Statins for non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in patients with no or very little alcohol consumption is characterised by hepatic histological changes similar to those associated with alcohol-induced liver injury. A range of histological changes can be seen. Some patients have fat accumulation in hepatocytes without significant inflammation or fibrosis (simple hepatic steatosis or NAFLD), but others have hepatic steatosis with prominent necro-inflammatory changes with or without associated fibrosis (this is NASH). Although NAFLD and NASH are common conditions, no effective medical treatment is available to correct the abnormal liver enzymes and adverse outcomes associated with them. This systematic review identified two randomised clinical trials with very small numbers of participants. One of the trials was a pilot trial and compared simvastatin with placebo, and the other trial assessed atorvastatin versus fenofibrate versus a combination of the two. The small pilot trial (n = 16 patients) assessing simvastatin versus placebo in NASH patients did not show significant effects on liver enzyme activities or liver histology. No adverse events were reported. The other trial compared atorvastatin versus fenofibrate versus a group receiving both interventions in 186 patients with NAFLD. There were no statistically significant differences between any of the three intervention groups regarding the 54 week mean activities of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, or alkaline phosphatases (liver enzymes) in the blood. The triglyceride levels seemed higher in the fenofibrate group compared with the atorvastatin group. Liver histology was not assessed in this trial. The presence of biochemical and ultrasonographic evidence of NAFLD seemed higher in the fenofibrate group compared with the other two intervention groups. Three patients discontinued treatment due to myalgia and elevated serum creatine kinase activity, one from the atorvastatin group and two from the combination group. Another patient from the atorvastatin group discontinued treatment due to raised alanine aminotransferase activity, over three times the upper normal limit. Both trials were at high risk of bias (that is, overestimation of benefits and underestimation of harms). Furthermore, the groups were small raising the risks of random errors (that is, play of chance). Accordingly, we did not find evidence to support or refute the use of statins for patients with NAFLD or NASH. Further unbiased trials with larger numbers of patients looking explicitly at patient-related outcomes of interest (for example, quality of life, development of cirrhosis, and mortality) are needed to assess the effects of statins on NAFLD or NASH.

Authors' conclusions: 

Based on the findings of this review, which included two trials with high risk of bias and a small numbers of participants, it seems possible that statins may improve serum aminotransferase levels as well as ultrasound findings. Neither of the trials reported on possible histological changes, liver-related morbidity or mortality. Trials with larger sample sizes and low risk of bias are necessary before we may suggest statins as an effective treatment for patients with NASH. However, as statins can improve the adverse outcomes of other conditions commonly associated with NASH (for example, hyperlipidaemia, diabetes mellitus, metabolic syndrome), their use in patients with non-alcoholic steatohepatitis may be justified.

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Background: 

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common causes of elevated liver enzymes in the general population. NASH and to some extent NAFLD have been associated with increased liver-related and all-cause mortality. No effective treatment is yet available. Recent reports have shown that the use of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with elevated plasma aminotransferases may result in normalisation of these liver enzymes. Whether this is a consistent effect or whether it can lead to improved clinical outcomes beyond normalisation of abnormal liver enzymes is not clear.

Objectives: 

To assess the beneficial and harmful effects of statins (that is, lovastatin, atorvastatin, simvastatin, pravastatin, rosuvastatin, and fluvastatin) on all-cause and liver-related mortality, adverse events, and histological, biochemical, and imaging responses in patients with NAFLD or NASH.

Search strategy: 

We performed a computerised literature search in the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded up to March 2013. We did fully recursive searches from the reference lists of all retrieved relevant publications to ensure a complete and comprehensive search of the published literature. We did not apply any restrictions regarding language of publication or publication date.

Selection criteria: 

All randomised clinical trials using statins as the primary treatment for NAFLD or NASH versus no treatment, placebo, or other hypolipidaemic agents.

Data collection and analysis: 

Data were extracted, and risk of bias of each trial was assessed independently by two or more review authors. Meta-analyses were performed whenever possible. Review Manager 5.2 was used.

Main results: 

When the described search method was used and the eligibility criteria of the search results were applied, 653 records were found. Only two of these were randomised clinical trials that were considered eligible for inclusion. We assessed both trials as trials with high risk of bias. One of the trials was a pilot trial in which 16 participants with biopsy-proven NASH were randomised to receive simvastatin 40 mg (n = 10) or placebo (n = 6) once daily for 12 months. No statistically significant improvement in the aminotransferase level was seen in the simvastatin group compared with the placebo group. Liver histology was not significantly affected by simvastatin.

The other trial had three arms. The trial compared atorvastatin 20 mg daily (n = 63) versus fenofibrate 200 mg daily (n = 62) versus a group treated with a combination of the two interventions (n = 61). There were no statistically significant differences between any of the three intervention groups regarding the week 54 mean activity levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase. The triglyceride levels seemed higher in the fenofibrate group compared with the atorvastatin group. Liver histology was not assessed in this trial. The presence of biochemical and ultrasonographic evidence of NAFLD seemed to be higher in the fenofibrate group compared with the atorvastatin group (58% versus 33%). Three patients discontinued treatment due to myalgia and elevated serum creatine kinase activity; one from the atorvastatin group and two from the combination group. Another patient from the atorvastatin group discontinued treatment due to alanine aminotransferase activity that was over three times the upper normal limit.

No data for all-cause mortality and hepatic-related mortality were reported in the included trials.

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