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]