Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Cochrane database of systematic reviews (Online) (Impact Factor: 5.94). 12/2013; 12(12):CD008623. DOI: 10.1002/14651858.CD008623.pub2
Source: PubMed

ABSTRACT 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.
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.
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.
All randomised clinical trials using statins as the primary treatment for NAFLD or NASH versus no treatment, placebo, or other hypolipidaemic agents.
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.
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.
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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    ABSTRACT: Metabolic syndrome (MetS) is a disease composed of different risk factors such as obesity, type 2 diabetes or dyslipidemia. The prevalence of this syndrome is increasing worldwide in parallel with the rise in obesity. Nonalcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease in western countries, affecting more than 30% of the general population. NAFLD encompasses a spectrum of liver manifestations ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. There is accumulating evidence supporting an association between NAFLD and MetS. Indeed, NAFLD is recognized as the liver manifestation of MetS. Insulin resistance is increasingly recognized as a key factor linking MetS and NAFLD. Insulin resistance is associated with excessive fat accumulation in ectopic tissues, such as the liver, and increased circulating free fatty acids, which can further promote inflammation and endoplasmic reticulum stress. This in turn aggravates and maintains the insulin resistant state, constituting a vicious cycle. Importantly, evidence shows that most of the patients developing NAFLD present at least one of the MetS traits. This review will define MetS and NAFLD, provide an overview of the common pathophysiological mechanisms linking MetS and NAFLD, and give a perspective regarding treatment of these ever growing metabolic diseases. Copyright © 2015. Published by Elsevier Ireland Ltd.
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May 17, 2014