Hypertension: Secondary causes

• Initially thought to explain 10% of HTN, but could be up to 30%
• More prevalent in those with resistant HTN
• Renal (commonest)
  • • Renal artery stenosis (RAS)
    • Renal parenchymal disease, and any cause of CKD
    • PCKD
    • Chronic pyelonephritis
    • SLE
    • Systemic sclerosis
    • Renal cell carcinoma
• Endocrine
  • • DM
    • Acromegaly
    • Pheochromocytoma
    • Primary hyperaldosteronism (incl Conns syndrome and CAH)
    • Cushing’s syndrome
    • Hyperthyroidism and hypothyroidism
• Vascular
  • • Coarctation
    • Aortic dissection
• Drugs (under-appreciated)
  • • Steroids
    • Hormonal tx: Oral combined contraceptive, EPO
    • Sympathomimetics, recreational drugs (cocaine, amphetamines), drugs to treat ADHD
    • ETOH (inc withdrawal)
    • Immunosuppressants – CNIs (tacrolimus, ciclosporin), leflunomide
    • Vascular endothelial growth factor tyrosine kinase inhibitors (used in cancer, raise BP in 85%)
    • Venlafaxine, MAO inhibitors, clonidine withdrawal, NSAIDs, mirabegron
• Other
  • • OSA
    • Pre-eclampsia
    • PAN
    • Porphyria
    • Polycythaemia
    • Cerebral – Raised ICP / HI / CVA
    • Fibromuscular dysplasia
    • Retroperitoneal fibrosis
    • Liquorice ingestion (pseudohyperaldosteronism)
• Consider age of patient
  • • Kids/adolescents – renal parenchymal disease and coarctation most common
    • Young adults – fibromuscular dysplasia, renal causes
    • Middle aged adults – Conn’s, OSA, Cushings, Phaeo
    • Older adults – atherosclerotic renovascular

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Screening

• Who to screen
  • • Resistant HTN
    • HTN onset <40 years
    • Rapidly worsening HTN (or sudden onset)
    • Severe HTN
    • Hypokalaemia
    • Target organ damage (especially if seems out of proportion)
    • Symptoms suggestive of secondary cause eg palpitations, bruits, suspected endocrine disease
• Ask about
  • • Headaches (could be due to HTN itself, OSA, phaeo)
    • Sweating, palpitations (phaeo, thyrotoxicosis)
    • Snoring, daytime sleepiness (OSA)
    • ETOH and drugs to enhance sporting performance (steroids, EPO)
• Examine for
  • • Renal masses, abdo bruits
    • Radio-femoral delay
    • Stigmata of endocrine causes (Cushing’s, thyroid disease, acromegaly)
• Bloods
  • • Renin and aldosterone levels (bear in mind interfering medications, more on this below)
    • Plasma metanephrines
    • TFTs, bone profile +/- PTH
    • If CKD – CKD screen, uACR, USS, +/- biopsy. Consider CT renal angiogram or renal doppler USS
    • Consider random cortisol and 24-hour urinary free cortisol, IGF-1, porphyria screen, sleep studies, autoantibodies, echo/CT aorta, adrenal imaging

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Renovascular HTN

• Especially likely in a young hypertensive patient (esp women < 50 years) with secondary hyperaldosteronism. Very elevated renin is suggestive (but not fully sensitive)
• Causes
  • • Fibromuscular dysplasia (young)
    • Atherosclerotic (old)
    • Rare causes
• Features
  • • Flash pulmonary oedema can occur
    • Asymmetrical kidneys on USS
    • Arteriopaths – 67% have CAD, 50% have PVD, 33% have cerebrovascular disease
    • May be bruits, pulsatile tinnitus, reduced eGFR (or sudden fall after RAS blocker)
• Investigation
  • • Can do MRA or CTA of renal vessels (or renal doppler USS)
    • Elevated renin
    • If fibromuscular dysplasia suspected – likely needs full body CTA or MRA
• It’s also possible that renal artery stenosis is bystander disease, and patient in fact has essential HTN
• Management
  • • Treat with ACE-I if unilateral disease (ACE-I only contraindicated in severe, bilateral disease).
    • Stenting for fibromuscular dysplasia (cures a majority and stabilises renal function)
    • Stenting is not generally useful in atherosclerotic renovascular disease (there are a few exceptions, see CKD section)
    • Optimise CV risk

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Primary hyperaldosteronism

• The most common curable cause of hypertension, present in around 9% of HTN, and underlies 20% of resistant HTN, and 12% of severe HTN
• Underdiagnosed (perhaps fewer than 5% of eligible patients are screened)
• More common as a cause in younger men, especially if hypokalaemic
• Associated with worse renal and CV outcomes
• 50% is Conns (benign adrenal adenoma), 50% is bilateral adrenal hyperplasia, rarely due to adrenal carcinoma
• Can be masked by CCB treatment
• If symptoms present (and often not) they’re often non-specific, but rarely it may present with tetany, muscle weakness, nocturia, or polyuria. Typically no oedema.
• Investigation (not straight forward!)
  • • Renin-independent aldosterone production, so: elevated aldosterone and low renin (and raised aldosterone to renin ratio). Renin is usually <8mU/L, or plasm renin activity <1ng/mL/h
    • Hypokalaemia in some (estimates vary widely, but probably around 75% normokalaemic)
      • • Typically K+ will stabilise not progressively fall
        • Chance of primary hyperaldosteronism in any hypokalaemic patient is about 30%
        • Often there is a larger than expected decrease in serum potassium when using a low-dose thiazide-type diuretic.
        • Useful to review historical K+ levels
        • High urinary K+ typical
    • Alkalosis (elevated bicarbonate level)
    • Plasma sodium level greater than 140 mmol/L
    • Sodium to creatinine ratio in urine – helps confirm if a patient is consuming enough dietary sodium to make PA testing accurate
    • Always check cortisol – low suggests cause is Conn’s, normal more suggestive of bilateral adrenal hyperplasia (as adenomas are sensitive to ACTH)
    • eGFR can be overestimated in patients with PA, masking the severity of renal disease
    • Check old imaging – are there any adrenal incidentalomas? (but absence does not exclude PA)
• Checking aldosterone and renin
  • • Often aldosterone renin ratio (ARR) used. However, some argue each hormone level should be interpreted individually
    • Significant intraindividual variability. Sensitivity of ARR is around 70% (so technically, two ARRs are required to exclude the diagnosis)
    • Most antihypertensive medications increase chance of a false negative (except betablockers which can do the opposite)
    • Can either stop medications first and check, or check and interpret in the context of their medication use
    • Currently advice is to test on the medications, and if results are inconclusive, withdraw meds and retest
    • Probably do need to stop spironolactone though – and this has a 6-week washout period
    • If low renin on medications – likely to be a true result. If not – may need to retest off meds
    • Drugs least likely to interfere with testing – doxazosin, verapamil MR, hydralazine, monoxidine, long acting CCBs
    • Practical issues
      • • Ask patient to avoid a low salt diet for 3 days prior to the test
        • In women, best to test 7 days after the 1^st day of the last period
        • Best to test in the morning, around 2 hours after waking up
        • Do test after patient seated for around 15 minutes
    • Some suggest correcting severe (<3) hypokalaemia first
      • • Hypokalaemia can cause false negatives
        • If hypokalaemic and result suggestive of Primary Hyperaldosteronism, you can trust it.
        • If renin suppressed but aldosterone not very high, still refer to endo.
        • If result unclear, can test again once K+ replete
    • Testing in CKD – interpretation can be more difficult. Renin can be high or low in CKD depending on stage and aetiology
    • False negative results can occur with
      • • Drugs
          • • ACE-I, ARBs (wash out 2 weeks)
            • Diuretics (wash out 4 weeks, MRA 6 weeks)
            • Some short acting CCB (wash out 2 weeks)
        • Renal impairment
        • Hypokalaemia
        • Sodium restriction
    • False positives can occur with drugs
      • • Betablockers (wash out 2 weeks)
        • Centrally acting drugs like clonidine or methyldopa (but these have less influence on results)
        • NSAIDs
        • Steroids
        • Some contraceptives (especially drospirenone)
    • Diagnostic thresholds
      • • Likely diagnosis if ARR > 2000
        • 800-2000 = possible
        • < 800 unlikely
        • Alternatively, diagnosis can be confirmed if low K+, undetectable renin and aldosterone > 550
    • Causes of low renin but normal aldosterone (best to discuss these with endo)
      • • Still Primary Hyperaldosteronism (either forme fruste, or testing affected by other factors)
        • Cortisol excess
        • Liddle’s syndrome
    • Can confirm with a saline infusion test (dynamic testing)
      • • Stop antihypertensives for 2 weeks prior, but could continue an alpha blocker like doxazosin)
        • Give 2L normal saline, check renin and aldosterone levels before and after.
        • Failure to suppress aldosterone confirms diagnosis of primary hyperaldosteronism
    • Alternatives to this are an oral sodium loading test, captopril challenge test or fludrocortisone suppression test
• Imaging
  • • Look for adrenal adenoma on CT scan or MRI
    • Might need adrenal vein sampling as part of surgical workup
• Management
  • • Treat with spironolactone
    • Surgery (lap adrenalectomy) cures HTN in 50% (indicated for Conn’s)

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Other causes

• Phaeochromocytoma
  • • Presentation can be variable, from asymptomatic HTN to circulatory collapse and shock
    • Symptoms include headache, sweating, tachycardia / palpitations, chest pain/ACS, pallor (vasoconstricted), anxiety (not flushing), arrythmias, CCF
    • Can be misdiagnosed as panic attacks, ACS or pre-eclampsia
    • HTN can be paroxysmal (swinging from high to low) and later sustained
    • See phaeo
• Obstructive sleep apnoea
  • • A very common cause of resistant HTN
    • Suggested by obesity, typical symptoms and BP that doesn’t dip at night
    • Can screen with STOPBANG score
    • See OSA
• Chronic kidney disease
  • • HTN can be the cause and/or the effect. Needs renal USS and uACR