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Editors

NiinaKoivuviita
MinnaSoinio
JohannaPäivärinta

Secondary Hypertension

Essentials

  • Approximately 5-10% of all patients with hypertension are diagnosed with a secondary cause to the condition. The share clearly increases (up to 20%) in patients with treatment-resistant hypertension.
  • The most common causes include renal and renovascular hypertension, which are both clinically characterized by secondary hyperaldosteronism, as well as primary hyperaldosteronism, which is much more common than previously thought.
    • Other endocrinological causes of hypertension are clearly more rare.
    • Of the other possible causes, sleep apnoea should also be considered, since it very commonly causes treatment-resistant hypertension (in over 30%).
  • Exclude secondary aetiology if hypertension is associated with any of the following atypical features:
    • poor response to therapy (therapy goals not reached with three medications)
    • onset before the age of 30 years
    • rapidly increasing blood pressure (BP) even at an older age or lost treatment response
    • severe hypertension, blood pressure > 180/110 mmHg
    • hypokalaemia
    • increased plasma creatinine concentration
    • proteinuria, or haematuria.
  • Another "diagnostic window" after starting blood pressure medication
    • Hypokalaemia provoked by a small dose of diuretic
    • Rapid decrease in eGFR when using a small dose of ACE inhibitor or ATR blocker (ARB)
    • Treatment-resistant hypertension

Aetiology

Renal hypertension

Renal hypertension due to renal parenchymal disease

  • Consider renal disease as the cause of hypertension in patients with increased plasma creatinine, proteinuria and/or haematuria. If the patient has none of the aforementioned (not even microalbuminuria) and ultrasonography shows normal renal anatomy, a parenchymal disease is unlikely. Normal creatinine concentration alone does thus not rule out renal hypertension (see Increased Blood Creatinine Concentration, Egfr and Renal Function Tests).
  • If the diagnosis is not evident, such as diabetic nephropathy, chronic glomerulonephritis, polycystic renal disease or secondary amyloidosis, refer the patient to a nephrologist. If necessary, the diagnosis is confirmed by renal biopsy.
  • Long-term hypertension may also cause renal disease (so-called hypertensive nephrosclerosis).

Renovascular hypertension

  • Suspect renovascular hypertension when
    • the patient has therapy-resistant hypertension or the response to therapy declines
    • the patient has clinical signs of general arteriosclerosis; especially peripheral arterial disease increases the probability of renal artery stenosis
    • an ACE inhibitor or an angiotensin receptor blocker causes an unexpectedly large increase in plasma creatinine concentration.
  • Investigations at hospital in case of suspicion: primarily Doppler ultrasonography; if necessary, an MR angiography or a CT scan is performed (the choice of investigation depends on the degree of renal insufficiency).
    • Captopril-enhanced nephrography is of no benefit in patients with renal failure.

Types of renovascular hypertension

  • Atherosclerotic renal artery stenosis (about 90%)
    • Typical patient: age about 70 years, moderate renal failure (eGFR about 35 ml/min), essential hypertension (in 97%), type 2 diabetes (in 32%), hyperlipidaemia (in 62%), smoking (in 70%), arteriosclerosis obliterans (ASO; in 68%), coronary heart disease (in 45%)
    • Prevalence around 7% in Americans over 65 years of age, even up to 25-30% in patients with generalized atherosclerosis
    • Increases the risk of cardiovascular mortality.
    • Angioplasty Balloon Angioplasty Vs. Medical Therapy for Hypertensive Patients with Atherosclerotic Renal Artery Obstruction is of questionable benefit (in both unilateral and bilateral stenosis). Stenting decreases the risk of restenosis.
    • Good pharmacological management of arterial disease risk factors is essential in the treatment: based on current research evidence, pharmacotherapy alone yields as good treatment outcomes as the combination of pharmacotherapy and balloon angioplasty.
      • Intensive treatment of hypertension according to the targets set for high-risk patients.
        • An ACE inhibitor/ARB should be included in the treatment; these agents have been proven to be beneficial for the prognosis.
      • Statin therapy is probably also beneficial.
      • Good control of diabetes, no smoking
  • Fibromuscular dysplasia (< 10%)
    • Patients are young or middle-aged adults; female predominance (10:1).
    • Balloon angioplasty often provides good and sustained response, if the blood pressure has not been elevated for a long time.

Principles of hypertension management in a renal patient

  • The progress of renal disease can be slowed by good management of hypertension. Target is below 130/80 mmHg.
  • A combination of more than three drugs is quite often needed.
  • ACE inhibitors and angiotensin receptor blockers (ARBs) are the primary drugs. They reduce proteinuria and slow down the progression of the renal disease. ACE inhibitors and ARBs can be used even in severe renal failure. NB: Their concomitant use is, however, contraindicated.
    • Check plasma potassium and creatinine concentrations already one week after the initiation of medication. Stabilization usually takes place within 4 weeks.
    • For plasma creatinine, an increase of about 30% from the baseline is allowed. If plasma creatinine increases more than 90 µmol/l from the baseline, discontinuation of ACE medication should be considered. Especially concomitant hyperkalaemia is alarming.
  • Decrease in body fluid volume and limitation of salt intake (< 3-5 g/day) are vital.
  • Benefit from thiazide diuretics in moderate to severe renal failure is questionable.
  • If the glomerular filtration rate (GFR) is below 30 ml/min, prescribe furosemide instead of thiazide diureticsIncreased Blood Creatinine Concentration, Egfr and Renal Function Tests. In progressive renal failure, larger than usual doses of furosemide are often needed.
  • Potassium-sparing diuretics and spironolactone should be avoided.
  • Calcium antagonists and/or beta-blockers are frequently used in combination therapy and do not cause problems.
  • Typical combination: ACE inhibitor/ARB + diuretic + calcium-channel blocker + beta-blocker
  • Moxonidine combined to a beta-blocker may paradoxically raise blood pressure, so it is hardly used anymore.
  • Long-acting nitrates reduce blood pressure as well.
  • If the treatment target is not reached with a combination of 3-4 drugs, consultation with a nephrologist is warranted.
  • NSAIDs should be avoided.

Endocrine hypertension

Causes and initial investigations

  1. Primary aldosteronism (Conn's syndrome Primary Hyperaldosteronism (Pha)) is the most common cause of endocrine hypertension and clearly more common than earlier thought.
    • The prevalence may be as high as 20% in patients with treatment-resistant hypertension.
    • The condition is a typical diagnosis by exclusion, since according to current knowledge only 9-37% of the patients have hypokalaemia.
    • Consider the diagnosis if the patient has a low plasma potassium concentration at onset (< 3.5 mmol/l) or persistent hypokalaemia on a small dose of diuretics (plasma potassium < 3 mmol/l).
    • High serum aldosterone concentration in association with low plasma renin concentration suggests primary hyperaldosteronism. For diagnostics: see Primary Hyperaldosteronism (Pha).
    • The cause is either a cortical adenoma or bilateral cortical hyperplasia (micro- or macronodular).
      • An adenoma is usually managed surgically.
      • Hyperplasia is more common than earlier thought because up to 50% of adenoma patients remain hypertensive after surgery.
    • Treatment aims at normotension, normokalaemia and normalization of excessive aldosterone secretion.
    • Spironolactone is the primary drug. It binds to mineralocorticoid receptors, thus inhibiting the effect of aldosterone. Alternatives include eplerenone or amiloride.
  2. Hyperparathyroidism Hypercalcaemia and Hyperparathyroidism
    • Four times more common in women than in men. Prevalence increases with age.
    • Traditionally the syndrome has had a many-faceted clinical picture: urinary tract stones, osteopenia/osteoporosis, general weakness, nausea, constipation, abdominal pains, changes of mood. Nowadays, the disease is more often diagnosed in symptomless patients on the basis of high plasma calcium concentration.
    • The cause is an adenoma of the parathyroid gland.
    • Investigations
      • Initially, plasma ionized calcium (or plasma calcium and albumin)
      • In the next phase, plasma PTH (increased also in secondary hyperparathyroidism caused by renal failure, in which plasma calcium concentration usually is low)
    • The mechanism behind hypertension is unclear; it is possibly caused by hypercalcaemia.
    • The choice of treatment depends on other possible symptoms.
    • The adenoma can be surgically removed.
    • Hypertension in a patient with mild hypercalcaemia and only few symptoms is treated pharmacologically and the patient is monitored.
  3. Cushing's syndrome Cushing's Syndrome
    • Typical clinical manifestations are the most important diagnostic clue.
    • Do not forget to ask about the patient's use of glucocorticoids.
    • Investigation in primary care: short 1 or 1.5 mg dexamethason test Cushing's Syndrome
    • The treatment is surgical.
  4. Pheochromocytoma Rare Endocrine Tumours
    • Typical clinical manifestations are the most important diagnostic clue. Blood pressure rises paroxysmally (40%) or permanently.
    • Rare (< 1% of all cases of secondary hypertension)
    • Caused by an adenoma that produces catecholamines
      • 90% located in the adrenal gland
      • 90% benign
    • Diagnosis by exclusion; symptoms are various
      • serum metanephrine and normetanephrine
    • The treatment is usually surgical.
  5. Hyperthyroidism Hyperthyroidism or hypothyroidism Hypothyroidism
    • Both hyper- and hypothyroidism are associated with hypertension. In hypothyroidism, the diastolic blood pressure more commonly increases, while in hyperthyroidism more commonly the systolic blood pressure.

Other causes

Exogenous causes

  • Exogenous causes are first to be excluded.
  • Drugs
  • Heavy alcohol use
  • Illicit drugs (cocaine, amphetamine)
  • Liquorice
    • Hypertension, hypokalaemia, low concentrations of plasma renin and serum aldosterone
    • Glycyrrhetinic acid is a metabolite of liquorice. It inhibits the enzyme (11-beta hydroxysteroid dehydrogenase, 11β-OHSD) that inactivates cortisol. This leads to increased binding of cortisol to mineralocorticoid receptors and causes a state that resembles hyperaldosteronism.
    • The enzyme inhibition lasts up to 2-3 weeks after ingestion of liquorice.
    • Deficiency of 11β-OHSD enzyme may also be congenital.

Endogenous causes

  • Sleep apnoea Sleep Apnoea in the Adult
    • Sleep apnoea has been identified as one of the most common causes of treatment-resistant hypertension
  • Coarctation of the aorta
    • Palpation of the femoral artery: weak or absent pulse
    • Difference in BP between upper and lower limbs (in young hypertensive patients both upper and lower limb BPs should always be recorded)
  • Liddle's syndrome http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=927
    • Hypertension, hypokalaemia, low concentrations of plasma renin and serum aldosterone
    • Autosomal dominant disorder
    • Causes sodium retention (mutation in the epithelial sodium channel of tubule cells causes uncontrolled sodium reabsorption).
    • Restriction of salt in the diet and amiloride (may require special license) are used in the treatment.

    References

    • Alcázar JM, Marín R, Gómez-Campderá F, Orte L, Rodríguez-Jornet A, Mora-Macía J, Spanish Group of Ischaemic Nephrology (GEDENI). Clinical characteristics of ischaemic renal disease. Nephrol Dial Transplant 2001;16 Suppl 1:74-7. [PubMed]
    • Textor SC, McKusick MM. Renal artery stenosis: if and when to intervene. Curr Opin Nephrol Hypertens 2016;25(2):144-51. [PubMed]
    • Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377(9784):2181-92. [PubMed]
    • Funder JW, Carey RM, Mantero F et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101(5):1889-916. [PubMed]
    • Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J 2014;35(19):1245-54. [PubMed]