Spironolactone Liver Function Impact: What the Clinical Evidence Actually Shows

Does spironolactone cause liver damage?

The Aldactone label does record liver injury. Under Liver/biliary in its adverse reactions section it lists "a very few cases of mixed cholestatic/hepatocellular toxicity, with one reported fatality" [1]. The label says the reactions on that list came from clinical trials or postmarketing reports, were reported voluntarily from a population of uncertain size, and so cannot reliably be given a frequency or always be tied causally to the drug [1]. A mixed cholestatic/hepatocellular pattern means the injury carries features of both reduced bile flow and liver-cell damage.

The label's warnings and precautions section covers four problems: hyperkalemia, hypotension and worsening renal function, electrolyte and metabolic abnormalities, and gynecomastia [1]. It directs serum potassium to be checked within one week of starting or titrating the drug and regularly afterwards, with periodic electrolytes, uric acid and blood glucose [1]. That section sets out a potassium and electrolyte schedule and no liver-enzyme testing schedule.

What the label says about liver disease

The label's section on hepatic impairment states that spironolactone can cause sudden alterations of fluid and electrolyte balance which may precipitate impaired neurological function, worsening hepatic encephalopathy and coma in patients with hepatic disease with cirrhosis and ascites [1].

Edema from cirrhosis that has not responded to fluid and sodium restriction is itself a labeled indication for spironolactone: 100 mg daily in single or divided doses, range 25 to 200 mg, started in a hospital setting and titrated slowly [1].

How the liver handles spironolactone

Spironolactone is rapidly and extensively metabolized [1]. The label divides the metabolites into those where the sulfur of the parent molecule is removed, such as canrenone, and those where sulfur is retained, 7-alpha-thiomethylspironolactone (TMS) and 6-beta-hydroxy-7-alpha-thiomethylspironolactone (HTMS) [1]. Mean time to peak plasma concentration is 2.6 hours for spironolactone and 4.3 hours for canrenone; mean half-lives are 1.4 hours for spironolactone and 16.5, 13.8 and 15 hours for canrenone, TMS and HTMS respectively [1]. Metabolites are excreted mainly in urine and secondarily in bile [1].

The label names no cytochrome P450 enzyme for spironolactone metabolism and lists no CYP-based drug interactions [1]. Its interaction section covers drugs and supplements that raise serum potassium, lithium, NSAIDs, digoxin immunoassays, cholestyramine, aspirin, abiraterone and mitotane [1].

The one pharmacokinetic statement the label makes about liver disease is that the terminal half-life of spironolactone has been reported to be increased in patients with cirrhotic ascites [1]. It also notes that the effect of age, sex, race/ethnicity and renal impairment on spironolactone pharmacokinetics has not been specifically studied [1].

What the acne studies show

The main randomized evidence in acne is the SAFA trial: 410 women aged 18 and over with facial acne persisting at least six months and judged to possibly warrant oral antibiotics, randomized to spironolactone (201 women; 50 mg daily to week 6, then 100 mg daily to week 24) or placebo (209 women) [2]. Acne-specific quality-of-life symptom scores favored spironolactone by 1.27 points at 12 weeks (95% CI 0.07 to 2.46) and 3.77 points at 24 weeks (2.50 to 5.03), and investigator-rated success at week 12 was 18.5% versus 5.6% [2]. No serious adverse reactions were reported, and apart from headache (20.4% versus 12.0%) adverse reactions were similar between groups [2].

The 2017 hybrid systematic review by Layton and colleagues covered 10 randomized trials and 21 case series, judged all trials at high risk of bias and the evidence low or very low quality [3]. One crossover trial found 200 mg daily beat placebo for inflamed lesions; menstrual side effects were more common at 200 mg and less frequent with a combined oral contraceptive; pooled potassium data supported the conclusion that routine potassium monitoring is not required in adult women with acne [3].

An uncontrolled single-centre series of 403 adult women treated for acne found a reduction or clearance in 75.5% of those with facial data, 84.0% chest and 80.2% back at first follow-up, with mean drug survival of 470.7 days; menstrual adverse effects were less common among women using combined oral contraception (odds ratio 0.23, 95% CI 0.11 to 0.50) [4].

The safety measurement reported in acne patients here is potassium. A retrospective study of 974 healthy young women taking spironolactone for acne found 13 abnormal potassium values in 1802 measurements (0.72%), against a 0.76% baseline rate in 1165 comparison women, and 6 of the 13 repeated normal [5]. Women with cardiovascular disease, renal failure or drugs acting on the renin-angiotensin-aldosterone system were excluded [5]. The authors concluded that routine potassium monitoring has low usefulness in that group, while the label still directs potassium monitoring [1][5].

How a liver reaction shows up

A drug-induced liver reaction can be silent. The American College of Gastroenterology guideline on idiosyncratic drug-induced liver injury describes presentations ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure or chronic hepatitis [6]. It treats drug-induced liver injury as a diagnosis of exclusion, with other causes of liver disease assessed before a drug is blamed [6]. It reports a mortality rate up to 10% when hepatocellular jaundice is present and says patients with progressive jaundice, with or without coagulopathy, should be referred to a tertiary care centre [6].

Putting the two sides together

Liver injury from spironolactone is documented in the label, and the SAFA trial reported no serious adverse reactions at 50 to 100 mg daily [1][2]. The label ties its liver reports to no particular dose or duration, and it specifies monitoring of serum potassium within 1 week of initiation or titration and regularly thereafter, along with periodic renal function, electrolytes, uric acid and blood glucose checks [1].