Endocrine Hypertension

Overview & Classification

1. Primary Aldosteronism (PA)

Pathophysiology

• Aldosterone-producing adenoma (APA / Conn adenoma) - unilateral, surgical cure possible
• Bilateral idiopathic adrenal hyperplasia (BAH) - medical management
• Unilateral adrenal hyperplasia, glucocorticoid-remediable aldosteronism (rare familial form)

Who to Screen

• Hypertension with spontaneous or easily provoked hypokalemia
• Resistant/refractory hypertension (not controlled on ≥3 agents)
• Early-onset hypertension
• Hypertension + atrial fibrillation
• Known adrenal adenoma + hypertension
• Family history of PA or early stroke
• Key point: absence of hypokalemia does NOT exclude PA - most patients are normokalemic

Screening Test: Aldosterone-Renin Ratio (ARR)

• Measured on a random morning sample (diurnal variation matters)
• ARR >20 with plasma aldosterone >15 ng/dL supports PA (some labs use ARR >200 ng/dL per ng/mL/h)
• Test is 70-90% sensitive and 70-100% specific
• Medications to consider holding: MR blockers (spironolactone, eplerenone), diuretics, beta-blockers, ACEi/ARBs - though this is complex (see below)

Confirmatory Testing

Localization

1. CT adrenal (thin 1 mm slices) - first step after biochemical confirmation
2. Adrenal vein sampling (AVS) - the definitive test for lateralization (unilateral vs bilateral); technically demanding, should be done at specialized centers
   • Selectivity index confirms successful cannulation (>2 unstimulated, >5 stimulated)
   • Lateralization index (LI) determines unilateral vs bilateral disease

Treatment

• Unilateral disease (APA): laparoscopic adrenalectomy - cures hypertension in many patients
• Bilateral disease (BAH): MR antagonists - spironolactone (first-line) or eplerenone (fewer anti-androgenic side effects)

2025 Update: The Endocrine Society issued an updated Clinical Practice Guideline on Primary Aldosteronism (PMID 40658480) and a supporting systematic review (PMID 40658500) in August 2025.

2. Pheochromocytoma & Paraganglioma (PPGL)

Clinical Features

• Headache (often severe, pounding)
• Sweating (profuse, diaphoretic)
• Palpitations / tachycardia

• Paroxysmal (classic) - episodic crises lasting 15 min to hours
• Sustained (in ~50%)
• Orthostatic (paradoxically, due to volume contraction)

Who to Screen

• Classic triad (headache, sweating, palpitations) ± hypertension
• Adrenal incidentaloma on imaging
• Family history / known mutation (VHL, RET, NF1, SDH genes)
• Resistant hypertension with paroxysmal features

Biochemical Diagnosis

• First-line: plasma-free metanephrines (highest sensitivity ~97%)
• Alternative: 24-hour urine fractionated metanephrines and catecholamines
• Sample ideally drawn supine for ≥20 minutes (reduces false positives)
• Advanced CKD raises metanephrine levels - adjust interpretation accordingly
• Interfering medications to be aware of: acetaminophen, levodopa, MAO inhibitors, SSRIs, tricyclics, sympathomimetics, some beta-blockers, cocaine

Imaging (after biochemical confirmation)

• CT or MRI abdomen/pelvis - first-line (most PPGLs are adrenal or para-aortic)
• CT/MRI chest, neck, head if abdominal imaging negative
• ¹²³I-MIBG scan - reserved for negative cross-sectional imaging despite markedly elevated biochemistry, or metastatic disease staging
• ⁶⁸Ga-DOTATATE PET - superior for paragangliomas; increasingly preferred

Workup Flowchart

Treatment

• Surgical excision after preoperative alpha-blockade (phenoxybenzamine or selective α₁-blockers)
• Beta-blockers added ONLY after alpha-blockade is established (adding beta-blocker first risks paradoxical hypertensive crisis by leaving alpha receptors unopposed)
• Biochemical follow-up at 6 months then annually; imaging annually for high-risk patients (large tumors, multifocal paragangliomas)

2026 Guideline: Japan Endocrine Society Clinical Practice Guideline for PPGL 2025 (PMID 41083371) - published Jan 2026.

3. Cushing Syndrome

Causes

Mechanisms of Hypertension

• Cortisol raises both cardiac output and total peripheral resistance
• At very high cortisol levels (especially ectopic ACTH), 11β-HSD2 is overwhelmed → cortisol binds mineralocorticoid receptors → pseudohyperaldosteronism → volume expansion and hypokalemia
• Cortisol inhibits vasodilatory nitric oxide
• Enhanced pressor responsiveness to catecholamines and angiotensin II
• Activation of cardiac and vascular MR → inflammatory, hypertrophic, and fibrotic changes
• Left ventricular hypertrophy disproportionate to BP level

Clinical Clues

Diagnosis

1. 24-hour urinary free cortisol (UFC) - elevated (>3-4x ULN is highly specific)
2. Late-night salivary cortisol (×2) - loss of normal circadian nadir
3. Overnight 1 mg dexamethasone suppression test - morning cortisol >1.8 mcg/dL is abnormal

Treatment

• Cushing disease: transsphenoidal pituitary surgery
• Adrenal adenoma: laparoscopic adrenalectomy
• Ectopic ACTH: treat primary tumor ± bilateral adrenalectomy
• Successful treatment usually reduces BP, though hypertension may persist in some patients

4. Thyroid Disease

Hypothyroidism (~40% have hypertension)

• Predominantly diastolic HTN
• Mechanism: ↑systemic vascular resistance, ↓arterial compliance
• Narrow pulse pressure despite stiff vessels (low cardiac output)
• Subclinical hypothyroidism also associated with HTN
• Treatment of thyroid disease normalizes BP in most patients

Hyperthyroidism

• Predominantly systolic HTN
• Wide pulse pressure (↑CO + ↓SVR)
• Can mimic pheochromocytoma with paroxysmal features, flushing, palpitations
• Specific antithyroid treatment normalizes BP in most cases

5. Primary Hyperparathyroidism

• Up to 70% of patients with parathyroid adenoma have hypertension
• Mechanisms: ↑cytosolic calcium → ↑vascular resistance and ↑CO; hypercalcemia-induced renal vasoconstriction; kidney damage from hypercalciuria
• No direct correlation between serum Ca or PTH levels and BP
• Parathyroid adenoma resection cures or improves BP in most patients with new-onset HTN

6. Acromegaly

• Hypertension is common, though prevalence partly explained by age and sex
• GH and IGF-1 are implicated (BP decreases after successful treatment in many)
• BP elevations are seldom severe

7. Renin-Secreting Tumors

• Rare (<200 reported cases); most are benign renal juxtaglomerular cell tumors (2-4 cm)
• Classic presentation: young woman (<30 y), severe hypertension (~206/131 mmHg), hypokalemia (<3 mmol/L in 70%), proteinuria, occasionally hyponatremia
• Mechanism: autonomous renin → ↑Ang II → secondary hyperaldosteronism + direct vasoconstriction
• Diagnosis: elevated plasma renin/prorenin that normalizes after tumor removal, renin demonstrated within tumor
• Treatment: surgical resection

Adrenal Incidentaloma: The Triple Screen

1. Pheochromocytoma - plasma-free metanephrines or 24-hr urine fractionated metanephrines
2. Glucocorticoid excess - morning cortisol after 1 mg overnight dexamethasone
3. Primary aldosteronism - plasma aldosterone and renin
4. Malignancy risk - if non-contrast HU >10, >4-6 cm, or growing → surgical resection

Clinical Features Suggesting Endocrine Hypertension