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Statins and the liver

 

Clinical bottom line

With statins alone, hepatitis and acute liver failure are rare, and probably no higher than those associated with other commonly used drugs, or the background rate in the general population.


Statins are contraindicated in patients with active liver disease, and should be used with caution in those with a history of liver disease or high alcohol intake [1]. Routine monitoring of liver enzymes during treatment with statins is recommended, mainly because premarketing clinical trials and animal studies showed minor elevations in serum alanine aminotransferase (ALT) enzyme levels, suggestive of possible hepatoxicity.

Randomised controlled trials have shown no difference between placebo and statin groups in the incidence of raised ALT levels (about 1%) [2, 3, 4], or withdrawals due to raised ALT levels [4]. No cases of serious liver disease were reported in trials.

Tolman [5] has reviewed the literature for lovastatin, which has been in use since 1986 and has 24 million patient-years of clinical experience.


Table 1. Effects of lovastatin on the liver [5]

Symptom
Evidence
ALT 3 x upper limit of normal Rate: 2.6% at 20 mg/day, 5% at 80 mg/day. Dose related. Reversible with continuing therapy
Hepatitis Rate: 9.7 per million patient-treatment years, but many mild and causality not established in most cases
Acute Liver Failure Rate: 1 per 1.14 million patient-treatment years. Equivalent to background rate of idiopathic acute liver failure

Estimates of rates for hepatitis and acute liver failure rely on spontaneous reporting, which is subject to bias, and almost always an underestimate. However, the authors point out that even if the reporting rate is 10%, the corrected rate for hepatitis (1/100,000) would be much lower than that seen with many commonly used drugs. For acute liver failure the rate of 1/130,000 would be equivalent to the background rate in the general population. Minor elevations in ALT were poorly predictive of hepatotoxicity and hence ineffective in preventing serious liver disease.

In a retrospective review of patient records in a primary care setting to determine the value of routine monitoring of enzyme levels (ALT and CK) in patients taking statins[5] there were 1194 patients, of whom 1014 (85%) had at least one monitoring test performed over the study period of one year. Of these, ten (1%) had significant elevation, and 5 (0.5%) had a moderate elevation of transaminase levels. None appeared to be related to statin use. Similar results were obtained for the analysis of CK levels (6 (0.9%) significant elevation, 14 (2.1%) moderate elevation, of which 2 were potentially due to a statin). They question the usefulness of routine monitoring in all patients taking statins.

Comment

In patients without a history of liver disease elevations of serum ALT are uncommon during treatment with statins and are poorly predictive of hepatotoxicity. The value of routine monitoring of liver enzymes is questionable. Hepatitis and acute liver failure are rare, and probably no higher than those associated with other commonly used drugs, or the background rate in the general population.

Reference

  1. British National Formulary, 2003.
  2. JC La Rosa et al. Effects of statins on risk of coronary heart disease. A meta-analysis of randomised controlled trials. JAMA 1999 282: 2340-2346.
  3. NR Law et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003 326: 1423-1429.
  4. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 360: 7-22.
  5. KG Tolman. The liver and lovastatin. Am J Cardiol 2002 89: 1374-1380.