Membership of the Royal College of Physicians (MRCP UK) Endocrinology and Metabolic Medicine Syllabus

List physiological and drug causes of hyperprolactinaemia that must be excluded before diagnosing a prolactinoma.

Physiological: pregnancy, breastfeeding, stress, nipple stimulation. Pathological non-tumour: primary hypothyroidism, chronic kidney disease, stalk compression (disconnection). Drugs: dopamine antagonists — antipsychotics (especially risperidone), metoclopramide, domperidone, and some antidepressants.

Distinguish Cushing's disease from Cushing's syndrome.

Cushing's syndrome is the clinical state of chronic glucocorticoid excess from any cause (most commonly exogenous steroids). Cushing's disease specifically refers to an ACTH-secreting pituitary adenoma — the commonest endogenous cause of Cushing's syndrome.

Name the first-line screening tests for Cushing's syndrome.

Any of: (1) overnight 1 mg dexamethasone suppression test (failure to suppress cortisol $< 50\ \mathrm{nmol/L}$); (2) 24-hour urinary free cortisol ($\times 2$); (3) late-night salivary cortisol (loss of diurnal rhythm). Confirm with low-dose dexamethasone suppression.

How does the high-dose dexamethasone suppression test and ACTH level distinguish causes of Cushing's syndrome?

Pituitary (Cushing's disease): ACTH detectable/high, cortisol SUPPRESSES on high-dose dexamethasone (>50%). Ectopic ACTH: ACTH high, NO suppression. Adrenal tumour: ACTH suppressed (low), no suppression of cortisol. Inferior petrosal sinus sampling confirms a pituitary source.

Contrast central diabetes insipidus, nephrogenic diabetes insipidus, and how the water deprivation test plus desmopressin distinguishes them.

Central DI: deficient ADH secretion; urine concentrates after desmopressin. Nephrogenic DI: renal resistance to ADH; urine does NOT concentrate after desmopressin. After water deprivation both fail to concentrate urine; the response to exogenous desmopressin separates them.

State the diagnostic criteria for SIADH.

SIADH = euvolaemic hyponatraemia with: serum Na$^{+}$ low and plasma osmolality low ($< 275\ \mathrm{mosmol/kg}$); inappropriately concentrated urine (osmolality $> 100\ \mathrm{mosmol/kg}$); urine Na$^{+}$ $> 30\ \mathrm{mmol/L}$; normal thyroid, adrenal and renal function; no diuretic use; clinically euvolaemic.

What is the danger of over-rapid correction of chronic hyponatraemia, and the safe correction rate?

Over-rapid correction risks osmotic demyelination syndrome (central pontine myelinolysis). Limit the rise in serum sodium to $\leq 10\ \mathrm{mmol/L}$ in the first 24 hours (some advise $\leq 8$), and $\leq 18\ \mathrm{mmol/L}$ over 48 hours.

What is the commonest cause of hyperthyroidism, and which antibody is characteristic?

Graves' disease (autoimmune) is the commonest cause. It is mediated by TSH-receptor stimulating antibodies (TRAb). Characteristic extra-thyroidal features include thyroid eye disease (ophthalmopathy), pretibial myxoedema, and thyroid acropachy.

How do thyroid function tests differ between primary hyperthyroidism and a TSH-secreting pituitary adenoma?

Primary hyperthyroidism (e.g. Graves'): high free T4/T3 with SUPPRESSED (low) TSH. TSH-secreting pituitary adenoma: high free T4/T3 with an inappropriately normal or HIGH TSH (secondary hyperthyroidism).

Outline the management of thyroid storm.

Supportive care plus: a beta-blocker (propranolol) for symptoms; a thionamide (propylthiouracil preferred, blocks peripheral T4→T3 conversion); then, at least 1 hour AFTER the thionamide, iodine (Lugol's/potassium iodide) to block hormone release; and hydrocortisone (reduces T4→T3 conversion). Treat the precipitant.

What is the main serious side effect of carbimazole, and what advice must patients be given?

Agranulocytosis (and neutropenia). Patients must be warned to stop the drug and seek an urgent full blood count if they develop a sore throat, mouth ulcers, or fever. Carbimazole is also teratogenic — propylthiouracil is preferred in the first trimester.

What is the commonest cause of hypothyroidism in iodine-replete areas, and its characteristic antibody?

Hashimoto's (chronic autoimmune) thyroiditis. It is associated with anti-thyroid peroxidase (anti-TPO) antibodies and often anti-thyroglobulin antibodies, producing a firm goitre or atrophic gland with raised TSH and low free T4.

Describe the clinical features and management priorities of myxoedema coma.

Severe decompensated hypothyroidism: hypothermia, bradycardia, hypoventilation/CO$_2$ retention, hyponatraemia, hypoglycaemia, and reduced consciousness. Management: IV levothyroxine (or liothyronine), IV hydrocortisone (cover coexisting adrenal insufficiency), gentle rewarming, and supportive ITU care. High mortality.

How are subclinical hypothyroidism and overt hypothyroidism distinguished biochemically?

Subclinical hypothyroidism: raised TSH with NORMAL free T4 (and usually few/no symptoms). Overt hypothyroidism: raised TSH with LOW free T4. Treatment of subclinical disease is generally considered if TSH $> 10\ \mathrm{mU/L}$ or symptomatic with positive antibodies.

Which features of a thyroid nodule raise suspicion of malignancy, and what is the key investigation?

Red flags: rapid growth, hard/fixed nodule, hoarseness/vocal cord palsy, cervical lymphadenopathy, age $<20$ or $>60$, history of neck irradiation, family history. Key investigation is ultrasound-guided fine-needle aspiration cytology (FNAC), reported using the Thy classification.

Compare papillary, follicular, medullary and anaplastic thyroid carcinoma.

Papillary: commonest (~70–80%), spreads via lymphatics, excellent prognosis. Follicular: spreads haematogenously (lung/bone), diagnosis needs histology (capsular/vascular invasion). Medullary: arises from parafollicular C cells, secretes calcitonin, associated with MEN 2. Anaplastic: rare, elderly, very aggressive, poor prognosis.

How is the corrected calcium calculated, and why is it needed?

$$\text{Corrected Ca} = \text{measured Ca} + 0.02 \times (40 - \text{albumin})$$ (calcium in $\mathrm{mmol/L}$, albumin in $\mathrm{g/L}$). Roughly half of plasma calcium is albumin-bound, so correction accounts for abnormal albumin and reflects the physiologically active ionised fraction.

What is the commonest cause of hypercalcaemia in the community versus in hospital, and the typical PTH in each?

Community: primary hyperparathyroidism (usually a single parathyroid adenoma) — PTH is high or inappropriately normal. Hospital inpatients: malignancy (PTHrP secretion, bony metastases, or myeloma) — PTH is suppressed (low). Together these account for ~90% of cases.

Outline the acute management of severe hypercalcaemia.

First-line: aggressive IV $0.9\%$ saline rehydration (e.g. 3–4 L/24h). Once rehydrated, give IV bisphosphonate (e.g. zoledronic acid) to inhibit osteoclasts — effect takes 2–4 days. Calcitonin gives faster but transient lowering. Treat underlying cause; consider steroids if myeloma/sarcoid/vitamin D excess.

Differentiate the calcium, phosphate and PTH pattern in primary hyperparathyroidism versus chronic kidney disease (secondary hyperparathyroidism).

Primary hyperparathyroidism: high Ca, low/low-normal phosphate, high PTH. Secondary (CKD) hyperparathyroidism: low or normal Ca, HIGH phosphate, high PTH (driven by hypocalcaemia and low calcitriol). Tertiary: autonomous PTH secretion after prolonged secondary, giving high Ca and high PTH.

What are Chvostek's and Trousseau's signs, and what do they indicate?

Both indicate neuromuscular irritability from hypocalcaemia. Chvostek's sign: tapping over the facial nerve causes ipsilateral facial muscle twitching. Trousseau's sign: inflating a BP cuff above systolic for ~3 minutes induces carpopedal spasm. Hypocalcaemia also prolongs the QT interval.

Contrast primary (Addison's) and secondary adrenal insufficiency in terms of cause, pigmentation, and aldosterone.

Primary (Addison's): adrenal cortex destroyed (autoimmune commonest in UK; TB worldwide) — high ACTH causes hyperpigmentation, and aldosterone is deficient (hyperkalaemia, hypotension). Secondary: pituitary ACTH deficiency — NO hyperpigmentation, aldosterone preserved (RAAS intact), so hyperkalaemia is uncommon.

What is the gold-standard test for adrenal insufficiency, and the expected result?

The short Synacthen (ACTH stimulation) test: measure serum cortisol before and 30 minutes after 250 $\mathrm{\mu g}$ IV/IM tetracosactide. A failure of cortisol to rise above approximately $420\text{–}550\ \mathrm{nmol/L}$ (assay-dependent) confirms adrenal insufficiency.

Describe the biochemical findings and emergency treatment of an Addisonian (adrenal) crisis.

Hyponatraemia, hyperkalaemia, hypoglycaemia, and hypotension/shock. Treatment: immediate IV hydrocortisone 100 mg, rapid IV $0.9\%$ saline rehydration, and IV glucose for hypoglycaemia. Take blood for cortisol/ACTH but do NOT delay steroids. Identify and treat the precipitant.

What are the classic biochemical and clinical features of phaeochromocytoma, and the key screening test?

Episodic/sustained hypertension with the triad of headache, palpitations and sweating (excess catecholamines). Screen with plasma free metanephrines or 24-hour urinary fractionated metanephrines/catecholamines. Remember the "rule of 10s" and associations with MEN 2, VHL, and NF1.

Why must alpha-blockade precede beta-blockade in phaeochromocytoma management?

Unopposed beta-blockade leaves alpha-mediated vasoconstriction unchecked, which can precipitate a hypertensive crisis. Patients are first alpha-blocked (e.g. phenoxybenzamine), then a beta-blocker added for tachycardia, before definitive surgical excision (adrenalectomy).

What is the screening test for primary hyperaldosteronism (Conn's syndrome), and the characteristic electrolyte picture?

Screen with the aldosterone-to-renin ratio (ARR): aldosterone HIGH with renin SUPPRESSED gives a raised ratio. Classic biochemistry is hypertension with hypokalaemia and a metabolic alkalosis (though many patients are normokalaemic). Confirm with a saline-suppression test, then adrenal imaging/venous sampling.

What is the most common enzyme defect in congenital adrenal hyperplasia, and the resulting hormone pattern?

21-hydroxylase deficiency (~90% of CAH). It impairs cortisol (and aldosterone) synthesis, so ACTH rises and precursors are shunted to androgens. Result: low cortisol/aldosterone (salt-wasting, hyperkalaemia) with high 17-hydroxyprogesterone and androgen excess (virilisation/ambiguous genitalia in females).

Distinguish hypergonadotrophic from hypogonadotrophic hypogonadism and give an example of each.

Hypergonadotrophic (primary gonadal failure): low sex steroids with HIGH LH/FSH — e.g. Klinefelter's (47,XXY) or Turner's (45,X). Hypogonadotrophic (secondary/central): low sex steroids with LOW or inappropriately normal LH/FSH — e.g. Kallmann syndrome (with anosmia) or pituitary disease.

State the Rotterdam criteria for diagnosing polycystic ovary syndrome.

PCOS requires at least 2 of 3: (1) oligo-/anovulation; (2) clinical and/or biochemical hyperandrogenism (hirsutism, raised free testosterone); (3) polycystic ovaries on ultrasound ($\geq 12$ follicles or ovarian volume $> 10\ \mathrm{mL}$). Other causes (CAH, Cushing's, tumour, thyroid, hyperprolactinaemia) must be excluded.

What target LDL cholesterol or percentage reduction is the goal in established cardiovascular disease, and which drug class is first-line?

High-intensity statins (e.g. atorvastatin 80 mg) are first-line, aiming for $> 40\%$ reduction in non-HDL cholesterol; guidelines target LDL-C $< 1.8\ \mathrm{mmol/L}$ (or non-HDL $< 2.5\ \mathrm{mmol/L}$) in secondary prevention. Add ezetimibe, then a PCSK9 inhibitor if targets are not met.

What are the diagnostic clues to familial hypercholesterolaemia, and how is it inherited?

Autosomal dominant (commonly LDL-receptor gene mutation). Clues: very high LDL/total cholesterol (total often $> 7.5\ \mathrm{mmol/L}$), tendon xanthomata, premature corneal arcus, and a strong family history of premature coronary disease. Diagnosed using the Simon Broome or Dutch Lipid Clinic criteria.

List the components used to diagnose the metabolic syndrome.

Central obesity plus any 2 of: raised fasting glucose ($\geq 5.6\ \mathrm{mmol/L}$) or known T2DM; raised triglycerides ($\geq 1.7\ \mathrm{mmol/L}$); reduced HDL ($< 1.03$ men, $< 1.29$ women $\mathrm{mmol/L}$); and raised blood pressure ($\geq 130/85\ \mathrm{mmHg}$). It reflects insulin resistance.

How is body mass index calculated and what BMI defines obesity?

$$\mathrm{BMI} = \frac{\text{weight (kg)}}{[\text{height (m)}]^{2}}$$ Overweight is $25\text{–}29.9\ \mathrm{kg/m^{2}}$; obesity is $\geq 30$ (Class I $30\text{–}34.9$, Class II $35\text{–}39.9$, Class III $\geq 40$). Lower thresholds apply for South Asian populations.

How is osteoporosis defined by DEXA T-score, and how does this differ from osteopenia?

Osteoporosis is a bone mineral density T-score $\leq -2.5$ (standard deviations below the young-adult mean). Osteopenia is a T-score between $-1.0$ and $-2.5$. Established (severe) osteoporosis is a T-score $\leq -2.5$ with one or more fragility fractures.

What tool estimates 10-year fracture risk, and what is the first-line drug treatment for osteoporosis?

FRAX (or QFracture) estimates the 10-year probability of major osteoporotic and hip fracture. First-line treatment is an oral bisphosphonate (alendronate or risedronate) plus calcium/vitamin D as needed. Alternatives: IV zoledronate, denosumab, or anabolic teriparatide for severe disease.

Contrast the calcium, phosphate, ALP and PTH pattern of osteomalacia with that of osteoporosis.

Osteomalacia (defective mineralisation, usually vitamin D deficiency): LOW calcium, LOW phosphate, HIGH alkaline phosphatase, and HIGH PTH (secondary hyperparathyroidism). Osteoporosis: calcium, phosphate, ALP and PTH are all typically NORMAL — it is a quantitative bone-mass defect, not a mineralisation defect.

Describe the characteristic biochemistry, X-ray findings and treatment of Paget's disease of bone.

Markedly RAISED alkaline phosphatase with NORMAL calcium and phosphate (disordered bone remodelling). X-rays show bony enlargement, cortical thickening, mixed lytic/sclerotic lesions, and bowing. It commonly affects pelvis, skull, femur and tibia. Symptomatic disease is treated with bisphosphonates.