Adrenal Disease: Insufficiency, Cushing Syndrome, Phaeochromocytoma, and Conn Syndrome

Definition / Overview

The adrenal glands produce three classes of hormones from anatomically distinct zones:

• Zona glomerulosa → aldosterone (mineralocorticoid)
• Zona fasciculata → cortisol (glucocorticoid)
• Zona reticularis → androgens (DHEA, androstenedione)
• Adrenal medulla → catecholamines (adrenaline, noradrenaline)

Adrenal disease therefore spans a spectrum from deficiency (adrenal insufficiency) to excess (Cushing syndrome, primary aldosteronism, phaeochromocytoma), each carrying distinct diagnostic challenges and therapeutic nuances relevant to the FRACP long case.

Adrenal Insufficiency

Pathophysiology and Classification

Primary adrenal insufficiency (PAI / Addison disease): destruction or dysfunction of the adrenal cortex causing deficiency of cortisol, aldosterone, and adrenal androgens. Autoimmune adrenalitis accounts for ~80% of cases in high-income countries; the adrenal gland is a target of organ-specific T-cell attack, usually with detectable 21-hydroxylase antibodies.

Secondary/tertiary adrenal insufficiency: ACTH deficiency (pituitary disease, hypophysitis, post-surgical) or CRH deficiency (hypothalamic); aldosterone axis is largely preserved since it is regulated by renin-angiotensin, not ACTH.

Common causes by tier:

Clinical Features

• Chronic PAI: fatigue, weight loss, anorexia, nausea, postural hypotension, salt craving, hyperpigmentation (elevated MSH co-secreted with ACTH), hyponatraemia, hyperkalaemia, hypoglycaemia, amenorrhoea, loss of axillary/pubic hair in women
• Secondary AI: similar but no hyperpigmentation (low ACTH), no hyperkalaemia (intact mineralocorticoid axis), may have features of panhypopituitarism
• Acute crisis: shock disproportionate to apparent illness, abdominal pain mimicking acute abdomen, fever, confusion - clinically indistinguishable from septic shock

Investigations

1. Morning serum cortisol (08:00-09:00): $\geq 450\,\text{nmol/L}$ makes AI very unlikely; $< 100\,\text{nmol/L}$ is strongly suggestive
2. Short Synacthen test (SST): 250 µg tetracosactide IV/IM; peak cortisol $< 500\,\text{nmol/L}$ at 30 or 60 min is abnormal (laboratory-specific cut-offs apply)
3. Plasma ACTH: elevated in PAI ($> 2\times$ upper limit), suppressed in secondary/tertiary AI
4. 21-hydroxylase antibodies: confirm autoimmune aetiology
5. Renin and aldosterone: assess mineralocorticoid status in PAI
6. Electrolytes, glucose, FBC: hyponatraemia, hyperkalaemia, eosinophilia, normochromic anaemia
7. Adrenal CT: adrenal enlargement (haemorrhage, granuloma, malignancy) or atrophy
8. MRI pituitary: if secondary AI suspected

Management

Acute adrenal crisis:

1. Establish IV access; draw cortisol and ACTH before treatment but <em>do not delay</em> treatment for results
2. Hydrocortisone 100 mg IV stat, then 50-100 mg IV every 6-8 hours (or continuous infusion 200 mg/24 h)
3. Aggressive IV 0.9% saline resuscitation; dextrose if hypoglycaemic
4. Identify and treat precipitant (infection, surgery, missed doses)
5. Fludrocortisone not needed while hydrocortisone dose is $\geq 50\,\text{mg/day}$ (sufficient mineralocorticoid effect)

Chronic replacement:

• Hydrocortisone 15-25 mg/day in 2-3 divided doses (largest dose on waking, mimicking diurnal cortisol rhythm)
• Fludrocortisone 50-200 µg/day for PAI (titrate to BP, postural symptoms, renin at upper normal)
• DHEA replacement (25-50 mg/day) may be considered in women with PAI and persistent fatigue/low libido
• <strong>Sick day rules:</strong> double or triple dose for febrile illness, vomiting → parenteral hydrocortisone; provide emergency IM kit (hydrocortisone 100 mg IM) and steroid emergency card
• Regular monitoring: clinical assessment, morning cortisol (pre-dose), renin, electrolytes, bone density (DEXA at baseline and 2-yearly), ACTH-related tumour screen in autoimmune AI

Cushing Syndrome

Pathophysiology

Excess glucocorticoid from any source. ACTH-dependent causes (90%): Cushing disease (pituitary corticotroph adenoma, 75%) and ectopic ACTH syndrome (bronchial/pancreatic carcinoid, small-cell lung cancer, 15%). ACTH-independent causes (10%): adrenocortical adenoma or carcinoma, macronodular or micronodular adrenal hyperplasia. Exogenous glucocorticoid use is by far the most common cause overall.

Clinical Features

Classic features reflect chronic hypercortisolaemia:

• Central adiposity, moon face, dorsocervical fat pad ("buffalo hump")
• Purple/violaceous striae (>1 cm wide), skin thinning, easy bruising, poor wound healing
• Proximal myopathy (difficulty rising from a chair)
• Hypertension, impaired glucose tolerance/diabetes, dyslipidaemia
• Osteoporosis (vertebral fractures)
• Neuropsychiatric features: depression, cognitive impairment, psychosis
• Hirsutism, menstrual irregularity, reduced libido, erectile dysfunction
• Opportunistic infections, impaired immunity

Clues to aetiology:

• Palpable abdominal mass, virilisation in women, or gynaecomastia in men → adrenal carcinoma
• Severe hypokalaemia, marked hyperpigmentation, rapid onset with little adiposity → ectopic ACTH (often from aggressive tumour)

Diagnostic Investigations

Establishing hypercortisolaemia requires at least two positive tests from:

Establishing aetiology:

1. Plasma ACTH: undetectable/suppressed → ACTH-independent (CT adrenals); elevated → ACTH-dependent
2. CRH stimulation test and/or 8 mg high-dose dexamethasone suppression: Cushing disease shows paradoxical stimulation/partial suppression; ectopic ACTH does not
3. MRI pituitary: often microadenoma ($< 6\,\text{mm}$); normal MRI does not exclude Cushing disease
4. Bilateral inferior petrosal sinus sampling (BIPSS): gold standard for distinguishing pituitary vs. ectopic ACTH - central-to-peripheral ACTH gradient $> 2$ basal or $> 3$ post-CRH confirms pituitary source
5. CT chest/abdomen/pelvis ± $^{68}$Ga-DOTATATE PET-CT for ectopic ACTH source

Management

• Cushing disease: transsphenoidal pituitary surgery (first-line, remission ~75-80%); radiotherapy or bilateral adrenalectomy for failed/recurrent disease; medical steroidogenesis inhibitors (metyrapone, ketoconazole, osilodrostat, cabergoline) as bridging therapy
• Adrenal adenoma/carcinoma: laparoscopic adrenalectomy; adrenal carcinoma requires mitotane ± systemic chemotherapy
• Ectopic ACTH: resect primary tumour where possible; medical steroidogenesis inhibition pending surgery; bilateral adrenalectomy for occult/refractory cases
• Post-operative: adrenal axis suppression persists; hydrocortisone replacement and cautious tapering over months guided by morning cortisol and symptoms
• Manage comorbidities: antihypertensives, diabetes management, antiresorptive therapy for osteoporosis, thromboprophylaxis (hypercoagulable state)

Phaeochromocytoma and Paraganglioma

Overview

Catecholamine-secreting tumours arising from chromaffin cells: phaeochromocytoma (adrenal medulla) or paraganglioma (extra-adrenal sympathetic/parasympathetic ganglia). Up to 40% are hereditary (RET, VHL, SDHB/C/D, NF1, MAX mutations) - genetic testing is warranted in all patients.

Rule of 10s (historical, now ~40% rule): approximately 10-40% bilateral, 10-15% extra-adrenal, 10-15% malignant (higher with SDHB mutations).

Clinical Features

• Classic triad: episodic headache, diaphoresis, and palpitations (often with hypertensive surges)
• Sustained or paroxysmal hypertension; hypertensive crisis precipitated by surgery, contrast, beta-blockade without alpha-blockade, tricyclics, metoclopramide
• Pallor (not flushing), anxiety, tremor, weight loss
• Phaeochromocytoma-induced cardiomyopathy (catecholamine cardiomyopathy): dilated or Takotsubo-like pattern

Investigations

1. Plasma free metanephrines (or 24-hour urine fractionated metanephrines): highest sensitivity ($>95\%$); preferred initial test
2. CT abdomen/pelvis: anatomical localisation; phaeochromocytoma characteristically $> 10\,\text{HU}$ unenhanced and shows avid enhancement
3. $^{123}$I-MIBG scintigraphy or $^{68}$Ga-DOTATATE PET-CT: functional imaging for metastatic disease, extra-adrenal paraganglioma, surgical planning
4. Genetic testing: all patients, guided by phenotype and family history
5. Cardiac assessment: ECG (LVH, arrhythmia), echo (cardiomyopathy)

Management

Pre-operative preparation (minimum 10-14 days):

1. Alpha-blockade first: phenoxybenzamine (non-selective, irreversible) starting 10 mg bd, titrated to BP; or doxazosin (selective $\alpha_1$, better tolerated)
2. Adequate fluid/salt loading to counteract catecholamine-induced volume contraction
3. Beta-blockade <em>only after</em> adequate alpha-blockade to avoid paradoxical hypertensive crisis (unopposed $\alpha$-mediated vasoconstriction): propranolol or atenolol for tachycardia/arrhythmia
4. Surgery (laparoscopic adrenalectomy) by experienced surgeon with intraoperative BP management (phentolamine, sodium nitroprusside, magnesium infusion available)
5. Post-operative hypotension common - anticipate and pre-emptively hydrate

Malignant/metastatic disease: MIBG radionuclide therapy ($^{177}$Lu-DOTATATE or $^{131}$I-MIBG), sunitinib, CVD chemotherapy (cyclophosphamide, vincristine, dacarbazine), long-term surveillance

Conn Syndrome (Primary Aldosteronism)

Pathophysiology

Autonomous aldosterone excess from the adrenal zona glomerulosa, independent of renin-angiotensin regulation. Prevalence is 5-12% of all hypertensive patients, rising to 20%+ in resistant hypertension. The most common causes are bilateral adrenal hyperplasia (idiopathic, ~60%) and unilateral aldosterone-producing adenoma (~35%). Somatic mutations in potassium channels (KCNJ5) and calcium channels are prevalent in adenomas; germline mutations cause familial hyperaldosteronism.

Clinical Features

• Hypertension, often difficult to control
• Hypokalaemia ($K^+ < 3.5\,\text{mmol/L}$) - though ~50% are normokalaemic; muscle weakness, cramps, polyuria, polydipsia (nephrogenic diabetes insipidus from hypokalaemia)
• Metabolic alkalosis
• Increased cardiovascular risk beyond that attributable to hypertension alone (atrial fibrillation, LVH, stroke)

Diagnostic Investigations

Step 1 - Screening:

• <strong>Aldosterone-to-renin ratio (ARR):</strong> aldosterone $> 300\,\text{pmol/L}$ with suppressed renin, and ARR $> 70\,\text{pmol/L per mU/L}$ (laboratory-specific cut-offs)
• Perform after correcting hypokalaemia; cease spironolactone, eplerenone, and amiloride for $\geq 4$ weeks; ACE inhibitors and ARBs may falsely lower ARR (acceptable if renin still suppressed)

Step 2 - Confirmatory testing (one of):

• Salt loading (IV saline 2 L over 4 h or oral salt loading $\times 3$ days): aldosterone fails to suppress $< 140\,\text{pmol/L}$
• Fludrocortisone suppression test
• Captopril challenge test

Step 3 - Subtype differentiation:

• <strong>CT adrenals:</strong> detect macroadenoma but misses $\sim 50\%$ of adenomas and cannot reliably distinguish adenoma from bilateral hyperplasia; CT cannot replace adrenal vein sampling
• <strong>Adrenal vein sampling (AVS):</strong> gold standard for lateralisation; lateralisation index $\geq 4:1$ confirms unilateral disease (or $\geq 3:1$ with ACTH stimulation); mandatory before surgical referral except in young patients ($< 35$ years) with classic CT adenoma

Management

Medical management with MRAs:

• <strong>Spironolactone</strong> 25-50 mg/day titrated to maximum 400 mg/day (most effective but anti-androgenic side effects: gynaecomastia, menstrual irregularity, erectile dysfunction)
• <strong>Eplerenone</strong> 25-50 mg bd (selective MRA, fewer sex steroid effects; less potent)
• Monitor potassium and renal function at 1-4 weeks, then 3-monthly; avoid in $\text{eGFR} < 30\,\text{mL/min}$
• Add antihypertensives (CCB, ACE inhibitor/ARB) as needed

Post-adrenalectomy: contralateral adrenal may be suppressed; monitor for transient AI; hyperkalaemia common in early post-operative period

Complications and Cross-Cutting Considerations

Adrenal Incidentaloma

• Discovered on imaging performed for another indication; prevalence ~5% at CT
• Evaluate for autonomous cortisol secretion (1 mg overnight DST), phaeochromocytoma (plasma metanephrines), primary aldosteronism (ARR if hypertensive), adrenocortical carcinoma (size $> 4\,\text{cm}$, heterogeneous, unenhanced HU $> 10$, washout $< 60\%$)
• Surveillance imaging at 6-12 months for indeterminate lesions $< 4\,\text{cm}$; surgical resection for $> 4\,\text{cm}$ or growing lesions

Autoimmune Polyendocrine Syndromes

• PAI commonly clusters with autoimmune thyroid disease, type 1 diabetes, and primary hypogonadism (APS type 2); screen periodically with TSH, fasting glucose, gonadal hormones

Perioperative and Sick-Day Management

• Any patient on chronic glucocorticoids or with known AI requires stress dosing for surgical procedures: minor surgery 25-75 mg hydrocortisone equivalent day of procedure; major surgery 100 mg IV at induction then 50 mg q8h × 24-48 h
• Patients with phaeochromocytoma require mandatory alpha-blockade before any procedure; contrast media can precipitate crisis

Cardiovascular Risk

• Cushing syndrome and primary aldosteronism both independently accelerate cardiovascular risk; regression of LVH and AF burden occurs after successful treatment of primary aldosteronism
• Phaeochromocytoma-induced cardiomyopathy is potentially reversible with tumour resection

Long-Case Approach and Exam Framing

In the long case, structure your adrenal presentation around:

1. <strong>Diagnostic certainty:</strong> which tests confirm the biochemical diagnosis, and have the correct confirmatory tests been performed (not just screening)?
2. <strong>Aetiology:</strong> subtype classification drives treatment - adrenal vs. pituitary vs. ectopic in Cushing; lateralisation in Conn; hereditary vs. sporadic in phaeochromocytoma
3. <strong>Comorbidity burden:</strong> hypertension, diabetes, osteoporosis, renal impairment, cardiovascular disease - each requires active management
4. <strong>Treatment trade-offs:</strong> surgical cure vs. medical management, shared decision-making around fertility, side effects of MRAs, or steroid dependence
5. <strong>Safety netting:</strong> sick-day rules, steroid emergency card, genetic counselling referral for hereditary phaeochromocytoma, long-term biochemical surveillance
6. <strong>Multidisciplinary care:</strong> endocrinology, endocrine surgery, radiology (interventional for AVS), genetics, cardiology - articulate who does what and when