Adrenal Disorders — DCE Clinical Case

LONG CASE

Patient brief (provided to candidate)

Mrs S is a 38-year-old accountant referred to the endocrinology clinic with an 8-month history of progressive changes that have alarmed her and her GP. She has gained 9 kg, all centrally, with a rounding of her face. She bruises easily on her arms and has developed wide purple stretch marks on her abdomen and flanks. Over the past 3 months she has noticed increasing difficulty climbing the two flights of stairs to her office — her thighs feel weak and she feels she is "made of lead." Her GP noted hypertension (BP 168/96) and new type 2 diabetes (HbA1c 62 mmol/mol). Her periods stopped 5 months ago. She describes low mood, irritability, and difficulty concentrating. She has not had any glucocorticoid therapy. She is a never-smoker, drinks alcohol moderately, and has no significant family history. [1]

On examination: she has central obesity with a BMI of 33, a round plethoric moon face, wide purple abdominal striae (over 1 cm), easy bruising on her forearms, and a small buffalo hump at the cervico-dorsal junction. She cannot rise from a squatting position without using her hands. BP 165/95, HR 82. No hyperpigmentation. No galactorrhoea. Visual fields are intact to confrontation. [1]

Investigations: 1 mg overnight dexamethasone suppression test — cortisol 310 nmol/L (failed suppression). Two 24-hour urine free cortisol — 560 and 600 nmol/24h (reference below 220). Late-night salivary cortisol — elevated on two samples. Plasma ACTH — 88 pg/mL (reference 7.2-63.3). Pituitary MRI — a 5 mm left-sided microadenoma; the rest of the pituitary is normal. Serum potassium 4.1 mmol/L (normal). DEXA scan — T-score -2.4 at the lumbar spine (osteopenia). [1]

Candidate opening statement (SASPOP)

"This is Mrs S, a 38-year-old accountant presenting with endogenous ACTH-dependent Cushing syndrome. Her main problems are: (1) confirmed cortisol excess — three positive screening tests: failed 1 mg overnight dexamethasone suppression test, 24-hour urine free cortisol at nearly three times the upper limit, and elevated late-night salivary cortisol; (2) ACTH-dependent disease — plasma ACTH is elevated at 88, so the source is either pituitary (Cushing disease) or ectopic; (3) a pituitary microadenoma on MRI that is suggestive but needs confirmation with bilateral inferior petrosal sinus sampling before committing to transsphenoidal surgery; (4) the metabolic consequences of cortisol excess — new hypertension, new type 2 diabetes, osteopenia, amenorrhoea from cortisol suppression of GnRH, and psychiatric symptoms. Her phenotype — central obesity, moon face, wide purple striae, easy bruising, proximal myopathy, buffalo hump — is classic for Cushing, and the proximal myopathy is the sign that best discriminates Cushing from simple obesity. Her normal potassium and the absence of hyperpigmentation favour Cushing disease over ectopic ACTH. My integrated plan is to confirm Cushing disease with BIPSS, proceed to transsphenoidal resection, and manage her metabolic comorbidities in parallel." [1]

Structured problem list

1. Endogenous ACTH-dependent Cushing syndrome, biochemically confirmed; pituitary microadenoma on MRI — requires BIPSS confirmation before surgery.
2. Proximal myopathy — from cortisol-induced type II muscle fibre catabolism; disabling but should improve with cure.
3. New type 2 diabetes (HbA1c 62 mmol/mol) — driven by cortisol-induced insulin resistance.
4. Hypertension (BP 165/95) — from cortisol mineralocorticoid effects and activation of the RAAS.
5. Osteopenia (T-score -2.4 lumbar spine) — cortisol suppresses osteoblasts; fracture risk.
6. Secondary amenorrhoea — cortisol suppresses GnRH; potential fertility and bone health implications.
7. Low mood and irritability — glucocorticoid effects on the brain.
8. Prothrombotic state — Cushing increases VTE risk 4-6-fold. [1]

Integrated management plan

1. Confirm Cushing disease with BIPSS (defence of the diagnosis): [1]

The pituitary MRI shows a 5 mm left-sided microadenoma, but up to 10% of normal people have incidental pituitary microadenomas. I cannot proceed to transsphenoidal surgery on the MRI alone — I must confirm the pituitary is the ACTH source with bilateral inferior petrosal sinus sampling. BIPSS measures the central-to-peripheral ACTH ratio at baseline and after CRH stimulation. A ratio at or above 2 at baseline, or at or above 3 post-CRH, confirms pituitary Cushing disease (Oldfield et al., PMID 1652686). The normal potassium (4.1) and the absence of hyperpigmentation both favour Cushing disease over ectopic ACTH, supporting my expectation that BIPSS will confirm the pituitary origin. If BIPSS is negative (no central gradient), I search for an ectopic ACTH source with CT chest/abdomen/pelvis and functional imaging (octreotide scan or Ga-68 DOTATATE PET). [1]

2. Definitive treatment — transsphenoidal resection: [1]

Once BIPSS confirms Cushing disease, I refer to an experienced pituitary neurosurgeon for selective transsphenoidal adenomectomy. Remission rates for microadenomas are 70-90%. Postoperatively, she will develop transient secondary adrenal insufficiency (the normal corticotrophs and the contralateral adrenal are suppressed and need months to recover). I start hydrocortisone replacement immediately postoperatively and taper over 6-18 months, monitoring with morning cortisol levels and Synacthen tests. If surgery fails or disease recurs, second-line options are stereotactic radiotherapy, medical therapy (metyrapone or ketoconazole to suppress steroidogenesis), or bilateral adrenalectomy (last resort due to Nelson syndrome risk). [1]

3. Manage the metabolic comorbidities: [1]

• Hypertension: start an ACE inhibitor (e.g. perindopril 5 mg daily) and titrate to target (below 130/80). Blood pressure should improve significantly after cortisol is controlled.
• Type 2 diabetes: start metformin 500 mg twice daily, titrate to 1000 mg twice daily. Her diabetes may resolve or improve dramatically after cure, as cortisol drives insulin resistance.
• Osteopenia: calcium and vitamin D supplementation; a DEXA scan now and repeat in 12 months after cure. If her T-score worsens or she sustains a fracture, start a bisphosphonate (alendronate 70 mg weekly). Her bone density should improve after cortisol is controlled.
• Amenorrhoea: check FSH, LH, oestradiol, and prolactin. Likely functional hypothalamic amenorrhoea from cortisol excess; should resolve after treatment. If not, consider bone protection.
• VTE prophylaxis: Cushing is a prothrombotic state. I would consider prophylactic anticoagulation perioperatively for her transsphenoidal surgery (individualise the bleeding risk). [1]

4. Psychiatric and psychological support: [1]

Her low mood and irritability are likely to improve with cortisol correction, but I would involve a clinical psychologist and consider specific treatment if symptoms persist. The impact of the diagnosis, the surgery, and the recovery period on her work and personal life needs to be addressed. [1]

5. Follow-up and surveillance: [1]

After surgery, I monitor for remission (morning cortisol, 24h UFC, late-night salivary cortisol) and for recurrence. I taper the hydrocortisone replacement as the HPA axis recovers. I repeat the DEXA scan at 12 months. Lifelong follow-up for recurrence (clinical features, cortisol testing annually) is necessary. [1]

Probing questions and model answers

Q: "Why can you not proceed to transsphenoidal surgery based on the MRI alone?"

"Because up to 10% of normal people have incidental pituitary microadenomas. A 5 mm lesion visible on MRI could be a coincidental finding, not the ACTH source. If I operate on the wrong lesion, the surgery fails — she still has Cushing, and she has undergone an unnecessary procedure. BIPSS confirms the pituitary is the ACTH source with 95-100% sensitivity and 100% specificity (Oldfield 1991), so I can operate with confidence. The Nieman 2008 guideline (PMID 18334580) recommends BIPSS when the MRI is normal, equivocal, or shows a small lesion that could be incidental — and in this case, a 5 mm microadenoma with ACTH-dependent Cushing fits that criterion." [1]

Q: "What if the BIPSS shows no central gradient — what is your differential then?"

"No central gradient means the ACTH is not coming from the pituitary — this is ectopic ACTH syndrome. I search for the source: small cell lung cancer is the commonest, so a contrast CT of the chest is first. I also look for bronchial carcinoids (often small, in the lung parenchyma), pancreatic neuroendocrine tumours, medullary thyroid cancer, and other neuroendocrine tumours. Functional imaging with octreotide scintigraphy (In-111 octreotide) or Ga-68 DOTATATE PET helps localise somatostatin-receptor-positive neuroendocrine tumours. If I find the tumour, surgical resection is the treatment. If I cannot find it, I control cortisol medically (metyrapone or ketoconazole) while continuing surveillance with repeat imaging every 6-12 months. Ectopic ACTH often causes very high cortisol with hypokalaemic alkalosis, so her normal potassium is reassuring for Cushing disease — but the BIPSS is the definitive discriminator." [1]

Q: "She has amenorrhoea. Could this be a prolactinoma or a mixed pituitary tumour?"

"Her amenorrhoea is most likely functional hypothalamic from cortisol excess (cortisol suppresses GnRH, reducing FSH and LH, causing secondary amenorrhoea). However, I should check a serum prolactin — if it is elevated, this could suggest stalk effect (a pituitary adenoma compressing the pituitary stalk, removing dopamine inhibition of prolactin) or a co-secretion of prolactin and ACTH (a plurihormonal adenoma, rare). I should also check her other pituitary hormones (TSH, free T4, FSH, LH, oestradiol, IGF-1) to rule out hypopituitarism from mass effect. Her intact visual fields and normal pituitary function on initial screening (no other hormone deficiencies described) make a significant mass effect unlikely. After cure of her Cushing, I expect her menstrual cycles to resume within months." [1]

Q: "How would you counsel her about the postoperative period?"

"I explain that after the adenoma is removed, her cortisol levels will drop to low/zero because her normal pituitary corticotrophs have been suppressed and need time to wake up. She will need hydrocortisone replacement (like an Addisonian patient) for 6-18 months, with sick-day rules, an emergency injection kit, and a MedicAlert bracelet during that period. She will feel better from the cortisol excess symptoms gradually over months — the weight will come down, her blood pressure and diabetes will improve, her strength will return. I will taper the hydrocortisone slowly as her own cortisol production recovers, monitoring with morning cortisol levels. I warn her about the small risk of recurrence (5-10% at 10 years) and the need for lifelong monitoring. I also address the psychological adjustment and the impact on her work." [1]

SHORT CASE

Instruction

"Examine this patient's face and hands. She is a 50-year-old woman with fatigue and weight loss." [1]

Systematic examination routine

1. End of bed observation (15 seconds): Observe the patient's overall appearance, body habitus, skin colour, and level of distress. State immediately: "This patient appears chronically unwell, with marked skin and mucosal pigmentation. She appears thin and fatigued."
2. The face — inspect systematically: Look at the general facial appearance. Observe for: hyperpigmentation (generalised and in specific sites), pigmentation of the buccal mucosa (ask the patient to open her mouth and inspect the inner cheeks, gums, and hard palate), pigmentation of the lips and perioral skin, and vitiligo (depigmented patches). Check the conjunctivae for pallor (anaemia of chronic disease).
3. The hands — inspect and examine: Look at the palmar surfaces for hyperpigmentation in the palmar creases (the creases are darker than the surrounding skin, a key sign). Check for vitiligo on the hands. Check the nail beds for pallor or pigmentation (longitudinal melanonychia can occur). Assess for proximal muscle weakness (not expected here, but contrast with Cushing).
4. Blood pressure: Check lying and standing blood pressure — look for a postural drop (systolic fall above 20 or diastolic fall above 10).
5. Extend the examination to the body: Look at recent scars (hyperpigmentation of scars is a specific sign), the areolae (darkened), extensor surfaces (elbows, knuckles), skin folds, and pressure points (belt line, bra strap). Look for a goitre (associated autoimmune thyroid disease). Check for signs of other autoimmune conditions: premature greying, vitiligo, signs of type 1 diabetes (injection sites, finger-prick marks). [1]

Key signs this patient demonstrates

• Hyperpigmentation of the palmar creases, buccal mucosa, gums, recent scars, and extensor surfaces — the cardinal sign of primary adrenal insufficiency.
• Vitiligo — coexisting autoimmune depigmentation, supporting an autoimmune aetiology.
• Postural hypotension — from aldosterone deficiency and volume depletion.
• Weight loss and thinness — from chronic cortisol deficiency.
• Goitre (if present) — associated autoimmune thyroid disease (autoimmune polyglandular syndrome type 2). [1]

Presentation template

"I examined the face and hands of Mrs X, a 50-year-old woman. She is thin and appears chronically unwell. There is striking generalised hyperpigmentation, most marked in the palmar creases — which are significantly darker than the surrounding skin — and in the buccal mucosa and gums, where there are bluish-black patches. There are depigmented patches consistent with vitiligo on the dorsum of both hands. Her blood pressure is 108/70 lying, falling to 88/58 on standing — a significant postural drop. I also noted hyperpigmentation of a recent abdominal scar and of the areolae. There is no proximal myopathy, no moon face, and no striae. These findings are consistent with primary adrenal insufficiency — Addison's disease — with associated vitiligo suggesting an autoimmune aetiology. I would like to complete my assessment by checking the full blood count and electrolytes (expecting hyponatraemia and hyperkalaemia), and sending a morning cortisol, plasma ACTH, and a short Synacthen stimulation test to confirm the diagnosis." [1]

Discussion questions

Q: "What is the mechanism of the hyperpigmentation?"

"The adrenal cortex is destroyed, so it cannot produce cortisol. The loss of negative feedback causes the pituitary to produce very high ACTH. ACTH is cleaved from the larger precursor pro-opiomelanocortin (POMC), which also produces melanocyte-stimulating hormone (MSH) and beta-lipotropin. The high ACTH and these co-secreted peptides stimulate melanocytes, causing the generalised and site-specific hyperpigmentation. This is why hyperpigmentation is present in primary adrenal insufficiency (ACTH is high) but ABSENT in secondary adrenal insufficiency (ACTH is low — the pituitary is the problem). It is the single best clinical discriminator between primary and secondary disease." [1]

Q: "Her potassium is 5.9. Why?"

"Because in primary adrenal insufficiency, the adrenal cortex is destroyed and cannot produce aldosterone. Aldosterone normally acts on the distal tubule to reabsorb sodium (in exchange for potassium, which is excreted). Without aldosterone, potassium is retained and sodium is lost — causing hyperkalaemia and hyponatraemia. This is another key discriminator from secondary adrenal insufficiency, where the zona glomerulosa and the RAAS are intact, aldosterone is preserved, and potassium is normal." [1]

Q: "How would you manage this patient if she presented in adrenal crisis?"

"I would not delay for tests. I would take blood for cortisol, ACTH, renin, aldosterone, and electrolytes, then immediately give IV hydrocortisone 100 mg stat, followed by 100 mg every 6-8 hours. I would give aggressive IV fluids — 1 litre of 0.9% saline stat, then continue at 1 litre per hour, with dextrose added if she is hypoglycaemic. I would identify and treat the precipitant (blood cultures, antibiotics if infection suspected). The hyperkalaemia will correct with hydrocortisone and fluids — I would not treat it separately unless there were severe ECG changes. Once stable, I would taper to oral hydrocortisone, add fludrocortisone (needed because her adrenal cannot produce aldosterone), and provide comprehensive education: sick-day rules, an emergency IM hydrocortisone injection kit, a MedicAlert bracelet, and a steroid card. I would also check 21-hydroxylase antibodies to confirm the autoimmune aetiology and screen for associated autoimmune conditions (thyroid, B12, type 1 diabetes, premature ovarian failure). Hahner et al. (PMID 25419882) found adrenal crisis still occurs at 8.3 per 100 patient-years in educated patients, so education must be thorough and reinforced." [1]

Q: "She is about to undergo elective surgery. How do you manage her perioperatively?"

"She needs stress-dose hydrocortisone because her HPA axis cannot respond to surgical stress. For major surgery: hydrocortisone 100 mg IM at induction, then 50 mg IM every 6 hours for 48-72 hours, then taper to maintenance over the next 1-2 days. For minor procedures (e.g. dental work): hydrocortisone 100 mg IM or IV at induction. She continues her fludrocortisone dose unchanged. The goal is to mimic the physiological cortisol response to stress, which in a healthy person raises cortisol output 2-10 fold. Without stress-dose cover, she is at risk of adrenal crisis and circulatory collapse under anaesthesia." [1]

Communication and shared decision-making

• Explaining the diagnosis of Cushing disease: "Your pituitary gland — a small gland at the base of your brain — has developed a benign tumour, about 5 mm, that is producing too much ACTH. ACTH is a hormone that tells your adrenal glands to make cortisol. The excess cortisol is causing the symptoms you have been experiencing — the weight gain, the bruising, the weakness, the high blood pressure and diabetes. The good news is this type of tumour is almost always benign (not cancer), and it can be removed by an operation through your nose (transsphenoidal surgery) that is well-established and usually successful."
• The BIPSS decision: "Before the operation, I need to do one more test — BIPSS — to confirm that the small tumour we see on the scan is definitely the one producing the excess hormone. This is important because sometimes these small tumours on scans are coincidental, and I want to be certain we are operating on the right thing."
• The recovery period: "After the surgery, you will need to take hydrocortisone tablets for 6 to 18 months while your own hormone system recovers. During that time, you will need to follow 'sick-day rules' — increasing your dose when you are ill — and carry an emergency injection kit. Most people feel dramatically better as the excess cortisol is brought under control: the weight comes off, the blood pressure and diabetes improve, the strength returns, and the mood lifts. I will support you through the whole process with a team including endocrinology, neurosurgery, and psychology."
• For the Addisonian patient: "Your immune system has destroyed your adrenal glands — two small glands above your kidneys that make essential hormones called cortisol and aldosterone. Without these hormones, your body cannot maintain blood pressure, blood sugar, or salt balance, and you can become very ill very quickly. The treatment is to replace these hormones for life — tablets called hydrocortisone and fludrocortisone. The most important thing is that you never stop them, and you know how to increase them when you are ill and give yourself an emergency injection. I will teach you and your family everything you need to know." [1]