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Overview
When to Suspect Secondary HTN
- Age < 30 at HTN onset
- Sudden onset in previously normotensive
- Severe / resistant HTN (⥠3 drugs incl diuretic at full dose)
- Hypokalemia without diuretic
- Episodic / paroxysmal BP
- Disproportionate target organ damage
- Family history of secondary HTN
- Specific clinical features suggesting cause
Major Categories
- Renal (renovascular + parenchymal) â 1-5%
- Endocrine (PA, pheo, Cushing, thyroid, parathyroid) â 1-15%
- Sleep-disordered breathing (OSA) â 30-50% of resistant HTN
- Drug/substance-induced â common
- Other (coarctation, neurogenic)
Renovascular HTN
Renal Artery Stenosis (RAS)
- Atherosclerotic RAS (ARAS) â older, multi-vessel
- 90% of RAS
- Risk: dyslipidemia, smoking, DM, age
- Often bilateral; may cause progressive CKD
- Fibromuscular Dysplasia (FMD) â young women, âstring of beadsâ
- 10% of RAS
- Bilateral 35%
- Can affect carotids â SCAD
Clinical Clues
- HTN onset < 30 or > 55
- Sudden worsening of previously controlled HTN
- Resistant HTN
- Flash pulmonary edema
- AKI on starting ACEi/ARB
- Abdominal/flank bruit
- Smoking, atherosclerosis elsewhere
- Hypokalemia (secondary hyperaldosteronism)
Workup
- Renal duplex ultrasound (peak systolic velocity > 200 cm/s suggests > 60% stenosis)
- CT angiography (gold standard for ARAS)
- MR angiography (no contrast in CKD; but gadolinium concern)
- Captopril renogram (functional, less used)
- Catheter angiography (gold standard but invasive)
Treatment
- ARAS:
- OMT primary (statin, ASA, ACEi/ARB, BP control)
- CORAL trial 2014: stent + OMT = OMT alone (mostly)
- Stent reserved for: flash pulmonary edema, refractory HTN, progressive CKD on OMT
- FMD:
- Balloon angioplasty without stent (often curative)
- Cure rate 50-60% for hypertension
Renal Parenchymal Disease
- Most common cause of secondary HTN overall
- Polycystic kidney disease, glomerulonephritis, diabetic nephropathy, CKD any cause
- HTN + â Cr + abnormal UA
- Mechanism: Na/volume retention, RAAS activation
- Treatment: ACEi/ARB, BP control, treat underlying disease
Primary Aldosteronism (PA)
Epidemiology
- 5-10% of all HTN (most common endocrine cause)
- 15-20% of resistant HTN
- Severely underdiagnosed
- 2024 update: screen broader population per ENDOCRINE SOCIETY 2024
Pathophysiology
- Autonomous aldosterone production from adrenal
- Suppresses renin
- Na retention â volume expansion â HTN
- K wasting â hypokalemia
- Aldosterone direct toxicity: cardiac fibrosis, vascular damage
Subtypes
- Aldosterone-producing adenoma (APA, Connâs) â 30-40%
- Bilateral adrenal hyperplasia (BAH, idiopathic) â 60%
- Familial hyperaldosteronism (Type I = GRA â glucocorticoid-remediable; Type II, III, IV) â rare
- Aldosterone-producing carcinoma â rare
Clinical Features
- HTN, often resistant
- Hypokalemia (40% only; 60% normokalemic)
- Metabolic alkalosis
- Family hx, age
Screening â Aldosterone/Renin Ratio (ARR)
- Conditions:
- Hold MRA (spironolactone, eplerenone) 6 weeks
- Hold β-blocker 1-2 weeks (â false positive)
- ACEi/ARB, CCB, α-blockers OK for screening
- Hold diuretics if possible
- Hold K+ supplement, NSAIDs
- Interpretation: ARR > 20 (ng/dL : ng/mL/h) AND plasma aldosterone > 15 ng/dL â suspicious
Confirmation
- One of four tests required:
- Oral sodium loading (24h urine aldosterone > 12 ÎŒg/24h)
- IV saline infusion (aldosterone > 10 ng/dL after 2L NS)
- Captopril challenge (aldosterone fails to suppress)
- Fludrocortisone suppression (rare)
- 2024 update: simplified algorithm â ARR + plasma aldosterone > 30 may be enough in some
Localization
- Adrenal CT â most patients
- Adrenal vein sampling (AVS) â gold standard
- Indicated when surgery contemplated
- Lateralization ratio > 4 (or > 2 with cosyntropin)
- Technically demanding; refer to experienced center
- C-11 metomidate PET (emerging, less invasive)
Treatment
- Unilateral adenoma: laparoscopic adrenalectomy
- Bilateral hyperplasia: MRA (spironolactone 25-50 mg or eplerenone 25-100 mg)
- Surgical cure: 30-50% (post-op may still need 1-2 antihypertensives)
Pheochromocytoma + Paraganglioma
Epidemiology
- < 1% of HTN
- 80-90% adrenal (pheo); 10-20% extra-adrenal (paraganglioma)
- 30% germline mutations (vs 10% old data) â VHL, MEN2, NF1, SDHx, FH, MAX, TMEM127
- 2024: ENDOCRINE SOCIETY recommends germline testing for ALL
Clinical (5 Ps)
- Pain (HA)
- Palpitations
- Perspiration
- Pallor
- Paroxysmal (episodic)
- Plus HTN (sustained or episodic), orthostatic, anxiety, weight loss
Diagnosis
- Plasma free metanephrines (preferred â 99% sensitive)
- 24h urine fractionated metanephrines (alternative)
- Caution: TCAs, decongestants, SNRIs, acetaminophen â false positive
- If positive â imaging:
- CT or MRI of adrenals + abdomen
- MIBG scan for extra-adrenal or metastatic
- DOTATATE PET/CT for SDHx-related paraganglioma
- FDG-PET for metastatic
Pre-Op Preparation (CRITICAL)
- α-blockade first (phenoxybenzamine 10 mg BID, titrate to BP 110-130/70)
- Add β-blocker only AFTER α-blockade (avoid unopposed α â crisis)
- Volume expansion (high salt diet, IV saline pre-op)
- Goal: BP 110-130/70, HR 60-70, orthostatic OK
- Duration: 7-14 days minimum
Surgery
- Laparoscopic adrenalectomy
- Open if > 6 cm or invasive
- Cortical-sparing if bilateral or genetic predisposition
- Hypotension common post-op (volume + α-blockade)
Genetic Testing (2024 â All Patients)
- SDHB, SDHC, SDHD, SDHAF2 (most common)
- VHL, RET (MEN2), NF1
- TMEM127, MAX, FH
- Family screening cascade
Cushingâs Syndrome
Causes
- ACTH-dependent:
- Cushingâs disease (pituitary adenoma â 70%)
- Ectopic ACTH (lung cancer, neuroendocrine tumor â 15%)
- ACTH-independent:
- Adrenal adenoma / carcinoma (10-15%)
- Macronodular adrenal hyperplasia
- Exogenous steroid â most common overall
Clinical
- Central obesity, moon facies, buffalo hump
- Purple striae > 1 cm wide
- Easy bruising, thin skin
- Proximal muscle weakness
- HTN, DM, hypokalemia, osteoporosis
- Mood changes
- Hirsutism, menstrual irregularity
Screening
- 24h urine free cortisol (UFC) â 2 measurements
- Midnight salivary cortisol
- 1 mg overnight dexamethasone suppression test (DST): cortisol > 1.8 ÎŒg/dL = abnormal
- Confirm with 2 of 3 abnormal
Differentiation
- Plasma ACTH: > 20 â ACTH-dependent; < 10 â ACTH-independent
- High-dose DST: pituitary suppresses, ectopic doesnât (often)
- CRH stimulation: pituitary responds
- IPSS (inferior petrosal sinus sampling): gold standard for pituitary vs ectopic
Imaging
- Pituitary MRI (with contrast)
- Adrenal CT
- Whole-body CT/PET for ectopic source
Treatment
- Surgery for adenoma (transsphenoidal pituitary; adrenalectomy)
- Medical: ketoconazole, metyrapone, mitotane, mifepristone (glucocorticoid receptor antagonist), osilodrostat (11β-hydroxylase inh, approved 2020)
- Radiation for residual
Obstructive Sleep Apnea (OSA)
Epidemiology
- 30-40% of HTN
- 70%+ of resistant HTN
- Underdiagnosed
Pathophysiology
- Recurrent upper airway collapse â hypoxia â sympathetic surge â â BP
- Especially affects nocturnal BP (non-dipping)
- Promotes RAAS activation
Clinical
- Snoring, witnessed apnea
- Daytime sleepiness (Epworth)
- Obesity (BMI > 30)
- Large neck circumference (> 17â â, > 16â â)
- Morning headaches
- AF, HF, refractory HTN
- STOP-BANG ⥠3 (high risk)
Diagnosis
- In-lab polysomnography (gold standard)
- Home sleep apnea test (acceptable)
- AHI ⥠5 mild, ⥠15 moderate, ⥠30 severe
Treatment
- CPAP â first-line; modest BP reduction (~ 2-3 mmHg)
- Mandibular advancement device
- Hypoglossal nerve stimulator (Inspire) â moderate-severe with adherence issues
- Weight loss + bariatric surgery if obese
- Tonsillectomy / UPPP in select pediatric / adult
Drug-Induced HTN
Common Agents
- NSAIDs (most common drug-induced)
- OCPs (estrogen-containing)
- Glucocorticoids
- Decongestants (pseudoephedrine, phenylephrine)
- Stimulants (cocaine, amphetamines, MDMA)
- EPO
- Calcineurin inhibitors (cyclosporine, tacrolimus)
- VEGF inhibitors (bevacizumab, sunitinib) â for cancer
- MAOIs + tyramine
- Caffeine (transient)
- Alcohol (chronic)
- Yohimbine, ginseng, licorice (mineralocorticoid effect)
Other Causes
Coarctation of Aorta
- Congenital narrowing distal to L subclavian
- HTN in arms; â BP in legs
- Reduced femoral pulses, delayed compared to radial
- Bicuspid AV association (60-80%)
- âRib notchingâ on CXR (collateral)
- Echo / CT / MRI confirms
- Treatment: surgical or balloon angioplasty + stent
- May have residual HTN even after repair
Hyperthyroidism
- Systolic HTN, wide pulse pressure
- TSH suppressed, free T4 elevated
- Treatment: anti-thyroid, β-blocker, definitive (RAI, surgery)
Hyperparathyroidism
- HTN from Ca-mediated vasoconstriction
- â Ca, â PTH
- Parathyroidectomy
Acromegaly
- IGF-1 elevated
- HTN from sodium retention + insulin resistance
- Surgery, somatostatin analogs
Polycystic Kidney Disease
- Inherited (ADPKD)
- HTN often before CKD
- ACEi/ARB
- Tolvaptan to slow cyst growth
Pregnancy
- See Ch276/278
- Gestational HTN, preeclampsia, eclampsia, HELLP
Neurogenic
- ICP elevation (Cushing reflex: HTN + bradycardia + irregular respirations)
- Spinal cord injury (autonomic dysreflexia)
- CNS lesions
- Autonomic dysfunction (POTS, paroxysmal)
𩺠åºééæ¥
- Suspect secondary HTN: < 30 yo, resistant, hypoK, abrupt, episodic
- Most common secondary endocrine: primary aldosteronism (PA) â 5-10% of HTN
- PA screening: ARR > 20 + plasma aldo > 15
- Pheo: plasma free metanephrines; α-blockade BEFORE β
- Cushing: 24h UFC Ã 2 + midnight salivary + DST
- RAS: renal Doppler / CTA; ARAS = OMT (CORAL); FMD = angioplasty
- OSA: STOP-BANG â polysomnography â CPAP