13.4 Adrenal Insufficiency & Endocrine Hypertension

2. Adrenal Insufficiency & Acute Addisonian Crisis

Primary vs. Secondary Adrenal Insufficiency

Adrenal insufficiency denotes deficiency of adrenocortical hormones. Pathophysiological and clinical differentiation is critical:

Diagnostic Evaluation of Adrenal Insufficiency

• Random / Morning Serum Cortisol (08:00–09:00): Cortisol $< 100\text{ nmol/L}$ strongly suggests adrenal insufficiency; cortisol $> 450\text{–}500\text{ nmol/L}$ excludes it; intermediate values mandate dynamic testing.
• Short Synacthen Test (SST): The definitive diagnostic investigation. Synthetic ACTH 1–24 ($250\text{ mcg}$ tetracosactide) is administered IM or IV; serum cortisol is measured at 0, 30, and 60 minutes. A normal response is a peak cortisol $> 450\text{–}500\text{ nmol/L}$. Failure to achieve this threshold confirms adrenal insufficiency.
• Plasma ACTH: Differentiates primary (high) from secondary (low) insufficiency.
• Adrenal Autoantibodies: Anti-21-hydroxylase antibodies are positive in $> 85%$ of autoimmune Addison's disease (isolated or within Autoimmune Polyendocrine Syndrome Type 1 [APS-1: AIRE gene mutation; candidiasis, hypoparathyroidism, Addison's] or Type 2 [APS-2: HLA-DR3/DR4; Addison's, autoimmune thyroid disease, type 1 diabetes]).

Chronic Replacement Regimen

• Glucocorticoid Replacement: Hydrocortisone $15\text{–}25\text{ mg}$ total daily dose, divided into 2 or 3 doses mimicking normal circadian physiology (e.g. $10\text{ mg}$ on waking, $5\text{ mg}$ at midday, $2.5\text{–}5\text{ mg}$ late afternoon; avoiding evening doses that provoke insomnia).
• Mineralocorticoid Replacement: Fludrocortisone $50\text{–}200\text{ mcg}$ once daily in the morning (required only in primary adrenal insufficiency). Dose titrated against sitting and standing blood pressure (avoiding postural drop), serum sodium, potassium, and plasma renin activity.
• Sick Day Rules: Patients must be educated to double their oral hydrocortisone dose during intercurrent febrile illness, carry a steroid emergency card and medical alert bracelet, and possess an emergency intramuscular hydrocortisone ($100\text{ mg}$) injection kit for vomiting or severe trauma.

Emergency Management of Acute Addisonian Crisis

An acute adrenal crisis is an immediately life-threatening emergency precipitated by infection, trauma, surgery, or medication non-compliance in an individual with primary or secondary hypoadrenalism. Presents with shock, refractory hypotension, severe vomiting, acute abdominal pain ('pseudo-peritonitis'), fever, and profound hypoglycaemia.

1. Immediate Hydrocortisone: Administer intravenous hydrocortisone 100 mg stat bolus, followed by $100\text{–}200\text{ mg}$ per 24 hours (either as a continuous IV infusion or $50\text{ mg}$ IV every 6 hours). Never delay hydrocortisone administration to perform diagnostic testing!
2. Rapid Volume Resuscitation: Infuse intravenous 0.9% normal saline ($1\text{ L}$ over the first hour, running 3 to 4 liters over 24 hours) to restore intravascular volume and correct hyponatraemia. If hypoglycaemia is present, administer intravenous $10%$ dextrose.
3. Identify & Treat Precipitants: Send blood cultures and administer empirical broad-spectrum antibiotics if infection is suspected.
4. Fludrocortisone Note: Fludrocortisone is NOT required acutely; at doses $> 50\text{ mg/day}$, hydrocortisone exhibits maximal, saturating cross-reactivity at the mineralocorticoid receptor.

3. Endocrine Hypertension

Primary Aldosteronism (Conn's Syndrome)

Autonomous, renin-independent aldosterone overproduction represents the most common surgically curable cause of secondary hypertension ($5\text{–}10%$ of all hypertensives, rising to $> 20%$ in resistant hypertension):

• Etiology: Bilateral idiopathic adrenal hyperplasia (60–65%) vs. Unilateral aldosterone-producing adenoma (APA / Conn's adenoma, 30–35%); rare causes include unilateral adrenal hyperplasia and glucocorticoid-remediable aldosteronism (GRA / Familial Hyperaldosteronism Type 1, chimeric $CYP11B1/CYP11B2$ gene).
• Pathophysiology: Excess aldosterone activates mineralocorticoid receptors in principal cells of the renal cortical collecting duct, upregulating epithelial sodium channels (ENaC) and basolateral $\text{Na}^+/\text{K}^+$-ATPase. This drives sodium retention and intravascular expansion (suppressing renin), accompanied by potassium excretion via ROMK channels and hydrogen ion secretion via intercalated cell $\text{H}^+$-ATPase. This yields hypertension, hypokalaemia, and metabolic alkalosis. Note: $> 50%$ of patients with primary aldosteronism are normokalaemic at presentation!
• Screening Test: Aldosterone-to-Renin Ratio (ARR): Measured morning in an upright, seated, non-stressed patient. Elevated plasma aldosterone concentration (PAC) with profoundly suppressed plasma renin activity (PRA) or direct renin concentration (DRC). An ARR $> 30\text{–}50$ (depending on laboratory units) is positive. Medication washout: Mineralocorticoid receptor antagonists (spironolactone, eplerenone) and amiloride must be stopped for at least 6 weeks; ACE inhibitors, ARBs, and beta-blockers must be stopped for 2 weeks. Alpha-blockers (doxazosin) and verapamil have minimal impact on ARR and are used for interim blood pressure control.
• Confirmatory Testing: Saline infusion test ($2\text{ L}$ $0.9%$ saline over 4 hours) or oral sodium loading; failure of aldosterone to suppress below $140\text{ nmol/L}$ confirms autonomy.
• Subtype Differentiation: High-resolution CT of the adrenals to visualize morphology, followed by Adrenal Vein Sampling (AVS). AVS is the mandatory gold standard to distinguish unilateral adenoma from bilateral hyperplasia in surgical candidates, because non-functioning incidental adrenal cortical adenomas are common and can lead to inappropriate adrenalectomy.
• Management:
  • Unilateral Adenoma: Laparoscopic unilateral adrenalectomy (cures hypokalaemia in $100%$ and cures or improves hypertension in $> 80%$).
  • Bilateral Hyperplasia: Medical therapy with mineralocorticoid receptor antagonists: Spironolactone ($25\text{–}100\text{ mg}$ once daily). In men developing gynaecomastia, mastodynia, or erectile dysfunction, switch to the selective MRA Eplerenone ($50\text{–}100\text{ mg}$ daily).

Phaeochromocytoma & Paraganglioma

Catecholamine-producing neuroendocrine tumors arising from chromaffin cells of the adrenal medulla (phaeochromocytoma, $80\text{–}85%$) or extra-adrenal sympathetic paraganglia (paraganglioma, $15\text{–}20%$):

• Classical 'Rule of 10s' (Traditional Teaching): $10%$ bilateral, $10%$ extra-adrenal (organ of Zuckerkandl, carotid body), $10%$ malignant (defined strictly by distant metastases to non-chromaffin tissue), and $10%$ familial. However, modern genetic profiling shows that $> 30\text{–}40%$ of all cases harbor germline mutations: MEN2A and MEN2B (RET proto-oncogene), Von Hippel-Lindau (VHL), Neurofibromatosis type 1 (NF1), and succinate dehydrogenase subunit mutations (SDHB [high malignancy risk], SDHD).
• Clinical Presentation: Paroxysmal triad of headache ($80%$), profuse diaphoresis ($70%$), and palpitations ($65%$), accompanied by severe episodic or sustained hypertension, anxiety/panic attacks, pallor, tremor, and orthostatic hypotension.
• Biochemical Diagnosis: First-line screening is measurement of 24-hour urinary fractionated metanephrines or plasma free metanephrines (sensitivity $> 97\text{–}99%$). Catecholamines are metabolized intratumorally by catechol-O-methyltransferase (COMT) into metanephrines and normetanephrines, which are released continuously, avoiding the false-negative results of pulsatile parent catecholamine surges.
• Imaging: Contrast-enhanced CT or MRI of abdomen/pelvis. Functional imaging with iodine-123 metaiodobenzylguanidine (123I-MIBG) or gallium-68 DOTATATE PET-CT for metastatic, recurrent, or paraganglionic disease.
• Preoperative Medical Preparation (CRITICAL EXAM PEARL):
  • $\alpha$-Blockade FIRST, then $\beta$-Blockade SECOND:
    1. Non-competitive $\alpha$-adrenergic blockade with oral Phenoxybenzamine (starting at $10\text{ mg}$ twice daily and uptitrated over 10 to 14 days) or selective $\alpha_1$-blockers (doxazosin). Generous salt and fluid intake are prescribed concurrently to expand the contracted intravascular volume.
    2. $\beta$-Blockers (e.g. propranolol, bisoprolol) are added ONLY AFTER full, effective $\alpha$-blockade is established (evidenced by orthostatic drop and nasal congestion), to control reflex tachycardia.
  • The Cardinal Rule: NEVER administer a $\beta$-blocker alone or prior to complete $\alpha$-blockade! Blocking vasodilator $\beta_2$ receptors in the presence of uninhibited $\alpha_1$ stimulation provokes catastrophic, uncontrolled systemic vasoconstriction, precipitating fatal hypertensive crises, intracranial haemorrhage, or acute pulmonary oedema.