Adrenal Disorders — Viva

The scenario

Mrs R is a 40-year-old marketing manager referred by her GP for evaluation of suspected Cushing syndrome. Over 8 months she has developed central weight gain (8 kg), a rounding of her face, easy bruising on her forearms, wide purple striae on her abdomen, and progressive difficulty climbing stairs (proximal leg weakness). She has new hypertension (BP 165/98) and new type 2 diabetes (HbA1c 64 mmol/mol). She has amenorrhoea for 4 months and low mood. She is not on any glucocorticoid therapy. [1]

Investigations from the GP: 1 mg overnight dexamethasone suppression test — cortisol 290 nmol/L (failed suppression). Two 24-hour urine free cortisol collections — 580 and 640 nmol/24h (reference below 220). Late-night salivary cortisol — elevated. Plasma ACTH — 92 pg/mL (reference 7.2-63.3). Pituitary MRI — a 4 mm right-sided microadenoma. Serum potassium — 4.0 mmol/L (normal). [1]

Part A — Candidate opening statement (SASPOP)

Examiner: "Please present this patient." [1]

Candidate model answer: [1]

"This is Mrs R, a 40-year-old marketing manager presenting with endogenous Cushing syndrome. Her main problems are: (1) confirmed cortisol excess — she has failed the 1 mg overnight dexamethasone suppression test, has markedly elevated 24-hour urine free cortisol at three times the upper limit, and has elevated late-night salivary cortisol, giving three positive screening tests per the Nieman 2008 Endocrine Society guideline; (2) ACTH-dependent disease — her plasma ACTH is elevated at 92, localising the problem to either the pituitary (Cushing disease) or an ectopic ACTH source; (3) a pituitary microadenoma on MRI, which is suggestive but NOT diagnostic — I need to confirm it is the ACTH source with bilateral inferior petrosal sinus sampling before committing to pituitary surgery; (4) the metabolic burden of cortisol excess — new hypertension, new type 2 diabetes, amenorrhoea from cortisol suppression of GnRH, and low mood. Her phenotype — central obesity, moon face, wide purple striae, proximal myopathy, easy bruising — is classic and the proximal myopathy in particular discriminates Cushing from simple obesity. My integrated plan is to confirm Cushing disease with BIPSS, proceed to transsphenoidal resection of the adenoma, and manage her metabolic comorbidities in parallel." [1]

Part B — Probing questions and model answers

Q1. "You mentioned you need BIPSS before surgery. Walk me through why the MRI microadenoma is not enough."

"The pituitary MRI shows a 4 mm microadenoma, but this alone cannot confirm Cushing disease. Up to 10% of normal people have incidental pituitary microadenomas, and the lesion I see could be a coincidental finding. If I proceed to transsphenoidal surgery based on the MRI alone, and the microadenoma is NOT the ACTH source (i.e., the real source is an ectopic ACTH tumour), the surgery will fail — she will still have Cushing, and she will have undergone an unnecessary brain operation. BIPSS is the gold standard for confirming the pituitary is the ACTH source. I catheterise both inferior petrosal sinuses and a peripheral vein, and measure ACTH at baseline and after CRH stimulation. A central-to-peripheral ACTH ratio at or above 2 at baseline, or at or above 3 after CRH, confirms the pituitary origin — Oldfield et al. (PMID 1652686) established this, with 95-100% sensitivity and 100% specificity. In this patient, with a visible microadenoma but the need to be certain before surgery, BIPSS is indicated." [1]

Q2. "Her potassium is 4.0 — normal. A colleague suggested this might be ectopic ACTH because of the high ACTH level. How do you respond?"

"The normal potassium actually argues AGAINST ectopic ACTH and supports Cushing disease. In ectopic ACTH syndrome, the ACTH and cortisol levels are typically very high — high enough to saturate the 11-beta-hydroxysteroid dehydrogenase type 2 enzyme in the kidney that normally converts cortisol to inactive cortisone. When this enzyme is overwhelmed, cortisol floods the mineralocorticoid receptor, causing apparent mineralocorticoid excess with hypokalaemic alkalosis. This hypokalaemia is found in 70-100% of ectopic ACTH but only 10-30% of Cushing disease. Her normal potassium is therefore reassuring for Cushing disease over ectopic ACTH. However, I cannot make the distinction on potassium alone — the ACTH of 92 is elevated but not extreme, and BIPSS will provide the definitive answer. I also note that she does not have hyperpigmentation, which would be expected with very high ACTH from ectopic sources." [1]

Q3. "You proceed to BIPSS and it confirms Cushing disease. What is the definitive management?"

"First-line treatment is transsphenoidal resection of the pituitary adenoma by an experienced neurosurgeon. For a 4 mm microadenoma, remission rates are 70-90%. The goal is selective adenomectomy — removing the adenoma while preserving the normal pituitary. Postoperatively, she will develop transient secondary adrenal insufficiency: the normal corticotrophs have been suppressed by the cortisol excess and need months to recover, and the contralateral adrenal gland is also suppressed. I will start hydrocortisone replacement (e.g. 15-20 mg/day) immediately postoperatively and taper over 6-18 months as the HPA axis recovers, monitoring with morning cortisol and repeat Synacthen tests. If surgery fails to achieve remission, or if the tumour recurs, my second-line options are stereotactic radiotherapy or radiosurgery (gamma knife), medical therapy with steroidogenesis inhibitors (metyrapone, ketoconazole, or osilodrostat) to control cortisol while awaiting the effect of radiotherapy, or pasireotide — a somatostatin analogue targeting somatostatin receptor subtype 5 on corticotroph adenomas, which Colao et al. (PMID 22397659) showed normalised UFC in 15-26% of patients, though with hyperglycaemia in 73%. Bilateral adrenalectomy is curative but a last resort — it commits her to lifelong steroid replacement and carries a 10-30% risk of Nelson syndrome." [1]

Q4. "How will you manage her metabolic comorbidities while she awaits surgery and during recovery?"

"The metabolic burden of Cushing is significant and drives the long-term morbidity. I will address each: (1) hypertension — start an ACE inhibitor or ARB, titrate to target; (2) type 2 diabetes — metformin first-line, titrate; consider insulin if HbA1c is very high or she is symptomatic; her cortisol excess is driving insulin resistance, so diabetes may improve dramatically after the cortisol is controlled; (3) osteoporosis — she needs a DEXA scan, and given the high fracture risk in Cushing, I would start a bisphosphonate if her T-score is below -2.5 or if she has a fragility fracture; calcium and vitamin D supplementation; (4) VTE prophylaxis — Cushing is a prothrombotic state with a 4-6-fold increased VTE risk, so I would consider prophylactic anticoagulation perioperatively for the transsphenoidal surgery; (5) infection surveillance — cortisol excess suppresses immunity, so I have a low threshold for screening and treating infection; (6) psychiatric support — her low mood may improve with cortisol correction, but she may need specific treatment; (7) amenorrhoea — likely from cortisol suppression of GnRH; this should resolve after treatment, but I will check FSH/LH/oestradiol and consider bone protection if amenorrhoea persists." [1]

Q5. "What is Nelson syndrome and how do you prevent it?"

"Nelson syndrome is the growth of a pituitary corticotroph adenoma after bilateral adrenalectomy for Cushing disease. When both adrenals are removed, cortisol production falls to zero, removing the negative feedback on the pituitary. Any residual corticotroph tumour cells proliferate unchecked, producing very high ACTH, causing marked hyperpigmentation, and potentially enlarging to cause mass effects (visual field defects, cranial nerve palsies, pituitary hormone deficiency). It occurs in 10-30% of patients after bilateral adrenalectomy. Prevention: this is one of the reasons bilateral adrenalectomy is a last resort for Cushing disease — I prefer transsphenoidal surgery or radiotherapy first. If bilateral adrenalectomy is necessary, I monitor the patient with pituitary MRI and plasma ACTH every 6-12 months, and treat any tumour growth with radiotherapy or repeat surgery. Prophylactic radiotherapy at the time of adrenalectomy is sometimes considered." [1]

Q6. "Switching topics. A different patient has resistant hypertension and a positive aldosterone-to-renin ratio. Walk me through subtype determination and the treatment decision."

"After confirming primary aldosteronism biochemically (a positive ARR confirmed by salt loading or a saline infusion test showing non-suppressible aldosterone), the next step is subtype determination: unilateral aldosteronoma (surgically curable, approximately 30%) versus bilateral idiopathic hyperplasia (medical therapy, approximately 60%). I start with an adrenal CT, but CT is unreliable — it misses small adenomas, misidentifies microadenomas, and cannot distinguish a functioning aldosteronoma from a non-functioning incidental adenoma. The gold standard for subtype is adrenal venous sampling (AVS): I catheterise both adrenal veins and compare the aldosterone-to-cortisol ratio from each side versus the periphery. Unilateral lateralisation (a ratio above 2-4 on one side with suppression on the other) indicates a surgically curable unilateral adenoma. AVS is indicated in all patients considering surgery, especially those above 40 (where incidental adenomas are commoner). If AVS shows unilateral disease, I refer for laparoscopic adrenalectomy, which cures or improves hypertension in most patients. If AVS shows bilateral disease, I treat medically with a mineralocorticoid receptor antagonist — spironolactone (more effective but causes gynaecomastia, impotence, and menstrual irregularity from androgen receptor blockade) or eplerenone (more selective, fewer side effects, but less potent and more expensive). The Funder 2016 guideline (PMID 26934384) is the reference for this algorithm." [1]

Part C — Short-case discussion: face and hands examination in adrenal disease

Examiner: "You are asked to examine the face and hands of a 45-year-old woman in the short-case station. Talk me through what you are looking for, and what findings would point you toward Cushing syndrome versus Addison's disease." [1]

Candidate model answer: [1]

"I begin at the end of the bed, observing the patient's overall appearance and habitus. From the face and hands alone, I am looking for the two classic adrenal phenotypes.

For Cushing syndrome, I examine for: a moon face (round, full, with fat deposition in the cheeks); facial plethora (red-purple discolouration from thin skin and increased vascularity); acne and hirsutism (from adrenal androgen excess in ACTH-dependent disease); and thin, fragile skin with easy bruising on the forearms. On the hands, I look for proximal muscle weakness — the single best discriminator between Cushing and simple obesity. I ask the patient to hold her arms outstretched and watch for early fatigue, then ask her to rise from a squatting position without using her hands — if she cannot, this is proximal myopathy. I also examine the abdomen for wide purple striae (wider than 1 cm, a cortisol-specific sign) and the upper back for a buffalo hump (cervical fat pad).

For Addison's disease (primary adrenal insufficiency), I examine for hyperpigmentation — the cardinal sign. I look specifically in the palmar creases (the pigmentation is darker than the surrounding skin), the buccal mucosa and gums (bluish-black patches), recent scars, the areolae (which darken), extensor surfaces, and skin folds and pressure points (belts, bra straps). I also look for vitiligo, which may coexist (autoimmune). I check for postural hypotension (a drop in systolic above 20 mmHg or diastolic above 10 on standing) — this reflects aldosterone deficiency and volume depletion. I look for signs of associated autoimmune disease: a goitre (autoimmune thyroid disease), premature greying, and signs of type 1 diabetes.

The key distinguishing question is the pigmentation and the blood pressure. Cushing is hyperpigmented ONLY in ectopic ACTH and Nelson syndrome (where ACTH is very high) — most Cushing disease and adrenal Cushing are NOT hyperpigmented. Addison's is ALWAYS hyperpigmented (the ACTH is very high). Cushing causes hypertension; Addison's causes hypotension (often postural). So a pigmented, hypotensive patient is Addison's; a non-pigmented, hypertensive, centrally-obese patient with proximal myopathy is Cushing." [1]

Examiner: "You find a moon face, plethora, easy bruising, and the patient cannot rise from a squat. What is your single next investigation?" [1]

"In a patient with clinical features suggestive of Cushing syndrome, the first-line screening test is a 1 mg overnight dexamethasone suppression test — give 1 mg of dexamethasone at 11 pm and measure cortisol at 8-9 am. A cortisol below 50 nmol/L (1.8 mcg/dL) excludes Cushing; a cortisol above 50 fails to suppress and requires further workup. I would also send a 24-hour urine free cortisol and a late-night salivary cortisol, as the Endocrine Society guideline recommends at least two of the three tests to confirm the diagnosis. Critically, I do NOT order imaging first — I confirm hypercortisolism biochemically before any pituitary or adrenal imaging." [1]

Part D — Examiner's high-yield traps

"The candidate who images the pituitary or adrenal before confirming hypercortisolism biochemically fails. Incidental lesions are common and will mislead you. Biochemistry first, always." [1]

"The candidate who gives a beta-blocker to a phaeochromocytoma patient before alpha-blockade fails — this is the most dangerous error in adrenal medicine. Alpha first, then beta." [1]

"The candidate who does not screen resistant hypertension for primary aldosteronism misses the commonest surgically curable cause of hypertension. The ARR is cheap, effective, and underused." [1]

"The candidate who does not know that secondary adrenal insufficiency has normal potassium and no hyperpigmentation (because the RAAS is intact and ACTH is low) does not understand the HPA axis." [1]

"The candidate who treats a sick Addisonian patient with hydrocortisone alone, without IV fluids and without searching for the precipitant, is not managing the crisis. All three are essential." [1]