Therapy for Nonalcoholic Fatty Liver Disease

They made me take cod liver oil: that is the height of luxury…. —Jean-Paul Sartre Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver chemistries in the United States and other developed countries, with an estimated prevalence of approximately 30% in the general population.1–3 NAFLD is commonly associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and other features of the metabolic syndrome. As a result, the prevalence of this disorder is expected to increase with the global epidemic of obesity and type 2 diabetes mellitus.4 NAFLD represents a spectrum of diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), characterized by steatosis and hepatocyte injury with or without fibrosis. NASH can progress to the development of cirrhosis and over a 10-year period 30% to 50% of these patients will suffer a liver-related death.5 As a result, there is a clear and urgent need for effective treatment options for patients with NAFLD. Although weight loss and lifestyle modifications have been shown to be effective, only a minority of patients are able to adhere to sustained and intensive dietary interventions.6,7 Likewise, bariatric surgery may provide benefit, but only to the severely obese patients.8 Therefore, the primary focus of studies on the treatment of NAFLD has been on pharmacologic agents that can be further categorized as insulin sensitizers, antioxidants, cytoprotective agents, antihyperlipidemic agents, antiobesity drugs, and novel agents.9 In this issue, the report by Tanaka and colleagues10 on the use of eicosapentaenoic acid (EPA), naturally obtained in the human diet by eating oily fish, such as salmon and sardines, and in fish oils, such as cod liver oil, is an opportunity to consider the present and future status of the medical management of patients with NAFLD. The thiazolidinediones (TZDs) are peroxisome proliferator activated receptor-γ (PPAR-γ) agonists that improve insulin sensitivity in patients with type 2 diabetes.11 Because insulin resistance is considered to play a key role in the pathogenesis of NAFLD, the use of TZDs as a treatment option has been widely evaluated. A pilot study of troglitazone, before the TZD being withdrawn from clinical use, in patients with NASH demonstrated improvement in serum aminotransferases and necroinflammatory grade.12 Subsequent studies with rosiglitazone13,14 and pioglitazone alone15,16 or in combination with vitamin E17 demonstrated similar biochemical and histologic improvement. However, long-term therapy is necessary to maintain these improvements18 and weight gain,19 potential hepatotoxicity, and the reported increased probability of cardiac events in diabetic patients treated with rosiglitazone20 may limit the use of TZDs in the treatment of NAFLD. Additional studies, larger and longer in duration, or using combination therapy, in which the possibly deleterious effects of TZDs on organ systems that are affected by the metabolic syndrome other than the liver are attenuated by another agent, such as the combination of rosiglitazone and conjugated linoleic acid,21 are clearly indicated before TZDs are to be considered standard treatment for NAFLD. In this regard, the results from the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial launched by the NASH Clinical Research Network in 2005 are eagerly awaited. Results of studies of dual PPAR-α and γ agonists, such as muraglitazar, in the treatment of type 2 diabetes22 suggest that these agents might also have potential as therapy in patients with NAFLD. However, concerns about cardiovascular risks and carcinogenicity have limited the clinical application of these agents.23 Given the reported cardioprotective effect of PPAR-δ agonists, the results of ongoing studies of dual PPAR-α and δ and PPAR γ and δ agonists, and PPAR-α, γ, δ pan-agonists are awaited. In this regard, the first clinically tested PPAR pan-agonist, bezafibrate, ameliorated the development of steatohepatitis in mice fed a methionine-deficient and choline-deficient diet24 and has been successfully used in the treatment of tamoxifen-associated and toremifene-associated NASH in patients with breast cancer.25 In addition, studies with selective PPAR-γ modulators, such as metaglidasen (MBX-102), MBX-2044, and PA-082, which are not associated with weight gain and edema, are awaited.26 The biguanide, metformin, is a preferred agent in the treatment of obese patients with type 2 diabetes. Findings that this insulin sensitizing agent improved aminotransferase elevations, steatosis, and hepatomegaly in the ob/ob mouse model of NAFLD27 were followed by several small human studies, demonstrating improvement in serum aminotransferases and liver histology.28–31 However, none of these studies were double-blinded or placebo-controlled and a recent report suggests no benefit of metformin over diet and exercise.32 The results of the ongoing Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) trial examining the effect of vitamin E, metformin, or placebo, in obese, nondiabetic children may better clarify the role, if any, of metformin in the treatment of NAFLD. Oxidative stress and endoplasmic reticulum (ER) stress have also been implicated in the pathogenesis of insulin resistance and, in turn, of NAFLD.33 The methyl donor, betaine, which promotes methylation of homocysteine to methionine, has been shown to ameliorate ER stress response in a model of intragastric alcohol-fed mice34 and, in a small pilot study, led to biochemical and histologic improvement in patients with NASH.35 However, betaine failed to improve serum aminotransferases or histology in a preliminary report of a larger, randomized,. placebo-controlled study.36 Although a pilot study using ursodeoxycholic acid (UDCA) in patients with NASH was encouraging,37 a larger, randomized trial demonstrated no superiority of UDCA over placebo.38 However, UDCA is safe and well-tolerated, and interest in this hepatoprotective bile acid as a treatment option in patients with NASH has been renewed by the finding that UDCA alleviates ER stress and hepatic steatosis and normalizes serum aminotransferases in mouse models of obesity and diabetes39 as well as the recent clinical trial results of combination treatment of UDCA and vitamin E.40 Hyperlipidemia is frequently present in patients with NASH, thus forming the basis for several trials of antihyperlipidemic agents. In pilot studies, probucol, a lipid-lowering agent with antioxidant properties, was found to be effective in improving serum aminotransferases; however, no histologic data were available.41,42 Similar findings were reported with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin.43 Epidemiologic studies and randomized controlled trials demonstrate that n-3 polyunsaturated fatty acids (n-3 PUFAs, also known as omega-3 PUFAs), a PPAR-α agonist and a major constituent of fish oil, reduce the risk of coronary artery disease by lowering serum triglycerides.44 Recent findings demonstrate that n-3 PUFAs improve hepatic steatosis and necroinflammation in a rat model of NASH45 and in patients with NAFLD.46 It is in this context that Tanaka and colleagues10 have now demonstrated that EPA, a major component of n-3 PUFAs, improves not only the biochemical features but also the histologic features in patients with hyperlipidemia and NASH. Of note, although serum-free fatty acid levels were improved, the homeostasis model assessment for insulin resistance and serum adiponectin levels were unaffected by EPA treatment. These results suggest that the combination of EPA with an insulin-sensitizing agent might offer greater efficacy over either agent alone in the treatment of NAFLD. EPA at a dose of 2700 mg/d was well tolerated. Of note, omega-3-acid ethylesters capsules are available in the United States in a prescription form (Lovaza; Reliant Pharmaceuticals Inc, Liberty Corner, NJ), each containing 465 mg of EPA and 375 mg of docasehexaenoic acid, although cost may be a limiting factor. Among the antiobesity agents, the intestinal lipase inhibitor, orlistat, now available without a prescription, has been examined in several small studies.47–50 The beneficial effect of this agent, and also the serotonin and norepinephrine reuptake inhibitor, sibutramine,51 is most likely related to weight loss rather than intrinsic properties of the agent. Furthermore, the lack of evidence on the effects of these agents on long-term weight loss and health outcomes, except for 1 randomized controlled study of orlistat versus placebo plus lifestyle changes,52 makes it difficult to define the role, if any, of pharmacologic treatment for weight loss in the management of NAFLD. Novel agents include angiotensin II, the major peptide of the renin-angiotensin system, which has been shown in animal models of NASH to play a role in the pathogenesis of hepatic steatosis and fibrosis.53,54 The effects of the angiotensin II type 1 receptor antagonist, losartan, were examined in a small number of patients with both NASH and hypertension.55 Serum markers of hepatic fibrosis (hyaluronic acid, type IV collagen, and procollagen III N-terminal propeptide) and aminotransferases significantly decreased and histology (necroinflammatory grade and fibrosis stage) improved in most patients. Further trials are awaited in larger number of patients. Telmisartan may offer advantages over other angiotensin II type 1 receptor antagonists because of its reported selective PPAR-γ modulating activity.56 Endogenous cannabinoids are novel lipid mediators that stimulate appetite by acting at CB1 receptors and CB1−/CB1− mice have been shown to be resistant to diet-induced obesity.57 Recently, the oral antagonist of the CB1 receptor, rimonabant, abolished hepatic steatosis, reduced hepatomegaly, decreased serum alanine aminotransferase and hepatic and plasma tumor necrosis factor-α levels, and increased plasma adiponectin levels in obese (fa/fa) rats,58 suggesting that the CB1 receptor may be a novel target for drug therapy in NAFLD. A randomized, controlled trial of rimonabant for 1 year in obese and overweight patients reported a 4.5% weight loss and favorable changes in lipid profiles that were maintained during an additional year of treatment reported.59 Effects, if any, on liver chemistries, however, were not reported and concerns about psychiatric adverse events resulted in the FDA's Endocrinologic and Metabolic Drug advisory panel to unanimously recommend against approval in June, 2007. Two other cannabinoid antagonists, taranabant and CP-945598, are currently under development and resolution of these safety concerns is awaited. Other novel strategies include the use of antisense oligonucleotides against diacylglycerol acyltransferase, which catalyzes the final step in hepatic triglyceride biosynthesis60 and acetyl-CoA carboxylase,61 neuropeptide Y receptor antagonists,62 the β-carboline alkaloid, harmine,63 and orally active small-molecule inhibitors of adipocyte fatty-acid–binding protein.64 In conclusion, treatment for NAFLD should be safe and based on an understanding, albeit incomplete at present, of its pathogenic mechanisms, with the goal of improvement in established disease and prevention of disease progression to cirrhosis and its complications. In addition, the preferred agent should be cost-effective, require only short-term or moderate-term use, and have lasting effects upon discontinuation. To date, no agent has met these qualifications and it is highly unlikely that a single agent will be found to treat NAFLD and all other aspects of the metabolic syndrome, including obesity, diabetes mellitus, hypertension, and hyperlipidemia. Nevertheless, additional trials with EPA, alone or in combination with other agents, in patients with NASH with and without hyperlipidemia, seem warranted.