human insulin (Actrapid HM) / Regular human insulin (Humulin R) - Prandial - onset 30min - duration 8h - admin: 30 mins before meal 3. Intermediate - NPH (Protaphane HM) / NPH (Humulin N) - Basal - onset 1h - duration 24h - admin OD / BD 4. Long - Glargine (Lantus) / Detemir (Levemir) - Basal - onset 3h - duration 24h - admin OD (OM or bedtime) 5. Ultra-long - Degludec (Tresiba) - Basal - onset 30min - duration 42h - admin OD 6. Premixed - 30% Novorapid + 70% NPH (NovoMix 30) / 30% Actrapid + 70% NPH (Mixtard 30HM) - mixed - onset 30 min - 24h duration - admin Novomix: 15min / Mixtard: 30min **Human insulin: can clump together (“dimerization”) and cause slow & unpredictable absorption —> insulin analogue** Initiation of insulin therapy in T2DM Basal insulin initial dose: 0.2U/kg/day or 10U intermediate or long-acting insulin at bedtime (0.5U/kg/day in obese patients), then fasting glucose 3x/week (target H’stix 4-7) 1. Multiple daily injection - Rapid / short-acting insulin before 3 meals (increased AM dose for Dawn phenomenon (increased BG from 2am to 8am due to counter-regulatory hormones, not a/w nocturnal hypoglycemia), increased dose for main meal) Intermediate / pre-mixed insulin at bedtime - initial dosage: 0.3-0.5U/kg - Preferred in : T1DM, More motivated / active patients - pros: Most physiological, Adjust pre-meal dose by meal size - cons: Frequent injections, Frequent H’stix: tds + nocte 2. BD insulin regimen - Premixed / intermediate-acting insulin: 2/3 dose before breakfast, 1/3 dose before dinner - 0.3-0.5U/kg - preferred in T2DM +daytime glycemia, Less motivated but regular lifestyle -pros: simple - cons: Require regular mealtime, Nocturnal hypogly —> Morning rebound hypergly (Somogyi phenomenon: Nocturnal hypoglycemia —> Rebound morning hyperglycemia due to counter-regulatory hormones) - oral DM drug: Keep metformin (sensitivity of insulin —> may use lower dose) Stop sulphonylurea (hypogly) 3. Once daily supplementary - Intermediate-acting insulin: Give at bedtime (night-time add on) - 0.2 unit/kg BW - preferred in T2DM + fasting glycemia - pros: simple, increase patient acceptance to insulin - cons: >0.5U/kg: weight gain, - oral DM drug: Keep metformin, Sulphonylurea half max dose Titration of insulin dosage - Hyperglycemia before meal: short-acting insulin before previous meal - Early morning hypoglycemia: decreased night insulin / have a snack before sleep Insulin use during intercurrent illness • Maintain calories intake • Requirement on insulin: increased due to catabolic effect of infection, decreased due to loss of appetite • Hstix QID, adjust insulin accordingly • Insulin use in critically ill patients o DKI o Insulin pump: if fluid overload; more frequent H’stix

Answer 6

Pre-op preparation • Investigations: standing/ lying BP, pulse, glucose, HbA1c, RFT/ electrolytes/ HCO3, ECG, urinalysis • Target: 5-11 mmol/L • Admit 1-2 days before major OT for DM control Day of operation • Well controlled: omit insulin/ OHA on day of OT (may continue if minor OT) • Poorly controlled / On insulin / High-dose OHA: start DKI infusion Q4-6h after fasting / at least 2h before operation o D5 500ml o 10mmol KCl (fixed dose to avoid error) o Insulin: add according to sliding scale • Monitoring: Hstix & K Q1h Post-op care • Continue DKI infusion until stable + resume eating o Resume insulin: give sc insulin 30 mins before off IV insulin • Monitoring: ECG, Hstix & K Q6h

Answer 7

IV contrast: RFT if no prior RFT within 12mo • Renal function normal (i.e. eGFR ≥ 30 within 6mo / ≥ 45 within 12mo): • Renal function normal but AKI: stop metformin on the day —> check RFT 48h after exam —> resume if normal • Renal function poor: consult medical, then manage as above IA contrast: • Stop metformin on the day —> check RFT 48h after exam —> resume if normal

Answer 8

Not to be confused with: • Insulin pump: for hyperglycaemia • DI drip: for hyperkalaemia

Answer 9

• Stop 3 days before elective OT / immediately before emergency OT • Start DKI when fasting and monitor BG • Check serum BOHB before and after OT • Resume SGLT2i when solid oral intake

Answer 10

Aetiology (6I): insulin deficiency (T1DM), infection (e.g. chest infection, UTI), inflammation (e.g. pancreatitis), infarct (silent MI), iatrogenic (e.g. anti-psychotics, steroids, SGLT2i), ingestion (e.g. meth, cocaine) Pathophysiology • Hyperglycaemia: increased gluconeogenesis & glycogenolysis + decreased glucose uptake into cells (lack of insulin) • Ketosis: absolute insulin deficiency —> lipolysis release acetyl CoA —> ketogenesis Clinical features • Polyuria & polydipsia • Hypovolemia: o Signs of dehydration (tachycardia, hypotension, dry mucous membrane) o Decreased consciousness - correlate with degree of hyperosmolarity but not acidosis o CVS (chest pain) o Abdomen: vomiting usually precedes abdominal pain (c.f. surgical causes) • K abnormalities: muscle weakness, arrhythmia • Acidosis: Kussmaul's breathing (deep, fast breathing pattern to compensate for HAGMA), fruity odour (acetone) Investigations + subsequent monitoring 1. Confirm diagnosis • Plasma & urine glucose —> monitor hourly • Urine dipstick ± plasma ketones/BOHB • ABG (repeat prn) • RFT, CaPO4 ± Mg —> monitor RFT hourly until BG <14 o PseudohypoNa: ECF expansion o HypoK / hyperK both possible: total K deficit due to K+ loss in osmotic diuresis, but serum K may remain high due to insulin deficiency (decrease uptake into cell) & metabolic acidosis • ± Amylase: increase even if no pancreatitis 2. Underlying cause • ECG: hyperK (tented T wave, widened QRS), hypoK (flattened T wave, prominent U wave) • CXR • Septic work-up: CRP, blood & urine C/ST • Clotting profile Management of DKA Principles: rehydration + insulin + K Monitor: vitals, I/O, H’stix, ketones, RFT, ABG Q1h 1. Rehydration: improve the circulatory volume and tissue perfusion • Resuscitation by IV NS 1-2L in first hour, then 100ml/h titrating against hydration status & urine output o Fluid in first 12hrs should not exceed 10% BW: avoid cerebral oedema o Give 0.45% NS if Na > 150 2. Insulin: clear the ketones, normalize the glucose and osmolarity • IV insulin infusion pump: to clear ketone o Only when K > 3.5 o Dose: 0.15 IU/kg bolus, then 0.1 IU/kg/h (target BG lower 3-4/h) o When BG ≤14: change NS to D5; and decreased insulin dosage to maintain BG 8-12, decrease monitoring to Q2-4h o Start SC insulin (maintenance) when AG normal and resume diet, then stop IV 2h after that - Estimate daily requirement = 70% of total dose - Give as intermediate-acting insulin: 2/3 in morning, 1/3 in evening 3. Correct electrolyte and acid base balance • KCl 10-20 mmol/h (if K < 5): titrate according to K level, aim K at 4-5 • NaHCO3: only if pH < 7.0 o Dosage: 50mmol (pH 6.9-7.0), 100mmol (pH < 6.9) o Must check K & ABG o No evidence of improving mortality, but with complications [Renal] 4. Identify and treat • Treat hypotension and circulatory failure precipitating cause • Antibiotics if evidence of infection 5. Avoid complications of treatment • Cerebral oedema: o MC in young patients < 20y o MOA: ?excessive rate of IV fluid infusion, rapid fall in [Na], rapid correction of hyperosmolality o Mx: r/o hypoglycaemia, IV mannitol or hypertonic saline (3%), hyperventilation, CT brain • Cognitive impairment (memory, attention, IQ) • DVT: hyperviscosity state

Answer 11

Overall similar to DKA, but • Pathophysiology: o Hyperosmolarity o No ketosis due to presence of small amount of insulin • Clinical features o Dehydration: more gradual onset, and thus more severe o K+ depletion: less severe o Ketosis/ acidosis absent: no Kussmaul's breathing o Hyperosmolality: change in mental state - more prominent • Investigations: o Serum urea is the best prognostic factor • Management: o Fluid replacement: more is required, NS or 1/2 NS if Na (to avoid hyperNa) o Insulin: less than DKA, ~half dose (i.e. 0.05U/kg/h) – watch out for overshoot hypoglycemia

Answer 12

1. DKA Plasma glucose: >14 Electrolytes: PseudohypoNa (ECF expansion), K+ depletion more severe ABG: pH < 7.3, HCO3 < 15 Effective osmolality (2[Na]+glucose): Variable Ketones: Moderate ketonuria (2+ on urine dipstix), Moderate ketonemia ≥3 mmol/L, High serum BOHB* 2. HHS Plasma glucose: >33.3 Electrolytes: HyeprNa (dehydration), K+ depletion less severe ABG: pH > 7.3, HCO3 > 15 Effective osmolality (2[Na]+glucose): >320 Ketones: Mild ketonuria / ketonemia Note: DKA/HHS can cause hemichorea-hemiballism • Investigation: CT brain (r/o subthalamic nucleus infarct) • Management: optimize glucose control with insulin pump / DKI drip

Answer 13

Definition: blood glucose ≤ 3.9 mmol/L Prolonged OGTT Procedure • Overnight fast • PO 75g anhydrous glucose • Check BG & insulin Q1h x 5 / when symptomatic Clinical features • Whipple's triad: BG < 3.9 + Symptoms of hypoglycemia + rapid relief by glucose administration • Sympathetic symptoms: palpitation, tachycardia, sweating, tremor - may be blunted in DM patients (Patient without: autonomic neuropathy, beta blocker, poor controlled type 1 DM) • Neuroglycopenic symptoms (due to decreased activity of CNS): dizziness, fatigue, confusion, seizure Investigations (taken at time of hypoglycemia) • Plasma glucose: Confirm hypoglycemia (H’stix is not accurate) • Plasma insulin & C-peptide • CBC, LRFT, CRP/ESR, septic workup, cardiac enzymes (silent MI) • HbA1c (ongoing glyceminc control) • Urine ± plasma ketones (absent = hyperinsulinism) • Special tests o Urine sulphonylurea [OHA overdose] o Prolonged fasting test [insulinoma] o Prolonged OGTT [reactive hypoglycemia] – limited use o Short Synacthen test + ACTH [Addison’s] o Glucagon stimulation test [GH def.] Aetiology Fasting-Excessive glucose utilisation 1. Insulin administration - high serum insulin - low C-peptide 2. Oral hypoglycemia drugs - high serum insulin - high C-peptide - History - Urine drug screen 3. Insulinoma - high serum insulin - high C-peptide even during fasting - Prolonged fast test 4. Extra-pancreatic tumours - Retroperitoneal fibrosacroma, hepatoma —> high big IGF-2 -> suppression.GH release —> low IGFBP3 and IGF1 —> high free IGF-2 —> low hepatic glucose production + high glucose uptake by peripheral tissues - low serum insulin - low C-peptide - high IGF-2 - low IGFBP3 Fasting-Diminished glucose production 5. Endocrine disease - Adrenal insufficiency - Pituitary insufficiency: low GH - Short Synacthen test + ACTH 6. Liver disease e.g. cirrhosis - low glycogen reserve - Hx of liver disease - LFT, USG small liver 7. Renal disease - Uraemia: decrease liver gluconeogenesis, low appetite - RFT 8. Autoimmune cause - Agoonist autoAb to insulin receptor and beta cells - Antibodies Post prandial 9. Autoimmune cause - Agonist Ab to insulin - Antibodies and increase insulin but reduce C-peptide 10. Post-gastrectomy syndrome - rapid absorption of glucose —> excessive insulin - History, low K, low PO4 11. Alcohol related - low gluconeogenesis - high ketones Management • Resuscitation (A, B, C) • Confirm hypoglycaemia by blood glucose (NOT H’stix), but do not delay treatment • Conscious: 10-15g simple carbohydrates (e.g. soft drink), then carbohydrate meal • Decreased consciousness: D50 40ml IV stat via large vein with saline flush (or D20 100ml), then D10 infusion • Unable to obtain IV access: IM glucagon 1mg or oral glucose (after airway protection) • Monitor BG & H’stix Q1h until stable, depending on RFT/LFT and type of drugs taken • Manage underlying cause o Insulinoma [SUR]: • Exclude MEN1 (check CaPO4, PTH, prolactin, gastrin) • Confirm Dx by prolonged fasting test and localization studies • Mx: frequent small meals, diazoxide (300-800decrease insulin secretion, S/E: hirsutism, fluid retention), octreotide, surgical resection o NICTH: surgical resection, increase caloric intake ± high-dose glucocorticoid / glucagon infusion / GH

Answer 14

Pathophysiology • Mechanisms: non-enzymatic glycation of proteins, activation of polyol pathway, formation of advanced glycated end-products (AGE), etc. • Pathology: thickening of capillary basement membrane, increased vascular permeability Macrovascular complications x3 1. Coronary heart disease - Risk of MI 3-5x higher - Leading cause of death in T2DM - "High risk" under the risk stratification for CHD —> intensive statin therapy 2. Ischaemic stroke - Risk of stroke 2.5x higher 3. Peripheral arterial disease - Intermittent claudication, foot ulcer, foot gangrene - Risk of LL amputation 15x higher Mx: - BP < 130/80 - LDL ≤ 1.8 - Smoking cessation Microvascular complications x3 1. Diabetic retinopathy Patho: increase retinal blood flow disrupts metabolism —> retinal vessels damage —> hypoxia —> compensatory neovascularisation (fragile) Fundoscopic findings: papilledema is NOT a feature! • Non-proliferative (NPDR): “MDS HIV” o Microaneurysms o Dot & blot haemorrhage (deeper than flame haem.) o Soft exudates (cotton wool spots) – infarcted nerves o Hard exudates – lipids leaked out o Venous beading o Intraretinal microvascular abnormalities (IRMA) • Proliferative (PDR): o Neovascularization (due to VEGF) o Vitreous haemorrhage • Diabetic macular oedema (DME): occur at any stage • Complications: o Tractional retinal detachment o Rubeosis (neovascularization at iris) o Secondary glaucoma Causes of visual loss in DM: • DR: sudden (vitreous haemorrhage, retinal detachment) vs gradual (DMO) • CV risk factors: glaucoma, cataract, AMD Mx: Vitreous haemorrhage: pan-retinal photocoagulation, vitreoretinal surgery Secondary glaucoma: control IOP DMO: • Intravitreal injection, e.g. anti- VEGF (bevacizumab), steroid • Macular grid laser 2. Diabetic nephropathy - Risk factors: high GFR, poor BP control, high HbA1c Clinical features • Glomerular hyperfiltration (0-5y): GFR • Microalbuminuria (5-10y): 30-300mg/day albumin • Macroalbuminuria (10-15y): > 300mg/day • Clinical nephrotic syndrome (diabetic glomerulosclerosis) • Progression to ESRD (15-30y) Renal biopsy findings: GBM thickening, mesangial expansion, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) Mx: Screening: uACR since Dx (T2DM) or 5 years after Dx (T1DM) • Normal: < 30mg/g (< 30mg/day) CV risk factors control: ACEI/ ARB (beneficial even if normal BP), statins, smoking cessation Glycemic control: SGLT2 inhibitors, GLP1 agonists, insulin ESRD: stop metformin & SGLT2i, use drugs that are not renally metabolized (glipizide, linagliptin, insulin) 3. Diabetic neuropathy Mixed patterns can occur: • Symmetrical sensory / sensorimotor neuropathy: length-dependent, symmetrical -> glove-and-stocking pattern —> foot ulcer, Charcot's joint • Asymmetrical motor neuropathy (diabetic amyotrophy): progressive weakness and wasting of proximal muscles • Mononeuropathy / “mononeuritis multiplex”: most commonly affect CN3, CN6, median n., femoral n., sciatic n., common peroneal n. o DDx: subacute combined degeneration of cord due to metformin-induced B12 deficiency —> test dorsal column • Autonomic neuropathy: CV (postural hypotension), GI (gastroparesis, alternating diarrhoea/constipation), GU (urinary retention, erectile dysfunction) Mx: Screening: 128 Hz tuning fork, 10g monofilament fibre Foot care education - Cleanse with soap and water - Apply topical moisteurizers - P&O for fit athletic shoes and thick socks, avoid walking barefoot - Treat all minor injuries & infection Neuropathic pain: SNRI (e.g. duloxetine), TCA (e.g. amitriptyline), pregabalin/ gabapentin Gastroparesis: domperidone, metoclopramide Diabetic foot • Multifactorial: PVD (macrovascular) + sensory neuropathy (microvascular) + autonomic neuropathy (↓sweating, microvascular) + poor glucose control (decreased wound healing) + poor footwear • Clinical features: o Neuropathy: paraesthesia, painless, ulcer, repeated microtrauma (cannot feel foot) • Charcot joint (neuropathic arthropathy): rocker-bottom foot, destruction of small joints o Ischaemia: loss of pulses, claudication, rest pain, gangrene • Prevention: foot hygiene (see above) • Treatment: treat infection (moisturiser + topical antibiotics), debridement of dead tissues, amputation Other complications • Cutaneous: o Diabetic dermopathy: atrophic brown spots commonly in pretibial region - "shin spots" (fig.) o Necrobiosis lipoidica diabeticorum (fig.) o Acanthosis nigricans o Granuloma annulare: ring popular lesions on back of hands and feet • Musculoskeletal: o Juvenile cheiroarthropathy: chronic stiffness of hand due to skin contracture over joints secondary to glycosylated collagen, positive Prayer's sign o Dupuytren's contracture o Frozen shoulder (adhesive capsulitis) • Cataracts: o Subcapsular and senile cataracts secondary to glycosylated lens protein and increased sorbitol

Answer 15

Hyperthyroidism - thyroid storm - thyroid heart disease: AF, HF - Osteoporosis - Thyrotoxic periodic paralysis Hypothyroidism - Proximal myopathy (change in myocyte permeability), increase risk of statin myopathy - Carpel tunnel syndrome (mucopolysaccharides deposition) - Frozen shoulder -Myxoedema coma: CHF, coma - Hyperlipidaemia & complications of obesity - Neuropsy: dementia, depression - Cretinism (in children)

Answer 16

TSH, fT4 Thyroid imaging • Radioisotope thyroid scan (123I) (Technetium-99): preferred in thyrotoxic patients with nodular thyroid o Supersede RAIU (lower radioactive dose, higher resolution) o Differentiate hot nodule (low malignant risk) vs cold nodule (5% malignant risk —> USG for FNAC) o C/I: pregnancy, breastfeeding o Different uptake patterns - low uptake: transient thyroiditis, extrathyroidal T4 source - Single uptake: Toxic adenoma - Mutiple uptake: toxic multi ocular goitre - whole gland uptake: Graves’ disease • Thyroid ultrasound +/- FNAC: preferred in euthyroid/ hypothyroid patients o Measure size of gland o Differentiate solid vs cystic nodule o Facilitate FNAC Anti-thyroid antibodies • TSH receptor antibodies*: Graves' • Anti-TPO, anti-thyroglobulin: Graves', Hashimoto's thyroiditis Investigations for complications Hyperthyroidism • Bone profile: increased Ca, increased ALP (bone remodelling / CMZ-induced cholestasis) • RFT: decreased K (TPP) • decreased red cell zinc Hypothyroidism: • CBC: macrocytic anaemia (non-megaloblastic) • Electrolytes: hypoNa (fluid retention) • Lipid: 2o cause of hyperlipidaemia • CK: thyroid myopathy (c.f. much higher CK in rhabdomyolysis) • Prolactin increased : due to increase TRH

Answer 17

1. Graves’ disease - Association: pernicious anaemia, Hashimoto, etc - Specific signs: • Graves' ophthalmopathy (ophthalmoplegia, exophthalmos, proptosis, chemosis) • Thyroid acropathy (clubbing) • Pretibial myxoedema (non-pitting edema) • Lymphoid hyperplasia (LN, spleen) Ix: - anti-TSH receptor - Anto-TPO, anti-TG - thyroid scan: diffuse uptake 2. Toxic solitary nodule Toxic MNG (19%) - Most common in elderly > 60y - Thyroid scan: focal/heterogenous uptake 3. Subacute thyroiditis (De Quervain's) (5%) - Fever, neck pain, preceded by URTI - Phase: thyrotoxic (6-8 weeks) —>hypothyroid (6-8 weeks) —> normalised - Management: self-limiting • Symptomatic (propranolol, NSAID): self-limiting • ATD not useful • FU for possible hyperthyroidism - Thyroid scan: decreased uptake - Increased ESR - Serology: all negative 4. Drugs - Amiodarone, lithium: hyperthyroid or hypothyroid - Iodine contrast (up to 18 weeks post-contrast) - Thyroid scan 5. HCG (pregnancy) - Separate reference range during pregnancy Mx: monitor fT4 (decline after 1st trimester), no Tx required - AVOID thyroid scan 6. Exogenous source - Iatrogenic over-replacement of T4 - Slimming agents (e.g. tiratricol) - USG Doppler: decreased flow - Blood thyroglobulin decrease - Stool T4 increase Other rarer causes: TSH-producing pituitary adenoma, Hashitoxicosis, post-partum thyroiditis, struma ovarii

Answer 18

Type 1 - pathogenesis: Iodine-induced hyperthyroidism, (Jod-Basedow phenomenon) - background pathology: Often present: pre-existing MNG / Graves’ - Amiodarone duration: Shorter (<2 years) - Ix: Doppler USG-high blood flow, Thyroglobulin-normal, IL-6 - normal - Mx: stop amiodarone, High dose anti-thyroid drugs (e.g. 40-60mg CMZ) ± Short-term lithium (~4wk) to speed up recovery ± Thyroidectomy, Treat until urine iodide normalizes Type 2 - Destructive thyroiditis (direct cytotoxicity of amiodarone) - no background pathology - longer amiodarone duration - (>2 year) - Ix: Ix: Doppler USG-low blood flow, Thyroglobulin-high, IL-6 - increase - Mx: stop amiodarone, High dose steroids 40-60mg/day (anti-inflammatory +inhibit conversion of T4 to T3) ± Short-term lithium (~4wk) ± Thyroidectomy Amiodarone-induced hypothyroidism • Occur in patients with pre-existing Hashimoto’s thyroiditis • Pathology: iodine load —> failure to escape from Wolff-Chaikoff effect • Management: T4 supplement

Answer 19

Management overview 1. Beta blockers - Symptomatic relief of thyrotoxicosis (Propranolol: + inhibit T4-T3 conversion) - C/I: Asthma, COPD, heart block, thyrotoxic heart failure (cautious) 2. Anti-thyroid drugs (ATD) - First episode of Graves’ disease / Preparation for RAI/ surgery / Pregnancy (PTU —> CMZ) - C/I: Agranulocytosis, Baseline ANC < 0.1 3. RAI - Graves’ disease with failed ATD - Toxic adenoma / toxic MNG - Complications: TPP, thyrotoxic heart disease - Post-thyroidectomy for CA - C/I: Pregnancy & breastfeeding (contraception for ≥6m), Retrosternal goitre (radiation thyroiditis —> oedema), Graves' orbitopathy: steroid cover if use inevitable, Thyroid storm: risk of transient hyperthyroidism, Iodine allergy 4. Surgery - 4C: uncontrolled, compression, CA, cosmetic Antithyroid drugs (ATD) 1. Carbimazole - TPO inhibitor - Start: 10mg BD / TDS; Max: 20mg TDS First line except below (∵more potent, longer half-life, less hepatotoxicity, less bitter taste) 2. Propylthiouracil - TPO inhibitor + Inhibit peripheral conversion conversion of T4 to T3 - 100-200mg TDS - preferred when first trimester pregnant (decrease found in placenta), Thyroid storm Onset: 6-8 weeks (t1/2 T4 7 days) —> propranolol cover + FU with TFT after 8 weeks Efficacy: • Graves': long term remission in 50% —> 2nd course of ATD or RAI • Toxic nodules/ MNG: ineffective – 100% relapse, only for control before RAI / surgery • Thyroiditis: ineffective Duration: 12-18 months —> another 18 months trial —> consider RAI / surgery • Start at high dose (e.g. carbimazole 10mg TDS) and titrate down depend on TFT • Role of TRAb level: persistently high conc. = higher risk of relapse —> continue ATD for 12 months more / consider RAI / surgery Monitoring: • fT4 every 8-10 weeks (reflect more the actual thyroid function c.f. TSH: with time lag) • CBC D/C, LFT Side effects • Allergic reaction (5%): Mx by antihistamine, switch another ATD (50% cross-reactivity) • Agranulocytosis (0.3%): NOT dose-related, mostly in first 3 months, caution if fever or sore throat o Management (SAQ!) - Discontinue all ATD —> Lifelong C/I to any ATD - Reverse isolation, septic work-up (blood C/ST, urine dipstix & C/ST, sputum, CXR ± LP) - Broad-spectrum antibiotics with anti-pseudomonal coverage (e.g. ceftriaxone + gentamicin) - G-CSF - Lithium (temporarily inhibit thyroid hormone synthesis & secretion) - ± TFT (r/o thyroid storm), ± Blood smear / bone marrow study (r/o haematological conditions) • Hepatotoxicity (0.1%): mostly in first 6 months o CMZ: cholestasis o PTU: allergic hepatitis à fulminant liver failure • Vasculitis: o ANCA-related vasculitis o Drug-induced lupus • Teratogenicity: all cross the placenta, but carbimazole is more teratogenic o Carbimazole: aplasia cutis o Propylthiouracil: preauricular sinus & cysts, CAKUT Radioactive iodine (RAI/ iodine-131) • Efficacy: long term remission in 80% —> 2nd course can be given after 6 months • Dosage: single oral dose, based on body weight and goitre size • Approach to RAI treatment o Rule out pregnancy by PT (avoid pregnancy for 6 months before RAI) & iodine allergy o Pretreatment by CMZ x 6/52 (maintain euthyroid) o Stop 1/52 before RAI (to maximise uptake of RAI) o Restart 1/52 after RAI till TFT normalised (risk of rebound hyperthyroidism, RAI takes ~3 months to work) o If failed (20%): retry RAI o If Graves' orbitopathy but RAI indicated: start prednisolone 1 day after RAI and taper off over 6-8 weeks • Post-treatment precautions: o Avoid close contact with children & pregnant women for 1 week o Contraception for ≥6 months (both males and females) o Avoid sharing cups/ utensils o Encourage fluid intake & frequent voiding + flush toilet twice • Advantages: o Rapid control of thyrotoxic symptoms within 2-3 weeks o Obvious reduction in goitre size within 1 year • Side effects: Early • Transient exacerbation of thyrotoxicosis ± thyroid storm o Radiation thyroiditis (1 - 3 weeks): pain, Mx NSAID, steroid o Rebound hyperthyroidism (weeks - months): Mx: carbimazole cover • Exacerbation of ophthalmopathy Late • Possible permanent hypothyroidism requiring thyroxine • ↑miscarriage rate

Answer 20

Pathophysiology: stimulation of fibroblasts results in • Accumulation of GAG in EOM • Increase in retrobulbar fat Risk factors • Smoking • Elderly male • RAI • Unstable thyroid function (too high/ low) Clinical features (severity is independent of thyroid status) • Sympathetic overactivation (for ALL thyrotoxicosis): lid retraction, lid lag • Graves' ophthalmopathy: proptosis, diplopia, chemosis, ophthalmoplegia (most commonly IR) • NO SPECS classification: to document severity • Clinical activity scale (CAS): to decide treatment Investigations: CT orbit Management (5S) • Smoking cessation • Stabilise thyroid function (avoid hypothyroid) • Symptomatic treatment: eye lubrication • Suppress inflammation: o High-dose IV pulse methylprednisolone (500-1000mg x 10-12 weeks) o Immunosuppressants (e.g. MTX, MMF) o IGF-1 receptor monoclonal body (teprotumumab): IGF-1 cross-talk with TSH-R expressing cells • Surgical decompression / External orbital RT if deformities severe - Sight-threatening complications: optic neuropathy (loss of colour vision as 1st sign), exposure keratopathy, globe subluxation

Answer 21

• Pathogenesis o Beta-subunit of hCG shares homology with beta-subunit of TSH o Physiological rise of hCG (peak at 10-12 weeks of pregnancy) stimulates TSH-R • Risk factors: high hCG (e.g. twin pregnancy, hyperemesis gravidarum, molar pregnancy) • Biochemically indistinguishable from other etiologies (e.g. Graves’), distinguished by: o Past history of thyroid disease, any thyrotoxic Sx pre-conception, any goitre, autoAb profile o Closely monitor fT4: expect to decline after 1st trimester • Anti-thyroid drugs are NOT indicated

Answer 22

• Primary (90%) o Autoimmune: Hashimoto's thyroiditis o Iatrogenic: post-ablative (RAI or thyroidectomy), drugs (amiodarone, lithium) o Post-viral: hypothyroid phase of subacute thyroiditis o Congenital hypothyroidism • Secondary: pituitary/ hypothalamic lesion o Pituitary tumor o NPC: tumor infiltration / post-RT o Empty sellar syndrome Hashimoto's thyroiditis • Chronic lymphocytic thyroiditis, autoimmune disease a/w HLA-DR3 & DR5 • Predominant in female (7:1) • Clinical course: o Initial destruction of thyroid glands —> release of T4 —> Hashitoxicosis” o Gradual thyroid function decline • Association: Graves', MG, T1DM, vitiligo, Addison's • Serology: positive anti-TPO & anti-TG o High anti-TPO titres predict likelihood of progressing from subclinical hypoT4 to overt hypoT4 Management of hypothyroidism Primary hypothyroidism • L-thyroxine: 50mcg daily, then titrate against TSH o 25mcg daily in elderly patients / IHD (worsen by increased HR) o Higher dose (dose by ~50%) for pregnant women (maintain euthyroidism —> prevent cretinism in fetus) o DDI: Ca, Fe, PPI / antacids, cholestyramine - separate administrations • Monitoring: TSH at 4 weeks (reflect long-term level c.f. fT4: normalised quickly within 1 week of drug intake) Central hypothyroidism • Evaluate rest of anterior pituitary axis: o Rule out concurrent adrenal insufficiency: replace hydrocortisone for 5 days before T4 (increase clearance of cortisol and thus risk of adrenal crisis) • Monitoring: fT4 (TSH is suppressed by exogenous T4)

Answer 23

Thyroid storm • Definition: acute exacerbation of thyrotoxicosis • Aetiology: infection/ trauma/ surgery in a hyperthyroid patient • Clinical features: o Hypermetabolic state: extreme hyperthermia (≥ 40oC), fast AF, vomiting, diarrhea o Altered mental state: delirium, agitation o Multiorgan failure (key feature!): congestive heart failure, renal failure, liver failure (jaundice) o Mortality: 30% • Scoring system: Burch-Wartofsky Point Scale (fig.) o ≥45 suggestive of TS; <25 unlikely TS • Differential diagnosis: o Infection: Sepsis, agranulocytosis (2° to anti-thyroid drugs) o Endocrine: Phaeochromocytoma crisis o Others: neuroleptic malignant syndrome, serotonin syndrome • Investigations: CBC, TFT, LFT, RFT, glucose, ECG (arrhythmia) Management of thyroid storm • Treat underlying cause • Monitoring: cardiac monitor, CVP, Swan Ganz, consult ICU • Supportive treatments: o Hyperthermia: paracetamol (NOT NSAID/salicylate: displace thyroxine from proteins —> T4 to T3 conversion), physical cooling o Dehydration & nutrition: IV fluid (2-4 L/day), IV glucose, IV thiamine o Heart failure: O2, digoxin / diuretics ± inotropes o Atrial fibrillation: digoxin (do NOT give amiodarone) • Definitive treatment: o PTU 200mg Q4h (±via NG tube): preferred over CMZ because also inhibit T4 —> T3 peripheral conversion - Consider lithium carbonate if C/I to ATD o Lugol’s iodine (10 drops Q8h): Wolff-Chaikoff effect to block thyroid hormone release - Must be given ≥1hr after PTU to avoid I- being used as substrate o Beta-blockers: propranolol 40-80mg Q4-6h (C/I: CHF, asthma, COPD, hypoglycemia —> use diltiazem) - Propranolol also inhibits T4 à T3 conversion o IV hydrocortisone 100mg stat: prevent T4 —> T3 conversion + lower body temperature + treat potential adrenal insufficiency o ± Cholestyramine: decreased enterohepatic circulation of thyroid hormones o Consider plasmapheresis and charcoal hemoperfusion if desperate cases

Answer 24

• Definition: severe hypothyroidism secondary to stressful events (e.g. trauma, infection, MI, cold exposure) • Clinical features o Hallmark features: decreased mental state, hypothermia o Cardiovascular: hypotension, bradycardia, pericardial / pleural effusion, pulmonary edema o Metabolic disturbances: hypoglycemia, hypoNa, respiratory acidosis o Generalized oedema • Investigations: TFT, RFT, Hstix, CPK (increased ), ACTH/ cortisol (adrenal insufficiency: overlapping S/S, thyroxine supplement precipitates adrenal insufficiency), ECG, ABG • Management o Treat underlying cause e.g. empirical antibiotics o Supportive: fluid (NS 200-300mL/h), glucose (D10) ± vasopressors o Maintain body temperature o Thyroid replacement: T4 200-500mcg PO stat (consider IV T3 5-20mcg BD if not PO) o Hydrocortisone 100mg Q6h IV (until adrenal insufficiency ruled out)

Answer 25

Stimulation test: to confirm adrenal insufficiency 1. Short Synacthen test (SST) / Basal ACTH - Normal dose SST: IM/IV Synacthen 250mcg, then measure plasma cortisol at time 0, 30, 60 min - Low dose SST (if suspect secondary adrenal insuff.): IV Synacthen 1mcg, then measure plasma cortisol at 0 & 30 min: more sensitive but require dilution - Physiologic response: peak > 550nmol/L with increment > 200nmol/L - Inappropriate response: no increase - Fasting not required - Can perform anytime of the day, but best in the morning Screening tests for Cushing’s 1. Overnight dexamethasone suppression test (ONDST) - most sensitive - Dexamethasone 1mg PO at 11pm, then serum cortisol at 9am mane - Normal < 50nmol/L - Inappropriate response: response > 140nmol/L - False positive: enzyme inducers (stop OCP ≥1wk before test) 2. 24h urine free cortisol - Collect 3 readings - Normal < 280nmol/24h - False negative in ESRD (decreased GFR), Incomplete collection 3. Low dose dexamethasone suppression test (LDDST) - Dexamethasone 0.5mg Q6h for 2 days , then serum cortisol - Normal < 50nmol/L 4. Late night salivary cortisol - chew on cotton wool at 11pm - Normal < 4nmol/L - Avoid smoking and tooth brushing 5. Late night plasma cortisol - Take blood at midnight - Normal <50 nmol/L Summary of tests - Cushing’s syndrome —> Diagnostic: ONDST, 24h UFC, LDDST / late night salivary cortisol / late night plasma cortisol (三中二 = diagnostic) —> Differentiating: plasma ACTH, CRH, imaging - Hyperaldosteronism —> Spot ARR —> Salt-loaded balance study - Hyperandrogenism —> Sex hormone profile - Phaeochromocytoma —> 24h urine metanephrines —> I-123 MIBG scan - Adrenal insufficiency —> Cortisol/ ACTH —> Short Synacthen test —> ARR - Hypogonadism —> Sex hormone profile

Answer 26

Aetiology Primary (high ARR) • Aldosterone-producing adenoma (“Conn’s adenoma”) (40%) • Bilateral idiopathic adrenal hyperplasia (60%) • Aldosterone-producing adrenocortical carcinoma (<1%) • Familial hyperaldosteronism* (rare) Secondary (low ARR) - high renin, high aldosterone • Renal artery stenosis • Renin-secreting tumors • Diuretics • Bartter / Gitelman - low renin, low aldosterone • Cushing’s syndrome • Exogenous mineralocorticoids • Syndrome of apparent mineralocorticoid excess (AR mutation for 11β- hydroxysteroid dehydrogenase type 2) • Liddle’s syndrome (AD mutation in ENaC) • Liquorice (low 11β-HSD activity) Clinical features • Hypertension • Hypokalemia (<30%): fatigue, weakness, tetany, polyuria / polydipsia (nephrogenic DI) Investigations • Bloods: electrolytes (high normal Na), ABG (hypoK, low Cl, metabolic alkalosis) • Urine: spot urine K • Screening: spot plasma renin activity & aldosterone concentration o Collect blood in the morning in a seated posture; stop MRA ± diuretics before testing [Grand round] o Primary hyperaldosteronism: plasma renin activity <1ng/mL/hour, plasma aldosterone conc. ≥ 20 ng/dL o Now use less aldosterone : renin ratio (ARR) [Grand round] • Confirmatory & discriminatory: salt-loaded balance study [PWH] (alternative: fludrocortisone suppression test) o Procedure: - PO NaCl 1800mg TDS for 5 days (± K supplement: prevent hypoK due to Na intake) - Admit on Day 5: confirm spot urine Na ≥100 mmol/L —> administer IV saline if inadequate - Collect plasma renin activity & aldosterone at 9AM supine + 1PM erect - Collect 24h urinary aldosterone o C/I in uncontrolled HT, CHF, risk of cardiac arrhythmia o Confirmatory: 9am plasma renin activity <1ng/mL/hour, plasma aldosterone conc. ≥ 10 ng/dL (≥277 pmol/L) o Discriminatory by comparing 9am and 1pm sample - BIAH: renin & aldosterone – sensitive to postural change (standing causes Ang II) - Adenoma: paradoxical decreased renin & aldosterone – aldosterone production becomes independent of RAAS but dependent on ACTH (highest in morning, fall afterwards) • Further discriminatory tests for unilateral vs bilateral disease [Grand round] o Imaging – CT or MRI adrenal o 131Iodocholesterol scintigraphy: low sensitivity for small lesions o Adrenal venous sampling: gold standard for diagnosis - Take blood cortisol & aldosterone from upper, middle, lower IVC, right and left adrenal veins - Adrenal vein to IVC cortisol > 10:1 = successful cannulation - Calculate cortisol-corrected aldosterone ratio for each adrenal vein, and divide higher to lower side to obtain ratio —> >4:1 = lateralize to higher side; <3:1 = bilateral Management • Primary aldosteronism: o Adenoma: laparoscopic adrenalectomy with 4 weeks pre-op spironolactone - Rule out concomitant Cushing’s syndrome: require peri-op steroid cover - Post-op: stop K supplement and MRI, liberal salt intake, titrate down anti-HT o BIAH: medical treatment (∵bilateral adrenalectomy can cause adrenal crisis) - Mineralocorticoid receptor antagonists (MRA) —> Spironolactone: more potent but non-selective (S/E: tender gynaecomastia, impotence) —> Eplerenone: less potent but better tolerated —> Newer drugs – non-steroidal MRA (e.g. esaxerenone, finerenone), aldosterone synthase inhibitors - Amiloride: ENaC inhibitor • Secondary hyperaldosteronism: treat underlying cause

Answer 27

1. Primary (Addison’s disease) - Aetiology: Autoimmune adrenalitis (MC) Infection: TB, meningococcaemia (W-F Sx) Tumor: adrenal met, lymphoma Congenital adrenal hyperplasia Rarer causes: APS, XALD - Pathophysiology: low GC, low MC, high ACTH - S/S: ↓GC effect: weight loss, weakness, anorexia, n/v, abdominal pain, fasting hypoglycaemia ↓MC effect: hyperK ↓GC + MC: postural hypotension, hypoNa (depletional & dilutional), salt craving ↑ACTH (~MSH): hyperpigmentation ↓Adrenal androgen: decreased body hair & libido (female) - associated disease: primary hypothyroidism, T1DM, PA, vitiligo - Ix: Low 9am cortisol (c.f. random cortisol in Addisonian crisis) High ACTH Short Synacthen test: cortisol <200 nmol/L from baseline and peak ≤ 550 nmol/L ARR (check for MC deficiency) - Ix if inconclusive Insulin tolerance test (rare), glucagon stimulation test, CRH stimulation test - Ix for causes: Adrenal autoantibodies (e.g. 21- hydroxylase, 17-hydroxylase) +/- TFT, B12/fol CT adrenals TB workup: CXR, early morning sputum for AFB, C/ST, PCR - Mx: Adequate fluid replacement Hydrocortisone 10mg BD / TDS (divided dose: mimic circadian rhythm) - monitor clinically for under/ over-replacement (no Ix available) Fludrocortisone 0.1mg/day; monitor plasma renin ( = inadequate) Cautions: • Steroid card indicating they are currently on steroid replacement • Stress dose (double dose) in stress, e.g. infection, trauma • Admission if severe vomiting or diarrhoea (decreased oral absorption of hydrocortisone) • Higher dose if DDI (e.g. anti-TB drugs) 2. Secondary / tertiary - Aetiology: 2o: hypopituitarism (e.g. Sheehan’s Sx) 3o: long-term steroid use, brain tumour - Pathogenesis: low GC but normal MC - S/S: Same except: • No skin hyperpigmentation • No salt craving, normal K, less postural hypotension • HypoNa only dilutional (∵SIADH- like in GC deficiency) - Associated disease: primary hypothyroidism, T1DM, PA, vitiligo - Ix: Low 9am cortisol Low ACTH SST: subnormal (consider low-dose SST 1mcg) - Ix if inconclusive: Insulin tolerance test (rare), glucagon stimulation test, CRH stimulation test - Ix: MRI pituitary - Mx: Adequate fluid replacement Hydrocortisone 10mg BD / TDS (divided dose: mimic circadian rhythm) - monitor clinically for under/ over-replacement (no Ix available) Fludrocortisone 0.1mg/day; monitor plasma renin ( high = inadequate) Cautions: • Steroid card indicating they are currently on steroid replacement • Stress dose (double dose) in stress, e.g. infection, trauma • Admission if severe vomiting or diarrhoea (low oral absorption of hydrocortisone) • Higher dose if DDI (e.g. anti-TB drugs)

Answer 28

Risk factors • Previously undiagnosed Addison's disease • Sudden compromise of adrenal function, e.g. adrenal haemorrhage • Known Addison's with intercurrent problem, e.g. trauma • Long-term steroid use > 2 weeks Clinical features • Severe abdominal pain, n/v/ diarrhoea —> dehydration, hypotension • Hypoglycaemia • Electrolyte disturbance: hypoNa, hyperK Investigations • RFT, electrolytes, glucose • Spot cortisol (during stress) ± ACTH • Short Synacthen test not required (already in stress) Management Treat on clinical suspicion, do NOT wait for cortisol results • IV rehydration: 4L D5 or NS at 500-1000mL/h first, then 200-300mL/h, chart I/O (cautious for fluid overload) • Correct electrolytes • IV hydrocortisone 100mg IV stat, then Q6h o IV/IM 4mg dexamethasone if concerned about assay interference • +/- Oral fludrocortisone 0.2mg daily PO, titrate to normalise K and BP • Treat underlying cause

Answer 29

Indications • Supraphysiological dose of steroids (>7.5mg/day prednisolone) for >2 weeks in the past year • Suspected adrenal / pituitary insufficiency • Patients on steroids for uncertain dose / duration Regimen • Major surgery: IV 100mg hydrocortisone on call to OT + IV 50mg hydrocortisone in recovery room + 50mg Q6h o Taper off if post-operative course smooth o Maintain at 100mg IV Q6h if complicated by sepsis, hypotension, etc. • Minor surgery (e.g. hernia repair): IV 100mg hydrocortisone single dose • Superficial surgery (e.g. dental surgery): no need

Answer 30

Aetiology • Pituitary: Cushing's disease, hyperprolactinaemia • Adrenal: CAH (late-onset), adrenal tumour • Ovarian: PCOS, theca cell tumour • Drugs: anabolic steroid, ACTH Clinical features • Female: o Virilisation: hirsutism, temporal balding, deepening of voice, acne, muscle mass o Defeminisation: loss of female secondary sex characteristics, i.e. amenorrhoea, decreased breast size, infertility • Male: o Reduced testicular size & spermatogenesis (inhibition of gonadotropin secretion) o Minimal effect on hair, muscle mass Investigations • Androgen profile: DHEAS, testosterone • LH/FSH (>2.5 in PCOS) • 17-OH progesterone (CAH) • CT adrenals and ovaries (tumour) Management • Correct underlying cause (e.g. discontinue causative drugs) • Anti-androgen, e.g. spironolactone • Surgical resection of tumour

Answer 31

Aetiology • Primary: congenital (Klinefelter's), infection (mumps orchitis), trauma • Secondary: congenital (Kallmann's), endocrine (Cushing's) Investigations • Sex hormone: LH/ FSH, testosterone • Semen analysis Management: androgen replacement therapy • S/E: acne, fluid retention, aggressiveness, BPH, OSA • Monitor: DEXA (osteoporosis if untreated), PSA (risk of BPH/ CA prostate)

Answer 32

Definitions - Pheochromocytoma: catecholamine-secreting tumour derived from chromaffin cells of adrenal medulla - Paraganglioma: tumour arising from chromaffin cells of sympathetic / parasympathetic nervous system • Sympathetic paraganglioma: usually catecholamine-secreting (i.e. “extra-adrenal pheochromocytoma”), located along sympathetic chain • Parasympathetic paraganglioma: usually non-functional, located in neck / skull base Aetiology • Sporadic (MC) • Familial (AD inheritance), e.g. NF1, MEN2 (RET oncogene), Von Hippel-Lindau disease, Carney triad (GIST + pulmonary chondroma + paragangliomas, due to succinate dehydrogenase gene mutation) Clinical features • Classic triad: paroxysmal headache, sweating, palpitations • Other S/S: young-onset paroxysmal HT + postural hypotension (due to adrenaline action), anxiety, pallor • Pressor response during procedures or with certain drugs (e.g. TCA, IV contrast) or food (cheese) • 10% rule: 10% familial, 10% bilateral, 10% extra-adrenal, 10% malignant, 10% secrete adrenaline/ dopamine (c.f. 90% NA), 10% children, 10% not associated with HT, 10% recurrence o Extra-adrenal: para-aortic (75%), urinary bladder (10%), thorax (10%), skull base / neck / pelvis (5%), organ of Zuckerkandl o Malignant pheo: histologically and biochemically indistinguishable, defined by metastasis • Pheochromocytoma crisis: APO, ICH 5P’s of pheo • Pressure (HT) • Pain (headache, chest pain) • Palpitation • Perspiration • Pallor (vasoconstriction) Investigations Biochemical screening: • Biopsy is NOT required: high risk of hypertensive crisis and hematoma • 24h urine catecholamines + fractionated metanephrines (more sensitive: continuous release) o Abnormal if >2x elevation o False positive: stress, OSA, drugs (e.g. TCA, α agonist, levodopa —> stop 1 week) • Plasma catecholamine / metanephrine (most specific, but need indwelling catheter >30min) o Preferred in chronic renal failure because 24h urine sample is difficult to interpret Imaging: localize tumor • Anatomical scan: CT with low-osmolar contrast / T2-MRI with gadolinium contrast o CT: alpha blockade prior to administration of IV contrast (∵risk of HT crisis) • Functional scan: I-123 MIBG scan (metaiodobenzylguanidine = NE analog) • PET-CT: 68Gallium-DOTATATE for neuroendocrine tumors Dynamic test • Clonidine suppression test: only if strong clinical suspicion but above tests inconclusive o C/I in pregnancy o Procedure: - Fast overnight —> Insert cannula 30 minutes before test —> Take bloods for Epi & NE x2 (5 mins apart) - Give PO clonidine 0.3mg with 250mL water - Closely monitor BP/P Q30min for postural hypotension and bradycardia - Take bloods for Epi & NE at 2h and 3h after clonidine

Answer 33

Definition • Reduced bone mineral density (BMD) below a defined lower limit of normal (T score ≤ -2.5) • Pathophysiology: bone remodelling cannot keep up with microtrauma, causing reduced bone mass with normal mineral-to-osteoid ratio (c.f. reduced in osteomalacia) Aetiology • Primary (MC): higher risk in post-menopausal female, smoking, alcohol, vit D deficiency, physical inactivity • Secondary: o Endocrine: DM, Cushing’s, hyperthyroidism, acromegaly o GI: cholestasis (e.g. PBC, PSC), pancreatic insufficiency o Pulmonary: COPD o Renal: CKD (2° hyperPTH) o Hemat: myeloma o Autoimmune: IBD, AS, RA o Drugs: corticosteroids, PPI, cyclosporine Clinical features • Asymptomatic (MC): incidental finding of osteopenia on X-ray • Fragility fracture: fracture with fall from standing height o Common sites: vertebrae (thoracic/lumbar), distal radius, hip, proximal femur o Collapse fracture: gradual-onset height loss, kyphosis, chronic pain Investigations • XR spine: thinning of cortex, codfish sign (biconcave vertebra), compression fracture • Dual energy x-ray absorptiometry (DEXA): assess BMD at lumbar spine & hip (MC sites of fracture) o T score: no. of SD below peak bone mass of a 30-year old adult of same sex and ethnicity - Osteopenia: T score -1.0 to -2.5 - Osteoporosis: T score ≤ -2.5 - Severe osteoporosis: T score ≤ -2.5 + at least one fragility fracture o Z score: compared to normal individuals of same age, sex & ethnicity; used in pre-menopausal F, M < 50y - Suspect secondary cause if Z score ≤ -2.0 o FRAX score: 10-year risk of major osteoporosis-related fracture - Limitations: only for >40 / post-menopausal F • Other scans: quantitative CT (volumetric bone density), trabecular bone scan (bone quality) • Underlying causes: CBC, LRFT, CaPO4, ALP, ESR, TFT, Ig pattern Management Lifestyle modification • Quit smoking & alcohol • Weight-bearing exercise • Ca and vit D rich diet ± supplements (to prevent 2o hyperparathyroidism) o Calcium (1200mg/day): milk, yogurt, salmon, broccoli, orange o Vitamin D (1000 IU/day): fortified milk, egg, fish • Sunlight exposure • Fall prevention and rehabilitation Pharmacotherapy Indications: • Osteoporosis (T-score ≤ -2.5) • Osteopenia (T-score -1.0 to -2.5) + FRAX score ≥ 20% for major osteoporotic fracture / ≥3% for hip fracture • Hx of fragility fracture Monitoring: DEXA 6 months later 1. Bisphosphates - PO alendronate (weekly) —> reassess 5 years —> taken on empty stomach in the morning + drinking plenty of water then sit up for 30 mins with no food/drinks —> C/I in renal failure, S/E in atypical fracture of femur, osteronecrosis of jaw, renal failure, hypoCa, GERD, flu-like symptoms (IV only) - IV zoledronate (yearly) —> reassess 3 years —> high risk case (new fragility while on bisphosphates), at least 4 weeks of Ca/VitD supplement beforehand —> C/I in renal failure, S/E in atypical fracture of femur, osteronecrosis of jaw, renal failure, hypoCa, GERD, flu-like symptoms (IV only) 2. RANKL inhibitor - SC Denosumab (Q6months) - high risk case (new fragility while on bisphosphates), at least 4 weeks of Ca/VitD supplement beforehand - OK for renal failure, S/E: similar to bisphosphates 3. SERM (weak anti-resorption) - PO Raloxifene - 8 years duration - for post menopausal women - S/E: risk of VTE 4. Calcitonin - Nasal spray - C/I in fish allergy 5. PTH analogue - SC teriparatide (daily) - 2 years max - SFI: reversed for severe case (T score <-3.5) - S/E: n/v, hyperCa, renal stones 6. Sclerostin inhibitor - romosozumab

Answer 34

• Definition: low mineral-to-osteoid ratio after epiphyseal closure (before epiphyseal closure: rickets) • Aetiology: vit D deficiency (malnutrition, liver disease, CKD), mineralization defect (Al, hypophosphatasia) • Clinical features: diffuse skeletal pain, fracture • Investigations: low CaPO4, vit D, high ALP, high PTH • Management: vit D supplementation, PO4 supplementation (if hypophosphatasia)

Answer 35

• Definition: chronic bone disorder characterized by excessive abnormal bone remodeling • Bone most affected: pelvis > femur > skull > others • Clinical features: severe bone pain, skeletal deformities, focal warmth (vasculiarity) • Complications: high-output HF (vascularity and workload), osteosarcoma • Investigations: CaPO4 normal, ALP, XR, bone scan • Management: analgesia, Ca & vit D supplement, bisphosphonates

Answer 36

MEN I (“3P”) - Pituitary adenoma (e.g. prolactinoma, acromegaly) - Parathyroid hyperplasia - Pancreatic NET: gastrinoma, insulinoma, VIPoma - Ix: MEN-1 mutation, PTH, glucose, MRI pituitary MEN IIA (“PMP”) - Parathyroid hyperplasia - Medullary thyroid carcinoma - Pheochromocytoma Familial MTC only: variant of MEN2A MEN IIB/III (“MMMP”) - Mucosal neuroma - Marfanoid body habitus - Medullary thyroid carcinoma - Pheochromocytoma Ix: - RET gain-of-function mutation - FNAC thyroid nodule - CT abdomen MEN4 - Parathyroid adenoma, pituitary adenoma, reproductive tumor - CDNK1B mutation

Answer 37

Type 1: autoimmune poly-endocrinopathy- candidiasis-ectodermal dystrophy (APECED) - AD (incomplete penetrance) - AIRE mutation - S/S: Addison's disease, T1DM Hypoparathyroidism Mucocutaneous candidiasis, nail dystrophy, dental enamel hypoplasia Type 2: Schmidt's syndrome - AR - Polygenic: HLA-DR3 - S/S: Addison's disease, T1DM Grave's disease Pernicious anaemia MG

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