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Primary Hyperaldosteronism (Pha)

Essentials

  • PHA is a common but underdiagnosed condition.
  • It is important to recognize because the treatment of mineralocorticoid excess will correct hypertension completely or partially and reduce the cardiovascular risk.
  • Measure plasma potassium concentration as an initial investigation in hypertensive patients even though most patients are normokalaemic.
  • Suspect PHA readily in cases such as
    • early onset hypertension
    • hypertension and spontaneous hypokalaemia or hypokalaemia during low-dose diuretic use
    • severe or treatment-resistant hypertension
    • sleep apnoea or atrial fibrillation with hypertension.
  • Refrain from measuring plasma renin levels in normokalaemic elderly people whose hypertension is easy to treat.

Aetiology

  • PHA is a condition characterised by excessive secretion of the mineralocorticoid hormone aldosterone independently from the renin-angiotensin system and not reduced by salt loading. This leads to an increased risk of cardiovascular disease, hypertension, sodium retention and potassium loss.
  • The cause of PHA is unilateral or bilateral adrenocortical adenoma, i.e. Conn's syndrome (rarely carcinoma) or unilateral or bilateral adrenocortical hyperplasia.
  • Other rare aetiologies include e.g. familial glucocorticoid-remediable aldosteronism (GRA).

When to suspect PHA

  • Suspect PHA if a hypertensive patient presents with
    • spontaneous hypokalaemia in the absence of diuretic use or hypokalaemia during low-dose diuretic use (plasma potassium < 3.5 mmol/l in the absence of diuretic use or < 3.0 mmol/l during low-dose diuretic use)
    • severe (> 150/100 mmHg) hypertension or hypertension resistant to combination drug therapy
    • adrenal incidentaloma
    • sleep apnoea and hypertension
    • early onset (under 40 years of age) hypertension or stroke (or, first degree relative with history of early onset hypertension and stroke)
    • hypertension and atrial fibrillation.

Symptoms and signs

  • Hypertension with or without hypokalaemia (the latter particularly if the patient is on a low-salt diet)
  • For symptoms and signs of hypokalaemia, see article Hypokalaemia Hypokalaemia
  • Nycturia is common.

Differential diagnosis

  • Other causes of hypokalaemia in association with hypertension
    • Diuretic use (increased renin concentration)
    • Renal hypertension (increased renin concentration)
    • Cushing's syndrome (normal to decreased renin concentration, signs of hypercortisolism)
    • Excessive consumption of liquorice or salty liquorice (ammonium chloride) sweets (low aldosterone and renin concentrations)
    • Other rare causes (e.g. Liddle syndrome http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=927).
  • See also article Hypokalaemia Hypokalaemia

Initial investigations in primary care

  • Na, K, plasma creatinine and, as an actual screening test, plasma aldosterone and renin and their ratio (ARR)
  • It may be necessary to repeat the screening test.
  • Do not hesitate to perform the test in patients with recently diagnosed hypertension.
  • The cause for hypokalaemia should always be investigated Hypokalaemia.
  • Spironolactone must not be started if further investigations are planned.

Performance and interpretation of the screening test

  • Plasma aldosterone and renin concentrations are determined with the patient in the sitting position after a night's rest (the sample is collected after the patient has been seated for at least 5 minutes).
    • The diagnosis of PHA should be confirmed or excluded by one or more confirmatory tests (in specialized care); see below here.
    • In addition to the aldosterone-renin ratio, the aldosterone and renin concentrations should be determined and considered separately to facilitate clinical decision-making.
    • Drugs apart from spironolactone need not necessarily be paused for the first assessment, i.e. the screening test (for interpretation in such cases, see below).
    • Intake of liquorice and salty liquorice (ammonium chloride) sweets must be stopped for four weeks before the tests.
    • Salt intake must be sufficient before the tests.
  • PHA is probable in a hypertensive patient if the renin concentration under random conditions is low, i.e. below the lower reference limit, and, simultaneously, plasma aldosterone is > 280 pmol/l (but in most cases exceeding 400 pmol/l). An aldosterone-renin ratio > 30 is generally regarded as abnormal.
    • Beta-blockers reduce both renin and aldosterone concentrations and increase their ratio but, even so, patients with PHA will typically have high aldosterone concentrations.
    • In PHA, ACE inhibitors and ARBs may increase renin concentrations to a varying degree, but even in such cases, low renin concentration strongly suggest PHA.
    • If a hypertensive patient has a tendency towards hypokalaemia and also has low renin and high aldosterone concentrations (> 550 pmol/l), no confirmatory test is needed.

Further investigations in specialized health care

  • After correcting any hypokalaemia, a confirmatory test with salt loading either orally or by intravenous NaCl infusion should be done, as necessary.
    • Antihypertensive medication should be paused for four weeks before the test unless there is severe hypertension. Drugs with little effect on ARR, such as verapamil, prazosin, moxonidine or doxazocine (may require special permit) can be used, as necessary.
    • Heart failure is a contraindication for salt loading.
  • Oral salt loading
    • Tests for 24-hour urinary potassium, sodium and aldosterone
    • Interpretation: excessive urinary excretion of potassium (> 30 mmol/24 hours) in relation to the plasma potassium concentration (> 3.3 mmol/l) during a high-sodium diet (24-hour urine sodium > 200 mmol) is suggestive of inappropriately high aldosterone activity, supported by high urinary aldosterone excretion (24-hour urinary aldosterone > 33 nmol).
    • A high-sodium diet may be achieved by instructing the patient to “use salt freely in the diet without any restrictions" and to take two 500-mg sodium chloride tablets 3 times daily for 3 days. In the third 24-hour period, the 24-hour urine aldosterone, 24-hour urine sodium and plasma potassium are determined (5 g of sodium chloride equals a 24-hour urine sodium excretion of approximately 87 mmol/24 hours).
  • Intravenous salt loading is done by administering 2 litres of NaCl 0.9% infusion from 8.30 a.m. to 12.30 (4 h). Serum aldosterone and cortisol, as well as plasma renin and potassium concentrations are measured before and after salt loading. S-Aldos >170 pmol/l after the test supports the diagnosis.
  • In patients with PHA, the possibility of autonomous cortisol secretion should also be examined.
  • CT scanning of the adrenal glands is the primary investigation if biochemical results are suggestive of PHA.
    • The interpretation of the imaging findings may be challenging.
      • In hyperplasia, nodules may be present, and their differentiation from a small unilateral adenoma may be impossible.
      • Adenoma may also be bilateral.
      • The incidence of non-functioning incidentalomas increases with age (> 40 years).
    • Due to the above problems, international protocols recommend the technically demanding adrenal vein catheterisation as a confirmatory test.
      • These examinations may be available only in very specialized centres. Find out about local availability and policies.

Treatment

  • Laparoscopic excision is the preferred management option for unilateral adenoma.
    • Surgery is in the long run more effective than pharmacological treatment.
    • A good surgical outcome is predicted by a short duration of hypertension (less than 5 years), a high preoperative aldosterone-renin ratio, no family history of hypertension and a positive treatment response to spironolactone.
  • Spironolactone (an aldosterone antagonist) is the drug of choice.
    • Adverse effects are common and dose-dependent (gynaecomastia in men and menstrual disturbances in women).
    • The initial dose is 12.5 mg once daily.
    • Particular caution must be exercised in impaired renal function.
    • The dose can be increased up to 100 mg/day according to response (blood pressure, plasma potassium, adverse effects) and tolerance.
  • Eplerenone is tolerated better but more expensive and it is not licensed for use in PHA.
  • Finerenone is the most recently launched mineralocorticoid antagonist but it is not indicated in the treatment of hypertension.
  • Amiloride (may require special permit) may also be tried if the use of spironolactone is not possible due to adverse effects.
  • Find out about local policies concerning the use and reimbursement of the aforementioned drugs.

References

  • Funder JW, Carey RM, Fardella C et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93(9):3266-81. [PubMed]
  • Funder JW. Primary aldosteronism and cardiovascular risk, before and after treatment. Lancet Diabetes Endocrinol 2018;6(1):5-7. [PubMed]
  • Young WF. Primary hyperaldosteronism. UpToDate, assessed Apr 16, 2021.
  • Hung A, Ahmed S, Gupta A et al. Performance of the Aldosterone to Renin Ratio as a Screening Test for Primary Aldosteronism. J Clin Endocrinol Metab 2021;106(8):2423-2435. [PubMed]