Statins and Liver Injury

Statins are inhibitors of hydroxymethylglutaryl coenzyme A reductase, the enzyme that catalyzes the rate-limiting step of the cholesterol biosynthetic pathway. As a class, statins are among the most frequently prescribed drugs worldwide. Lovastatin was the first statin introduced (in 1987); since then, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and pitavastatin (Livalo, Kowa) have been used clinically.¹ Cerivastatin was withdrawn from the market in 2001 secondary to a high risk of development of rhabdomyolysis. Statins are currently approved and used for reduction of elevated cholesterol levels and cardiovascular risk reduction. In addition, there are growing data on favorable effects of statins in dementia, hepatocellular carcinoma, and colonic neoplasia.^2,3 Several population-based studies have demonstrated that statin use is associated with a decreased risk of esophageal and gastric cancers.^4,5 Statin use also has been associated with an improved response to interferon treatment for chronic hepatitis C and a reduction in portal pressure in patients with portal hypertension and metabolic syndrome.^6-8

Clinical trials have shown that statin use has been associated with elevations in serum alanine aminotransferase (ALT) levels in approximately 3% of persons who take the drugs. Such elevations are not clinically significant in the great majority of cases; indeed, ALT levels greater than 3 times the upper limit of normal (ULN) are seen in only a small minority of patients. With continued use, the mild elevations of serum aminotransferases generally resolve. This phenomenon, which has been observed for a number of drugs, is not well understood but has been called adaptation.

Clinically important drug-induced liver injury (DILI) is very rare with statin use. Patterns of liver abnormalities seen with statins include: (1) asymptomatic elevations of ALT: usually transient and mild (ALT <3 x ULN), as already described; (2) hepatitis: with ALT >3 x ULN and clinical symptoms of liver disease; (3) cholestatic or mixed hepatitis: with development of jaundice; and (4) autoantibody-associated DILI with the presence of antinuclear antibody (ANA) and antismooth muscle antibody or antimitochondrial antibody with or without plasma cells on liver biopsy. Acute liver failure (ALF) develops in a very small minority of persons who are taking statins; indeed, the incidence is not different from that in the general population.⁹ The overall risk of DILI with statin use is estimated to be approximately 1 in 100,000 with the estimated risk of ALF being approximately 1 in 1,000,000. Statins are often used in patients with diabetes mellitus, which itself is a risk factor for ALF. Recent analysis of the US drug-induced liver injury network (DILIN)¹⁰ database (unpublished observations) identified 22 cases of definite, highly likely, or probable statin-induced DILI. Twelve (55%) of 22 cases were predominantly hepatocellular in nature, with 10 (45%) of 22 being cholestatic or mixed.

Statins have been used in patients with underlying liver disease. Post hoc analysis from GREACE (Greek Atorvastatin and Coronary Heart Disease Evaluation study) showed a reduction in cardiovascular events in patients with nonalcoholic fatty liver disease and coronary artery disease who were treated with atorvastatin.¹¹ The cardiovascular benefit was greater in those with elevated baseline aminotransferase levels. Perhaps somewhat surprisingly, statin use was associated with a reduction in the mean serum aminotransferase levels in these patients.

A previous placebo-controlled, double-blind, randomized study established the safety and efficacy of statins in patients with well-compensated chronic liver disease. Overall, fewer patients in the statin group (pravastatin) had elevations in their serum ALT levels compared with the placebo group (7.5% vs 12.5%; P=.13).¹² In the same study, the subjects on the statin were less likely to have progression in hepatic fibrosis. In the cohort with nonalcoholic fatty liver disease, statin use was associated with a significant reduction in the amount of hepatic steatosis.¹³

Kerzner and colleagues describe an interesting case of statin-induced liver injury with a cholestatic pattern, reproduced on rechallenge with the same drug.¹⁴ Statins have rarely been implicated in the pathogenesis of autoimmune hepatitis–like syndrome.¹⁵ Cases with chronic DILI (abnormal liver tests for more than 6 months) had fairly high titers of autoimmune markers (ANA and antismooth muscle antibody). Causality assessment in patients with suspected DILI can be very challenging, and the differential diagnosis includes acute viral hepatitis (A, B, C, D, and E), cytomegalovirus, and herpes simplex virus (HSV). Although acute HSV seems very unlikely in the patient described by Kerzner and colleagues,¹⁴ hepatitis E was not excluded. A recent publication from the DILIN identified several cases of hepatitis E that initially had been thought to be due to DILI.¹⁶ In evaluating unexplained elevations in liver enzymes with statin use, it is also important to exclude myalgia and myositis, which may lead to increases in serum aminotransferase levels, predominantly aspartate aminotransferase levels, but with far greater increases in serum creatine phosphokinase (CPK) levels.

In summary, statins overall are safe and effective drugs with proven benefit in not only cardiovascular risk reduction but also in possibly having beneficial effects in prevention of various cancers and metabolic syndrome. Indeed, it has been suggested that virtually all adults in developed countries should be taking statins. As a class, they have a low risk of adverse events, with benefits mostly outweighing the risks. It is recommended that liver chemistries and CPK levels be checked before initiating therapy. However, routine monitoring of liver tests while on treatment is not recommended. Rather, such testing should be performed only if there are symptoms or signs that suggest possible liver injury. In patients who develop jaundice or other systemic symptoms or signs suspected of being associated with statin use, rechallenge with the same drug is generally not recommended. After resolution of the acute injury, use of a different statin can be considered for clear indications, such as elevated serum cholesterol levels, but with careful and frequent monitoring of liver tests, especially during the first 6 months of treatment.