Nonalcoholic Fatty Liver Disease

Clinical Presentation

NAFLD is largely asymptomatic. Many patients show minimal or no clinical symptoms, although fatigue can be a significant problem [4]. Most patients are diagnosed after discovery of abnormal liver enzyme levels on routine blood tests. When taking the patient's history, physicians should concentrate on determining the presence of conditions associated with NAFLD and excluding alternative causes of steatosis, such as excessive alcohol intake, alternative causes for elevated liver enzyme levels (eg, viral hepatitis, celiac sprue, autoimmune liver disease, and hemochromatosis), and/or concomitant medications known to cause increased chronic hepatitis or hepatic steatosis (eg, glucocorticoids, tamoxifen, amiodarone, and methotrexate). Liver aminotransferase levels are insensitive for diagnosing NAFLD versus NASH, as levels of aminotransferases may fluctuate or can be normal in patients with histologic features of NASH [5]. NAFLD is associated with higher overall and liver-related mortality in the general US population. Cardiovascular disease, cirrhosis, and cancer are the 3 leading causes of death among persons with NAFLD [6, 7].

Natural History

Retrospective studies have shown that fibrosis progresses in 25%–38% of patients with NAFLD, with ballooned hepatocytes (swollen liver cells) and inflammation on index biopsy being the strongest predictor for hepatic fibrosis [8]. End-stage NASH accounts for 30%–75% of all cases of cirrhosis for which the cause is unknown. About 7% of patients with compensated NASH-related cirrhosis develop hepatocellular carcinoma within 10 years, and 50% will require a transplant or will die from a liver-related cause [9]. The overall and liver-related mortality of patients with NAFLD is higher than for age- and sex-matched populations, principally due to increased liver- and cardiovascular-related mortality [10].

Diagnostic Evaluation

In the absence of overt signs or symptoms of advanced liver disease (eg, splenomegaly, ascites, thrombocytopenia, muscle wasting, or hepatic encephalopathy), patients with NAFLD typically have blood test results that are normal or show mild elevations of aminotransaminases, alkaline phosphatase, and gamma glutamyltranspeptidase. Ultrasound, computed tomography, and routine magnetic resonance imaging are all excellent at detecting steatosis, but none can reliably detect NASH or fibrosis.

Although a liver biopsy is not required to establish a diagnosis of NAFLD, it may be indicated for accurate staging of the disease (ie, determining the presence of NASH and/or advanced hepatic fibrosis). Histology remains the gold standard for making the important distinction between simple steatosis, which is generally nonprogressive and readily reversible, versus steatohepatitis, which has the potential to progress to severe fibrosis or cirrhosis. A liver biopsy may also identify other causes of liver disease in patients thought to have NAFLD or vice versa. Histologic grading and staging of NAFLD are potentially important for studying disease severity and progression, particularly in the context of clinical trials to assess novel therapeutic approaches [11].

Newer techniques for disease staging, including proton magnetic resonance spectroscopy and transient elastography, show promise but require further study before they will be ready for routine use [12]. Various clinical and laboratory markers have been shown to be associated with advanced fibrosis (bridging fibrosis or cirrhosis) in NAFLD patients: age greater than 45–50 years, body mass index above 30 kg/m², the presence of type 2 diabetes, and an aspartate aminotransferase-to-alanine aminotransferase ratio greater than 1 (AST:ALT > 1). At present, it would seem reasonable to restrict liver biopsy to patients with at least some of these risk factors.

Together with serum markers of inflammation and fibrosis, various risk factors have been combined into a number of different diagnostic algorithms. However, many of these algorithms currently require independent validation and comparison before they can be applied to routine clinical practice [12].

Current Management Strategies

Current management strategies are directed at treating the individual components of metabolic syndrome, when present. The cornerstone of treatment focuses on gradual and sustained weight loss. Any significant weight reduction—whether it is a result of dietary change, exercise, or bariatric surgery—has been shown to be effective at reducing liver enzyme levels and improving histology [13]. Several small, largely uncontrolled studies have shown an improvement in either alanine aminotransferase levels or steatosis following diet-induced weight loss (with or without exercise) [14-16]. There is less evidence that NASH or fibrosis can be improved with weight loss alone.

A recent randomized controlled trial that compared 48 weeks of intensive lifestyle intervention (a combination of diet, exercise, and behavior modification) versus structured education demonstrated significantly greater weight loss and improved NASH histological activity scores in the lifestyle intervention group [17]. This study also showed that patients who achieved greater than 7% weight loss had significantly greater improvements in all 3 components of the NASH activity score (steatosis, lobular inflammation, and ballooned hepatocytes) compared with those who lost less than 7% body weight. Therefore, aiming for a weight loss of 7% through diet and exercise appears to be a reasonable target in overweight and mildly obese patients [1, 12].

Weight loss surgery is also effective in improving NASH. A 2008 meta-analysis of NAFLD and bariatric surgery–induced weight loss found that more than 90% of NAFLD patients with bariatric surgery–induced weight loss had improvement or resolution of hepatic steatosis. In addition, over 80% of patients with NASH showed improvement, with almost 70% showing complete resolution. Finally, 65.5% of patients with mild hepatic fibrosis showed improvement or resolution of hepatic fibrosis [18]. However, bariatric surgery may not be effective in reversing more advanced stages of hepatic fibrosis, and it may be associated with risk for postsurgical hepatic decompensation.

Pharmacologic Therapies

Currently, there are no pharmaceutical treatments approved by the US Food and Drug Administration for NAFLD. However, due to the strong association between NAFLD, type 2 diabetes, and dyslipidemia, therapies used to treat type 2 diabetes and/or dyslipidemia have been investigated as potential treatments for NAFLD. The rationale for NAFLD therapies is based on a growing understanding of disease pathogenesis, with a particular focus on several mechanisms: improving insulin resistance and levels of hepatic free fatty acids; reducing oxidative, endoplasmic reticulum, and cytokine-mediated stress; and optimizing the balance between liver injury and repair mechanisms [19-21].

Evidence that insulin resistance may contribute to both inflammation and fibrosis in NAFLD has led to several pilot studies of metformin and glitazones for treatment of NAFLD. The most encouraging results have been reported for the glitazone class of drugs that acts as agonists for the peroxisome proliferator activated receptor γ. Five randomized controlled trials of glitazones have been reported, all of which showed an improvement in alanine aminotransferase levels and steatosis [22-26]; most studies also showed an improvement in NASH. Thus far, no study has shown a convincing benefit on fibrosis. In the largest randomized controlled trial to date, pioglitazone significantly improved each individual aspect of liver injury, but it failed to achieve the study's endpoint—a 2-point improvement in NASH activity score with no worsening of fibrosis more often than placebo [27]. The recently published FLINT trial examined the effect of obeticholic acid versus placebo in patients with NASH or borderline NASH. After 72 weeks of treatment, obeticholic acid was noted to be effective at improving liver histology, but this study showed no significant difference in resolution of NASH [28].

While lipid-lowering agents have not been extensively studied in NAFLD, there are scientific reasons to support the use of fibrates (conventional triglyceride-lowering agents) for this condition. To date, the only controlled study with histological follow-up reported that clofibrate had no effect on liver biochemistry or histology after 1 year of treatment [29]. While statins have not been extensively studied for NAFLD, they can be safely prescribed for treatment of hyperlipidemia in the setting of type 2 diabetes and high cardiovascular risk. There is no evidence that patients with preexisting NAFLD are at increased risk of statin-induced idiosyncratic hepatotoxicity, so clinicians should not withhold statin therapy in patients with NAFLD if there is some other indication for their use [30].

Oxidative stress is believed to be involved in liver injury in NASH patients. For this reason, antioxidants such as vitamin E have been investigated as potential treatments for NASH. Results from trials with vitamin E have been mixed. An Italian study published in 2005 compared the effect of metformin, vitamin E, and diet in NAFLD patients and found vitamin E to have no clinical benefit over weight loss [31]. However, a more recent study examined the efficacy of vitamin E or pioglitazone versus placebo. Both treatment arms showed significant improvements in both histology and serum enzyme levels. Vitamin E was effective for improving all histologic categories (steatosis, lobular inflammation, and ballooned hepatocytes), and pioglitazone showed improvements in both steatosis and inflammation [27]. Enthusiasm for the potential benefits of pioglitazone and vitamin E should be tempered by the finding that improvement in NASH was noted in only 34% of the subjects who received pioglitazone and 43% of those who received vitamin E, and steatohepatitis resolved in only 47% and 36%, respectively. Neither agent was associated with a significant improvement in the mean fibrosis score after 96 weeks of treatment [27].

The discovery of a safe and effective pharmacological intervention for NAFLD and/or NASH would have important implications for global public health. The evaluation of new pharmacologic targets for NASH is limited by the heterogeneous phenotype of the disease and the lack of noninvasive biomarkers for diagnosis and staging. Table 1 provides examples of investigational therapies that are in preclinical or clinical development for the treatment of NAFLD and/or NASH. More up-to-date data on therapies under investigation may be acquired from www.clinicaltrials.gov.

Future Directives

There are many opportunities for improvement in the diagnosis and treatment of NAFLD. One important initiative is to identify noninvasive markers that can be used to diagnose and stage NAFLD and NASH. As previously mentioned, the current standard for diagnosis and staging is liver biopsy, which is invasive and requires a significant time investment from both patients and physicians. Noninvasive imaging methods are both expensive and nonspecific.

In addition to focus on biomarker discovery, development of pharmaceutical treatments for NAFLD and NASH is a priority for those patients who fail lifestyle modification and/or have NASH with fibrosis. Many of the therapeutic options presented in this review have plausible mechanisms for the treatment of NASH. While some therapies, including weight loss, may be able to reverse NASH, no treatments to date have shown the ability to significantly improve fibrosis, and many therapies have yet to be tested in patients with cirrhosis. Finally, the long-term effects of these treatments and their ability to have a lasting impact without long-term use will require future investigation.