Spironolactone is an aldosterone receptor antagonist and potassium-sparing diuretic widely used in the therapy of edema particularly in patients with cirrhosis in which hyperaldosteronism appears to play a major role. Spironolactone has been linked to rare cases of clinically apparent drug-induced liver disease.
Spironolactone (spir on oh lak' tone) is a competitive inhibitor of the mineralocorticoid receptor in the late distal tubule and collecting duct of the kidneys which causes a decrease in sodium reabsorption and potassium excretion in the distal tubule. As a result, spironolactone promotes a sodium diuresis but maintains body potassium levels. Spironolactone is particularly helpful in edematous states caused or exacerbated by hyperaldosteronism, which is typical of the edema and ascites caused by cirrhosis. Because of its potassium-sparing actions, spironolactone is also used in combination with thiazide or loop diuretics in an attempt to prevent hypokalemia. Chronic low dose therapy with spironolactone has also been reported to improve survival in patients with heart failure after myocardial infarction. Spironolactone was approved for use in the United States in 1960 and continues to be widely used. Spironolactone is available in 25, 50, 75 and 100 mg tablets generically and under the brand name of Aldactone. Fixed combinations of spironolactone and hydrochlorothiazide are also available under the brand name Aldactizide. The typical dose of spironolactone is 25 mg one to three times daily initially with modification of the dose based upon clinical efficacy and tolerance to maintenance doses of 75 to 450 mg daily. The major side effects of spironolactone are due to its anti-androgen-like effects and include hair growth and gynecomastia.
Clinically apparent liver injury from spironolactone is rare and only a few instances have been reported as isolated case reports. The liver injury typically arises after 4 to 8 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular or mixed. Immunoallergic features (rash, fever, eosinophilia) are rare as is autoantibody formation. Recovery has occurred within 1-3 months of stopping and all cases have been mild and self-limited in course (Case 1).
Mechanism of Injury
The mechanism of spironolactone hepatic injury is unknown but is most likely due to a metabolic idiosyncrasy.
Outcome and Management
Reported cases of liver injury due to spironolactone have been mild with either no or minimal jaundice and recovery within a few months of stopping the medication. Recurrence on rechallenge has been reported but there is no information or cross-reactivity to the hepatic injury with other diuretics. Because eplerenone has a similar chemical structure, it is likely to cause a similar hepatic injury.
|Medication:||Spironolactone (100 mg 2-3 times daily)|
|Severity:||Mild (Enzyme elevations without symptoms or jaundice)|
|Time After Starting||Time After Stopping||ALT (U/L)||Alk P (U/L)||GGT (U/L)||Other|
|Spironolactone (100 mg three times daily) given for 1 month|
|6 weeks||2 weeks||255||225||140|
|8 weeks||4 weeks||70||150||80|
|12 weeks||8 weeks||35||105||20|
|24 weeks||20 weeks||30||90|
|1 year||1 year||25||85||20|
|Spironolactone (100 mg two times daily) restarted for 1 month|
|6 weeks||2 weeks||125|
|10 weeks||6 weeks||20||80||30|
|Normal Values||<40||<110||< 40|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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