Adrenal Disorders — Written Clinical Reasoning

SAQ 1 — Adrenal Crisis: Emergency Management and Diagnostic Reasoning (20 marks, 30 minutes)

Prompt: This patient is in adrenal crisis. Outline your immediate emergency management (with drug doses and route), the diagnostic reasoning that confirms primary adrenal insufficiency, and the long-term management and patient education plan. Justify each decision with reference to the Endocrine Society guideline. [1]

Model Answer

Step 1 — Immediate emergency management (the first 30 minutes) (6 marks): [1]

This is a life-threatening adrenal crisis. I do NOT delay treatment for further tests — the mortality of untreated crisis is significant. My immediate actions: [1]

1. Secure the airway and give high-flow oxygen (she is drowsy and hypoxic risk). Establish IV access (two large-bore cannulae).
2. Take blood FIRST (within 1-2 minutes, before hydrocortisone if possible, but do NOT delay hydrocortisone beyond this): cortisol (already low at 45 — confirms), ACTH (already high at 520 — confirms primary), renin, aldosterone, electrolytes, glucose (already low at 2.1), FBC, blood cultures. The cortisol and ACTH results are already available and are diagnostic.
3. IV hydrocortisone 100 mg stat, then 100 mg every 6-8 hours (or a continuous infusion of 200 mg over 24 hours). At these doses hydrocortisone provides sufficient mineralocorticoid activity — fludrocortisone is not needed acutely. The Bornstein 2016 Endocrine Society guideline (PMID 26760044) is explicit: treat first if the patient is sick.
4. Aggressive IV fluid resuscitation: 1 litre of 0.9% saline stat, then 1 litre over 1 hour, then guided by clinical response. Add dextrose (e.g. 1 litre of 5% dextrose alternating with saline) — she is hypoglycaemic at 2.1 mmol/L, which is dangerous. Treat the hypoglycaemia directly: 50 mL of 50% dextrose IV (or 100 mL of 10% dextrose if central access is unavailable).
5. Correct electrolytes: The hyperkalaemia (6.4) is from aldosterone deficiency and will resolve with hydrocortisone and fluids over the next few hours. I do NOT give insulin-dextrose or calcium resonium routinely unless there are ECG changes of severe hyperkalaemia (wide QRS) — those would be treated with the standard hyperkalaemia protocol. Check an ECG now.
6. Identify and treat the precipitant: Blood and urine cultures, chest X-ray. Start broad-spectrum antibiotics (e.g. ceftriaxone 2g IV) once cultures are taken — she is febrile (38.5) and infection (likely gastroenteritis) is the commonest precipitant. [1]

Step 2 — Diagnostic reasoning — why this is primary adrenal insufficiency (3 marks): [1]

The diagnosis is confirmed by:

• Cortisol 45 nmol/L (markedly low — a stressed patient should have cortisol above 500 nmol/L; a value below 200 in an unwell patient is strongly suggestive of adrenal insufficiency).
• ACTH 520 pg/mL (markedly elevated, over 8 times the upper limit) — this is the key finding: the ACTH is HIGH, confirming the problem is at the ADRENAL level (primary). In secondary adrenal insufficiency (pituitary), ACTH would be low or inappropriately normal.
• Hyperpigmentation (palmar creases, buccal mucosa, scars) — pathognomonic: high ACTH/MSH cross-stimulates melanocytes. This is ABSENT in secondary adrenal insufficiency.
• Hyponatraemia (119) with hyperkalaemia (6.4) — the hallmark of aldosterone deficiency (primary). In secondary, the RAAS is intact, aldosterone is preserved, and potassium is NORMAL. This is the single best biochemical discriminator.
• Hypoglycaemia — cortisol is needed for gluconeogenesis; deficiency causes fasting hypoglycaemia.
• Autoimmune context (type 1 diabetes, autoimmune thyroid disease) — this is autoimmune polyglandular syndrome type 2 (Schmidt syndrome), the commonest cause of Addison's in developed countries. [1]

The short Synacthen test (250 mcg cosyntropin, cortisol at 0, 30, 60 min) would confirm a peak cortisol below 500 nmol/L, but in this acute setting it is unnecessary — the cortisol is already critically low with a high ACTH, and treatment should not wait. The Synacthen test can be done after recovery to document the baseline deficit formally. [1]

Step 3 — Finding the cause (2 marks): [1]

After stabilisation:

• 21-hydroxylase antibodies — to confirm autoimmune Addison's (positive in 80-90% of autoimmune cases). This is the expected cause given her autoimmune history.
• Adrenal CT — small/atrophic adrenals confirm autoimmune disease; enlarged adrenals suggest infiltrative/malignant causes; calcified adrenals suggest old TB.
• Screen for and manage associated autoimmune conditions (thyroid, B12/pernicious anaemia, premature ovarian failure) — she already has type 1 diabetes and thyroid disease. [1]

Step 4 — Long-term replacement therapy (4 marks): [1]

Once stable and able to take oral medications:

• Hydrocortisone 15-25 mg/day in divided doses — e.g. 10 mg on waking, 5 mg at midday, 5 mg at 4-5 pm. The largest dose is in the morning (mimicking the circadian peak); the smallest dose is latest (to avoid insomnia). Titrate to well-being, with a day curve (serial cortisol measurements through the day) if symptoms persist.
• Fludrocortisone 50-200 mcg/day (typically 100 mcg) — ESSENTIAL in primary adrenal insufficiency, because the adrenal cannot produce aldosterone. Monitor with blood pressure (including postural), serum sodium, and plasma renin (aim for high-normal renin).
• Continue treatment for any precipitating cause (e.g. infection).
• Address bone health (DEXA — she is at risk of osteoporosis from chronic illness, not from the hydrocortisone replacement at physiological doses, but she may have other risk factors). [1]

Step 5 — Patient education and prevention of future crises (3 marks): [1]

This is the most important long-term intervention. Hahner et al. (PMID 25419882) showed that adrenal crises still occur in 8.3 per 100 patient-years in EDUCATED patients, with a 6% mortality per crisis — so education must be comprehensive and reinforced:

• Sick-day rules: double oral hydrocortisone for minor illness (fever, infection); triple or give IM hydrocortisone 100 mg for severe illness, vomiting, or surgery. Provide WRITTEN instructions.
• Emergency hydrocortisone injection kit (100 mg vial, syringes, instructions) — teach the patient and at least one family member to give IM hydrocortisone. She carries this at all times.
• MedicAlert bracelet stating "Adrenal insufficiency — requires hydrocortisone."
• Steroid card with diagnosis, medications, and emergency instructions.
• Education on never omitting steroids, recognizing early crisis symptoms (nausea, vomiting, weakness, dizziness), and when to seek urgent medical attention. [1]

Step 6 — Communication and shared decision-making (2 marks):

• Explain the diagnosis in plain language: "Your adrenal glands, which sit above your kidneys, have been destroyed by your immune system. They cannot make the hormones you need to stay alive — cortisol and aldosterone. We will replace these hormones for life."
• Discuss the autoimmune context and screen family members if there is a family history of autoimmune endocrinopathy.
• Address the psychological impact of a lifelong diagnosis requiring daily medication and emergency preparedness. [1]

SAQ 2 — The Cushing Diagnostic Algorithm (20 marks, 30 minutes)

Prompt: A 42-year-old woman presents with central obesity, moon face, wide purple abdominal striae, proximal muscle weakness, hypertension (BP 160/98), and new type 2 diabetes. Her 1 mg overnight dexamethasone suppression test cortisol is 310 nmol/L (normal suppression below 50), 24-hour urine free cortisol is 620 nmol/24h (reference below 220, x3 upper limit), and late-night salivary cortisol is elevated. Her plasma ACTH is 85 pg/mL (reference 7.2-63.3). A pituitary MRI shows a 3 mm left-sided microadenoma. Discuss the diagnostic reasoning that establishes ACTH-dependent Cushing, the role of bilateral inferior petrosal sinus sampling in this patient, and the definitive management. [1]

Model Answer

Step 1 — Confirm Cushing syndrome (the screening is complete) (3 marks): [1]

She has Cushing syndrome confirmed by all three first-line screening tests: a failed 1 mg overnight dexamethasone suppression test (cortisol 310, should suppress below 50), elevated 24-hour urine free cortisol (620, three times the upper limit), and elevated late-night salivary cortisol (loss of the midnight nadir). The Nieman 2008 Endocrine Society guideline (PMID 18334580) recommends two of three positive tests to confirm hypercortisolism in a patient with compatible clinical features. I have excluded the commonest cause (exogenous steroids) by drug history. [1]

Step 2 — Establish ACTH-dependent vs ACTH-independent (3 marks): [1]

Her plasma ACTH is 85 pg/mL — elevated (reference 7.2-63.3). This is ACTH-DEPENDENT Cushing. The source is either:

• Cushing disease — pituitary corticotroph adenoma (70% of endogenous ACTH-dependent Cushing), or
• Ectopic ACTH syndrome — from a non-pituitary tumour (small cell lung cancer, carcinoid, pancreatic neuroendocrine tumour) (15%). [1]

This distinction is critical because the treatment differs fundamentally (pituitary surgery vs finding and resecting an ectopic tumour). [1]

Step 3 — The role of bilateral inferior petrosal sinus sampling (BIPSS) in this patient (5 marks): [1]

The pituitary MRI shows a 3 mm microadenoma — but this is NOT sufficient to diagnose Cushing disease. The problem: up to 10% of normal people have incidental pituitary microadenomas, and a 3 mm lesion could be incidental. Without proof that this is the ACTH source, committing to transsphenoidal pituitary surgery risks operating on the wrong lesion (and failing to cure the Cushing while subjecting the patient to unnecessary surgery). [1]

BIPSS is indicated in this patient to confirm that the ACTH is coming from the pituitary (and therefore that the microadenoma seen on MRI is the culprit). The technique, established by Oldfield et al. (PMID 1652686):

• Catheterise both inferior petrosal sinuses (which drain the pituitary) and a peripheral vein.
• Measure ACTH simultaneously 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 stimulation, confirms pituitary (Cushing disease). A ratio below 2 at both times suggests ectopic ACTH.
• Oldfield's study found a basal IPS:P ratio at or above 2 had 95% sensitivity and 100% specificity, and post-CRH ratio at or above 3 achieved 100% sensitivity and 100% specificity. [1]

A positive BIPSS in this patient confirms Cushing disease. The MRI lateralisation (left-sided microadenoma) can then guide the surgeon, though intraoperative confirmation is used. [1]

Step 4 — Why BIPSS and not the high-dose DST? (2 marks): [1]

The high-dose (8 mg) dexamethasone suppression test (HDDST) is an alternative: Cushing disease suppresses (cortisol falls by at least 50%), ectopic ACTH does not. But the HDDST has significant false-positive and false-negative rates (sensitivity approximately 80%, specificity approximately 80%), and it is now second-line to BIPSS, which is the gold standard for this distinction. [1]

Step 5 — Definitive management (5 marks): [1]

Once BIPSS confirms Cushing disease:

• First-line: transsphenoidal resection of the pituitary microadenoma by an experienced neurosurgeon. Remission rates are 70-90% for microadenomas. Postoperatively, the patient develops transient secondary adrenal insufficiency (the suppressed normal corticotrophs and the contralateral adrenal need months to recover) and requires glucocorticoid replacement until the HPA axis recovers (monitor with morning cortisol and Synacthen tests over 6-18 months).
• If surgery fails or disease persists: stereotactic radiotherapy/radiosurgery, medical therapy (metyrapone or ketoconazole to suppress steroidogenesis; pasireotide, a somatostatin analogue, Colao et al. PMID 22397659, normalised UFC in 15-26% but caused hyperglycaemia in 73%), or bilateral adrenalectomy (curative but risks Nelson syndrome and lifelong steroid dependence).
• Manage comorbidities throughout: treat hypertension, diabetes, osteoporosis (DEXA, bisphosphonate), VTE prophylaxis (Cushing is prothrombotic), and screen for infection.
• The untreated prognosis is poor: 50% 5-year mortality from cardiovascular disease, infection, and thromboembolism — definitive treatment is essential. [1]

Step 6 — Communication (2 marks):

• Explain the diagnosis and the staged investigation plan in plain language. Emphasise that the BIPSS is needed to confirm the pituitary is the source before surgery, to avoid operating on the wrong lesion.
• Discuss the surgical approach, the expected recovery period (months of steroid replacement), and the long-term surveillance for recurrence.
• Address the metabolic comorbidities and the need for a multidisciplinary approach (endocrinology, neurosurgery, psychology). [1]