Secondary hypertension

• Secondary hypertension has an identifiable cause. It is uncommon overall, but in young adults and in resistant or severe hypertension it becomes frequent enough that missing it means missing a cure.
• Suspect it from the history and examination: young age, sudden or accelerated hypertension, resistant hypertension, an acute rise from a previously stable baseline, electrolyte abnormalities, or exposure to blood-pressure-raising drugs and substances.
• The common, potentially reversible causes are primary aldosteronism, renal parenchymal disease, renovascular disease (atherosclerotic renal artery stenosis and fibromuscular dysplasia), obstructive sleep apnoea, coarctation of the aorta, and endocrine disease (pheochromocytoma/paraganglioma, Cushing syndrome, thyroid disease, hyperparathyroidism).
• Some causes are drug- or substance-related (NSAIDs, oral contraceptives, glucocorticoids, liquorice, stimulants, calcineurin inhibitors) and can be treated by withdrawing the agent.
• A handful of single-gene salt-handling disorders (Liddle syndrome, apparent mineralocorticoid excess) mimic primary aldosteronism but do not respond to aldosterone antagonists.

By the end of this page you should be able to:

1. List the clinical situations that should raise suspicion of a secondary cause of hypertension.
2. Choose the right first test for each common cause and interpret the result.
3. Work through an investigation algorithm for a patient with suspected secondary hypertension.
4. Explain how primary aldosteronism is screened, confirmed, subtyped and treated.
5. Distinguish atherosclerotic renal artery stenosis from fibromuscular dysplasia and know when revascularisation helps.
6. Describe the preoperative preparation of a pheochromocytoma and the drug causes of hypertension.
7. Adapt the work-up to a low-resource setting.

Secondary hypertension is usually classed by mechanism:

• Renal. Renal parenchymal disease and renovascular disease (renal artery stenosis).
• Endocrine. Primary aldosteronism, pheochromocytoma and paraganglioma, Cushing syndrome, thyroid disease, primary hyperparathyroidism, and the monogenic syndromes.
• Vascular. Coarctation of the aorta.
• Sleep. Obstructive sleep apnoea (OSA).
• Drug or substance-induced. NSAIDs and COX-2 inhibitors, oestrogen-progestogen contraceptives, glucocorticoids, liquorice, stimulants, calcineurin inhibitors and others.
• Monogenic salt-handling. Liddle syndrome, apparent mineralocorticoid excess, familial hyperaldosteronism, glucocorticoid-remediable aldosteronism, Gordon syndrome, congenital adrenal hyperplasia.

Only a small fraction of all hypertensive patients have a secondary cause, but the fraction rises sharply in selected groups.^[1][2]

• In unselected hypertensive adults, secondary hypertension accounts for roughly 5% to 10%.^[2]
• In young adults (18 to 40 years) with confirmed hypertension, modern studies report an identifiable cause in about 30% (29.6% in one study of 2090 young adults).^[1]
• In children under 12 years, 70% to 85% of hypertension has a secondary cause, most commonly renal parenchymal disease and coarctation of the aorta.^[1][2]
• Primary aldosteronism is now estimated at 5% to 10% of all hypertensive patients, 17.8% of young-onset hypertension and 20% to 30% of resistant hypertension.^[3]
• Pheochromocytoma and paraganglioma occur in about 0.2% to 0.6% of patients with sustained hypertension.^[4]

Extensive testing of every hypertensive patient is low-yield, costly and produces false positives. Test when the picture points to a secondary cause.^[2] Current guidance (2024 ESC and 2025 ACC/AHA) converges on the same clinical triggers.^[1]

A reasonable basic battery for newly diagnosed hypertension is: accurate blood pressure measurement on two or more occasions, urinalysis, serum creatinine/eGFR, electrolytes including potassium, fasting glucose, lipids and ECG.^[2] Imaging and hormone tests are added only when the history or examination points that way.

The sections below follow a common pattern: presentation, testing, treatment.

Primary aldosteronism (PA) is excess aldosterone secretion independent of the renin-angiotensin system, most often from an aldosterone-producing adenoma or bilateral adrenal hyperplasia. It is the commonest curable endocrine cause of hypertension and is under-diagnosed.^[2][3]

• Recognition. Hypertension with hypokalaemia is the classic picture, but only a minority have low potassium; many have a normal potassium level. PA is the commonest cause of drug-resistant hypertension.^[2][3]
• Screening. The aldosterone-to-renin ratio (ARR) is the best initial test. Measure plasma aldosterone and renin after potassium repletion; an inappropriately high aldosterone with suppressed renin raises suspicion. About 25% of patients have normal aldosterone levels, so the ratio is more sensitive than aldosterone alone. Draw it in the morning, 2 hours after waking, upright.^[2][3]
• Drug wash-out. Agents that distort the ARR should be withdrawn before testing: NSAIDs, aldosterone antagonists, amiloride, triamterene, potassium-wasting diuretics and liquorice 4 weeks beforehand; beta blockers, central alpha-2 agonists, ACE inhibitors, angiotensin receptor blockers, renin inhibitors and dihydropyridine calcium channel blockers 2 weeks beforehand. If blood pressure must be maintained, use less-interfering agents (e.g., extended-release verapamil, hydralazine, doxazosin, prazosin, terazosin).^[2]
• Confirmation. A positive screen is followed by one of the confirmatory tests to demonstrate autonomous aldosterone secretion: saline infusion test, fludrocortisone suppression test, captopril challenge test or oral sodium loading test.^[3]
• Subtyping. Once PA is confirmed, adrenal CT is performed. Adrenal vein sampling (AVS) is the gold standard for telling unilateral disease (aldosterone-producing adenoma, roughly 35% to 50%) from bilateral disease (idiopathic hyperaldosteronism, roughly 50% to 60%), because imaging and lateralisation often disagree.^[3]
• Treatment. Unilateral adenoma with lateralisation on AVS is treated by unilateral adrenalectomy (often laparoscopic), which gives a high biochemical cure rate. Bilateral disease, or anyone unfit for or declining surgery, is treated with a mineralocorticoid receptor antagonist (spironolactone or eplerenone) plus correction of hypokalaemia.^[2][3]
• Practice tip. In established hypertension, a trial of spironolactone 25 mg daily for 4 weeks can be informative: a fall in BP under 10 mm Hg makes PA unlikely, while a fall over 12 mm Hg makes it probable.^[3]

Renal parenchymal disease is the commonest cause of secondary hypertension in children and remains a major cause in adults, especially older adults with chronic kidney disease.^[2]

• Recognition. An elevated serum creatinine or eGFR fall, proteinuria, abnormal renal ultrasound, or hypertension out of proportion to age.
• Tests. Urinalysis, serum creatinine/eGFR, renal ultrasound as first-line imaging in children, plus evaluation of the underlying renal diagnosis.
• Treatment. Treat the kidney disease; blood pressure control (salt restriction, renin-angiotensin blockade, diuretics) slows progression of chronic kidney disease. Avoid nephrotoxic drugs where possible.

Renovascular hypertension is a common, potentially reversible cause, accounting for only about 1% of mild hypertension but 10% to 45% of severe or malignant hypertension in white patients.^[2] Two patterns matter:

• Atherosclerotic renal artery stenosis (ARAS). Older adults (over 55) with vascular disease elsewhere; often severe hypertension with a unilateral small kidney or flash pulmonary oedema.
• Fibromuscular dysplasia (FMD). Younger adults, especially women; the classic "string of beads" on angiography; revascularisation has good cure rates.
• Clues. Creatinine rise of at least 50% within a week of starting an ACE inhibitor or ARB; a renal bruit; a unilateral small kidney with a size difference over 1.5 cm; recurrent flash pulmonary oedema.^[2]
• Tests. Investigate if the patient is healthy enough and willing to undergo revascularisation. Doppler ultrasound (sensitivity roughly 75%, specificity 90%), CT angiography or MR angiography with gadolinium are the usual non-invasive tests; invasive angiography is reserved for those who would intervene. A captopril renogram has a reported sensitivity and specificity around 90%.^[2]
• Treatment. Medical therapy (ACE inhibitor or ARB unless contraindicated, statin, antiplatelet, tight risk-factor control) is equivalent to revascularisation in most trials of atherosclerotic disease, with similar BP control and cardiovascular outcomes and without procedural risk. Revascularisation (angioplasty, with or without stenting) is more strongly considered for FMD, for rapidly declining renal function, for flash pulmonary oedema, and for bilateral severe disease. Surgical revascularisation is rarely needed.

Pheochromocytomas (adrenal) and paragangliomas (extra-adrenal) are catecholamine-secreting tumours of chromaffin tissue. They are rare but dangerous and largely reversible with treatment.^[2][4]

• Recognition. Paroxysmal or sustained hypertension with the classic triad of headache, palpitations and sweating; labile BP, postural hypotension, constipation, hypertensive crises. About 0.2% to 0.6% of sustained hypertension.^[4]
• Tests. Initial biochemical testing should measure plasma free metanephrines or urinary fractionated metanephrines. Plasma free metanephrines have very high sensitivity (about 99%) and a near-maximal negative predictive value, so a normal result reliably excludes the tumour; the sampling conditions differ between guidelines: the NANETS 2010 guideline calls for supine sampling after about 15 to 20 minutes of intravenous catheter insertion and no food, caffeinated beverages, strenuous physical activity or smoking for about 8 to 12 hours beforehand, whereas Lenders 2017 calls for supine rest for at least 20 minutes and does not impose a blanket 8 to 12 hour caffeine avoidance. ^[4][5] A plasma metanephrine level more than 4-fold above the upper reference limit carries close to 100% probability of tumour; results 1 to 4-fold above require clonidine suppression testing and repeat sampling. ^[5] Imaging (CT or MRI) is for localisation only after biochemical confirmation.
• Preparation and treatment. Surgery is the only cure (laparoscopic preferred). All patients, even asymptomatic or normotensive ones, require preoperative alpha-blockade for 10 to 14 days (phenoxybenzamine 10 to 20 mg twice daily, or doxazosin/terazosin), plus volume expansion. A beta-blocker may be added only after adequate alpha-blockade. Adequate alpha-blockade reduces perioperative complications to under 3%.^[4][5] Arrange genetic testing: contemporary reviews report a germline mutation in roughly 30% to 40% of patients (about 40% in the Korean joint position statement; nearly half in Lenders 2017), compared with 24% to 27% in the older NANETS 2010 data. ^[4][5][10] The syndromes include MEN2, VHL, NF1 and SDHB. Follow-up with plasma or urinary metanephrines for at least 10 years.^[4]

Cushing syndrome is cortisol excess. Most cases are iatrogenic from prescribed glucocorticoids, which cause hypertension in only about 20% of patients; endogenous tumour-related Cushing causes hypertension in 80% or more.^[2]

• Recognition. Central obesity, moon facies, proximal muscle weakness, easy bruising, striae, glucose intolerance.
• Tests. When suspected, two first-line tests among: 24-hour urinary free cortisol, late-night salivary cortisol, or low-dose dexamethasone suppression. Refer to endocrinology if any abnormal, or if suspicion remains high despite normal results.^[2]
• Treatment. Treat the cause: withdraw the offending steroid where possible, or resect the adrenal or pituitary tumour. Hypertension is managed as for other secondary causes, with awareness of hypokalaemia and fluid retention.

• Hyperthyroidism raises systolic blood pressure and widens pulse pressure by increasing cardiac output. Hypothyroidism raises diastolic blood pressure by increasing systemic vascular resistance and is a common cause in older adults.^[2]
• Tests. TSH is the sensitive first test; free T4 (and T3) as indicated.
• Treatment. Normalise thyroid function: antithyroid drugs, radioiodine or surgery for hyperthyroidism; levothyroxine for hypothyroidism. Hypertension often improves, but may still need treatment during the transition.

Primary hyperparathyroidism (unexplained hypercalcaemia with inappropriately raised or unsuppressed PTH) affects vascular reactivity, circadian blood pressure rhythm and renal function, and is a recognised secondary cause.^[2]

• Tests. Serum calcium and intact PTH; exclude other causes of hypercalcaemia.
• Treatment. Parathyroidectomy when indicated; otherwise standard antihypertensive therapy and monitoring of calcium and renal function.

Coarctation is a common cause of secondary hypertension in children, especially boys, but is frequently missed until adulthood.^[2]

• Recognition. Upper-limb hypertension with reduced or absent femoral pulses and a brachial-femoral delay, an arm-to-leg (upper-to-lower) systolic pressure difference over 20 mm Hg, and a murmur. In adults, rib notching or the "figure 3" sign on chest radiograph.
• Tests. Transthoracic echocardiography is sufficient in children; MR angiography is preferred in adults.
• Treatment. Intervention (surgery, balloon angioplasty or stenting) is recommended when the trans-coarctation pressure gradient exceeds 20 mm Hg, or when a re-coarctation has a gradient of at least 20 mm Hg or there are symptoms, left ventricular hypertrophy or heart failure.^[9]

OSA is a leading treatable cause of secondary hypertension, common in obese middle-aged men who snore, with apnoeic episodes, daytime sleepiness, headache and non-dipping night-time blood pressure.^[2]

• Tests. Polysomnography is the standard; in moderate-to-severe disease, clinical assessment tools with night-time pulse oximetry may suffice.
• Treatment. Continuous positive airway pressure (CPAP) plus weight loss and the usual antihypertensives. Treatment of OSA can improve blood pressure control, sleep quality, daytime sleepiness and mortality.^[2]

A thorough medication and substance history is mandatory, because these causes are curable.^[2]

Commonly blood-pressure-raising agents include:^[2]

• NSAIDs and COX-2 inhibitors. Salt and water retention, particularly with CKD or heart failure.
• Oral contraceptives. 5% of users of combined oral contraceptives (at least 50 mcg oestrogen and 1 to 4 mg progestogen) develop hypertension, more so with smoking, obesity, family history, renal disease and prior gestational hypertension.
• Glucocorticoids. Hypertension is more common with endogenous Cushing syndrome, but steroids also raise BP.
• Liquorice. 3 g or more per day can cause a mineralocorticoid excess picture (found in chewing tobacco and liquorice tea).
• Stimulants and sympathomimetics. Amphetamines, cocaine, decongestants, diet pills; caffeine excess.
• Calcineurin inhibitors. Cyclosporine, tacrolimus (and sirolimus).
• Others. Erythropoietin, VEGF inhibitors, some antidepressants (SNRIs, TCAs, MAOIs), carbamazepine, lithium, oral decongestants.

Management is to reduce or stop the offending agent where clinically possible.

These present in childhood or young adulthood with hypertension, hypokalaemia and metabolic alkalosis, with suppressed renin and aldosterone.^[6][7]

• Liddle syndrome. Autosomal dominant gain-of-function mutation of the epithelial sodium channel (ENaC; SCNN1A/B/G), causing increased distal sodium reabsorption, salt-sensitive hypertension, hypokalaemia and metabolic alkalosis. It does not respond to aldosterone antagonists; the treatment is an ENaC blocker such as amiloride (and triamterene), with sodium restriction.^[6][7]
• Apparent mineralocorticoid excess (AME). Autosomal recessive deficiency of 11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2), so cortisol activates the mineralocorticoid receptor, producing sodium retention, hypokalaemia, metabolic alkalosis and hypercalciuria/nephrocalcinosis. Treatment is a mineralocorticoid receptor antagonist (spironolactone, eplerenone) plus an ENaC blocker (amiloride), with thiazides for hypercalciuria and potassium supplementation. Liquorice ingestion is an acquired phenocopy.^[6]
• Familial/other. Familial hyperaldosteronism types (including glucocorticoid-remediable aldosteronism, treated with low-dose glucocorticoids), Gordon syndrome (pseudohypoaldosteronism type II, hyperkalaemic hypertension, responsive to thiazides), congenital adrenal hyperplasia and Geller syndrome are rarer but worth remembering.

• Children. Think renal parenchymal disease, coarctation and monogenic causes; screen all hypertension before puberty.
• Pregnancy. Methyldopa, labetalol and nifedipine are typical choices; ACE inhibitors and ARBs are contraindicated; secondary hypertension should be excluded in early-onset or severe cases.
• Older adults. Atherosclerotic renal artery stenosis, renal failure and hypothyroidism are common.

• History and a basic examination detect most secondary hypertension: measure blood pressure in both arms (and a leg if coarctation suspected), palpate femoral pulses, look for thyroid, Cushing and syndrome-specific clues.
• The cheapest high-yield tests are urinalysis, serum creatinine and potassium, and a TSH. Renal ultrasound is preferable to CT where resources are limited.
• Mineralocorticoid receptor antagonists, ACE inhibitors/ARBs and thiazides are widely available and inexpensive; amiloride availability varies.
• CPAP and sleep studies are often unavailable; symptom-based screening, weight reduction and standard antihypertensives remain the fallback.
• Refer early when intervention changes the outcome: adrenalectomy for a confirmed unilateral aldosterone-producing adenoma, renal revascularisation for high-risk renovascular disease, and surgical removal of a pheochromocytoma in a centre with alpha-blockade and experienced anaesthesia.
• Send resected tissue for histology; test for genetic causes only when funds allow, targeting young patients with a suggestive phenotype or a family history.

• Secondary hypertension has an identifiable cause; it is uncommon overall but common in young, severe and resistant hypertension.
• Suspect it from red flags: young age, resistant or malignant hypertension, acute BP rise, hypokalaemia, renal bruit, coarctation signs, OSA symptoms, paroxysmal headaches/palpitations/sweating, Cushingoid features, thyroid symptoms or drug exposure.
• Primary aldosteronism is the commonest curable endocrine cause: screen with ARR, confirm, subtype with adrenal CT and AVS; treat unilateral disease with adrenalectomy and bilateral disease with a mineralocorticoid receptor antagonist.
• Atherosclerotic renal artery stenosis is usually managed medically; FMD, flash pulmonary oedema and rapidly declining function favour revascularisation.
• Pheochromocytoma requires biochemical proof (plasma free or urinary metanephrines), then 10 to 14 days of alpha-blockade before laparoscopic surgery.
• Cortisol excess, thyroid disease and hyperparathyroidism are common, reversible endocrine causes.
• NSAIDs, oral contraceptives, steroids, liquorice, stimulants and calcineurin inhibitors are curable causes; always take a drug and substance history.
• Liddle syndrome and apparent mineralocorticoid excess mimic primary aldosteronism but are treated with ENaC blockers (amiloride), not aldosterone antagonists.
• Adapt testing to the setting: basic labs, urinalysis and renal ultrasound first; refer early for the causes that need intervention.

Cardiac physical examination; ECG interpretation; heart failure; atrial fibrillation and flutter; approach to tachyarrhythmias. Also review renal parenchymal disease, renovascular disease, endocrine hypertension and resistant hypertension as separate or future topics. References are numbered 1 to 7 and listed in the front matter.