Statins in liver disease?

A middle-aged patient arrives to his regularly scheduled clinic appointment looking for refills of his medication. His PMH includes HTN, hyperlipidemia, diabetes mellitus, obesity, and cirrhosis secondary to nonalcoholic fatty liver disease. His medications include antihypertensive and antihyperglycemic drugs in addition to atorvastatin 80 mg by mouth daily. At this time, you recall that statins have a risk for hepatotoxicity and are concerned whether it should be refilled at this time. What are the considerations for continuing statin therapy in this patient with known liver disease?

Elevation of liver enzymes is a well-known risk of statin therapy. Since the first statin was approved by the FDA in 1987, regular monitoring of liver enzymes to screen for elevations was routine practice. However, in 2012, the FDA revised the prescribing information for all statins to recommend serum aminotransferases be measured at baseline and then only thereafter if clinically indicated. There were primarily two reasons for this change:

1. The risk of irreversible liver damage from statins in extremely rare (with estimated prevalence from 1/100,000 up to 1/1,000,000)
2. There is no evidence that supports that testing prevents liver damage in someone who continues their statin therapy(1)

These FDA recommendations have likely significantly reduced direct and indirect healthcare costs as the new cholesterol guidelines have more recently expanded eligibility for statin therapy to include an estimated 56 million adults in the U.S. population.(2)

Currently in the U.S., all statins’ prescribing information includes the contraindication of active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. The warning/precaution section also includes the risk for liver enzyme elevation.

In the large randomized controlled trials, exclusion criteria generally include elevation of liver enzymes (JUPITER, TNT, ASCOT, etc.). There have, however, been a few small studies which address this issue. Lewis et al(3) administered statins in a randomized, placebo-controlled trial to patients with compensated liver disease and measured ALT for up to 36 weeks. Nonalcoholic fatty liver disease and chronic hepatitis C were frequently present in their 326 patients. There was no difference in elevations of ALT between groups. A retrospective study by Chalasani et al(4) examined patients with elevated liver enzymes that received six months of statin therapy and compared them to both patients receiving statins with normal enzymes and also to a statin-free group. There was no difference in liver enzyme elevation between the group with baseline abnormalities and the statin-free group.

Since patients with nonalcoholic fatty liver disease are at a high risk of cardiovascular disease, withholding statin therapy is a disservice to this population (risk of dying from cardiovascular disease was more than seven times greater than dying of liver disease in a study of NAFLD). In the GREACE study(5), statins or placebo were administered to 1600 patients with coronary heart disease. Looking at the cohort that began the study with elevated liver enzymes, 10% of the statin group experienced cardiovascular events compared to 30% who did not receive a statin. Also in the statin group, ALT and AST decreased 35% and 47% respectively compared to the non-statin group whose ALT and AST further increased by 12%.

Some pleiotropic effects of statins:

• Statins are inhibitors of the mevalonate pathway by competitively inhibiting HMG-CoA reductase, an early, rate-limiting step in cholesterol biosynthesis. There are a number of other mechanisms that likely cause their cardioprotective effects including enhanced nitric oxide production, inhibiting monocyte infiltration into arterial walls, inhibition of platelet aggregation, and anti-inflammatory effects.
• Plausible mechanisms for protective effects of statins have been demonstrated in nonalcoholic fatty liver disease, primary biliary cirrhosis, the development of infections, and the development of hepatocellular carcinoma in hepatitis B. Statins have been shown to increase nitric oxide availability which reduced the hepatic vein pressure gradient in patients with portal hypertension when compared to placebo6. A reduction in variceal bleeding has yet to be shown. In inhibiting the mevalonate pathway, statins may reduce certain factors important in activating cancerous cells. A nested case-control study showed a lower risk of hepatocellular carcinoma with statin use and this persisted in both patients with and without liver disease at baseline.(7)

So while statins may increase liver enzymes in some patients, this is a rare event that patients with existing stable liver disease do not seem to be at increased risk for. ‘Hepatotoxicity’ does not seem like the appropriate term for the effects of statins since they seem to have salutary effects on liver function. The term ‘hepatotoxicity’ is more appropriate for something like acetaminophen which has clear dose-related adverse effects. It may be more appropriate to think of statins as having idiosyncratic reactions that are not predictable (say, by dose).

Back to the patient case

From what we’ve seen above, it seems that statin avoidance is not absolute in liver disease. If this patient’s liver disease is deemed to be compensated and there are baseline liver enzymes on record, statin therapy should be continued at this time (without transaminase testing) and may be beneficial in reducing various complications.

Take home points:

• Check baseline serum aminotransferase levels when initiating a statin 
• Only check serum aminotransferase levels if clinically warranted after baseline 
• In patients with compensated chronic liver disease, statin therapy does not seem to increase the risk of elevating liver enzymes and may have beneficial cardiac and noncardiac effects 
• New benefits and uses of statins are likely to be discovered in the future

References:
1. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/drugs/drugsafety/ucm293101.htm Accessed March, 2014.
2. Pencina MJ, Navar-Boggan AM, D’Agostino RB, et al. Application of new cholesterol guidelines to a population-base sample. N Engl J Med 2014.
3. Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicentered trial. Hepatology 2007;46:1453-63.
4. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126:1287-92.
5. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010;376:1916-22.
6. Abraldes JG, Albillos A, Banares R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009;136:1651-8.
7. El-Serag HB, Johnson ML, Hachem C, et al. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-8.

photo by euthman