Nonalcoholic fatty liver disease: A manifestation of the metabolic syndrome
ABSTRACTNonalcoholic fatty liver disease (NAFLD) has become the most common form of liver disease, affecting 20% to 30% of the US population. Its clinical manifestations are usually absent or subtle, and it usually comes to medical attention incidentally when aminotransferase levels are found to be elevated or a radiographic study reveals that the liver is fatty. Primary NAFLD is now considered the hepatic manifestation of the metabolic syndrome. The pathogenesis is thought to be a multiple-hit process involving insulin resistance, oxidative stress, apoptosis, and adipokines. In general, the prognosis for simple steatosis is very good; however, nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and hepatocellular carcinoma in 10% to 15% of patients. There is no established treatment for NAFLD except for weight loss and treating each component of the metabolic syndrome.
KEY POINTS
- The clinical spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma.
- NAFLD is closely associated with metabolic syndrome, insulin resistance, and obesity.
- Weight loss and treating components of the metabolic syndrome are central to the treatment of NAFLD. Insulin sensitizers such as biguanides and glitazones, antioxidants such as vitamin E, and lipid-lowering agents have shown promise in small clinical trials, but the evidence remains preliminary.
NO CONSENSUS ON TREATMENT
Weight loss
Modest weight loss—less than 2 pounds (1 kg) per week—is associated with a decrease in the incidence of metabolic syndrome and can also improve the histologic features of NASH in more than 80% of cases.24 Loss of as little as 4% to 5% of body weight is also associated with lowering of aminotransferase and fasting insulin levels.25
The mechanism of benefit is via loss of adipose tissue, which decreases insulin resistance. Weight loss by any means, including bariatric surgery for morbid obesity or use of weight-reducing agents, has been correlated with improvement in liver enzyme levels, liver histologic findings, or both.24,26
However, the traditional low-calorie, low-fat diet may not be optimal for NAFLD patients. In one study,27 patients consuming more than 54% of their calories from carbohydrates compared with those consuming less than 35% had an odds ratio of 6.5 for hepatic inflammation. This finding is not surprising in light of prior research in which high carbohydrate intake increased hepatic de novo lipogenesis. On the other hand, there was no association between total caloric or protein intake and hepatic steatosis or fibrosis. Contrary to traditional beliefs, patients with higher fat intake had less inflammation, steatosis, and fibrosis.
Insulin sensitizers
Given that insulin resistance seems to be the main pathophysiologic culprit in NAFLD, two classes of insulin sensitizers have been studied:
Biguanides act mainly by increasing hepatic insulin sensitivity and reversing insulin resistance induced by tumor necrosis factor alpha.
Glitazones improve insulin sensitivity in both diabetic and euglycemic patients by activating the nuclear transcription factor called peroxisome proliferator-activated receptor (PPAR) gamma.
Both biguanides and glitazones have been found to lower liver enzyme levels, decrease insulin resistance, and improve histopathologic findings. However, the effects of glitazones do not persist after the drugs are stopped, and these drugs and are also associated with an average weight gain of 3 to 6 kg.28,29
Although these data are encouraging, they are preliminary, and more evidence is needed to establish the safety and efficacy of these drugs in treating patients with NASH.
Antioxidants
Antioxidants such as vitamin E, n-acetyl-l-cysteine, s-adenosylmethionine (SAMe), and betaine have been investigated in the treatment of NAFLD.
Vitamin E has been most widely studied. Being fat-soluble, vitamin E can stabilize mitochondrial function and is theorized to inhibit lipid peroxidation and subsequent free radical reactions. Smaller, nonrandomized trials have found that vitamin E improves biochemical markers of liver inflammation. However, in one of the largest randomized controlled trials (with 45 patients), patients taking vitamin E showed improvement in their fibrosis scores but no differences in their necroinflammatory activity or alanine aminotransferase levels.30 Most studies of antioxidants show at least mild improvement in biochemical or histologic signs of NAFLD.31
SAMe and betaine are important antioxidants. However, most studies of SAMe and betaine have been small and inconclusive.
Two large phase III clinical trials are under way at the National Institute of Diabetes and Digestive and Kidney Diseases. They should clarify the role of these agents in the treatment of NASH. The PIVENS (Pioglitazone vs Vitamin E vs Placebo for the Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis) study has completed enrollment of 240 patients, but the final data are not available. The second study, TONIC (Treatment of Nonalcoholic Fatty Liver Disease in Children) will be one of the largest studies of NAFLD in children; it will be looking at vitamin E, metformin, or placebo over a 2-year follow-up. The TONIC study is still under way, so the final data are not yet available.
Ursodeoxycholic acid, another cytoprotective agent, has traditionally been used for primary biliary cirrhosis, but the data are conflicting on its efficacy in NAFLD. Of note, some bile acids are hepatotoxic and facilitate apoptosis via a Fas ligand-mediated pathway. On the other hand, ursodeoxycholic acid is a hydrophilic bile acid that may act to displace the hepatotoxic hydrophobic endogenous bile acids and potentially has an antiapoptotic and cytoprotective effect in NAFLD. Although liver enzyme levels declined in a few of the studies of ursodeoxycholic acid in patients with NAFLD, a large randomized clinical trial (in 166 patients) did not show any significant difference from placebo in liver enzyme levels or liver histologic findings.32
Lipid-lowering drugs
Lipid-lowering drugs target the high levels of triglycerides and low levels of high-density lipoprotein cholesterol that often occur in insulin resistance and metabolic syndrome associated with NAFLD. A few small studies found that aminotransferase levels fell with both statins and gemfibrozil (Lopid).33 Even if liver enzyme levels are abnormal, most experts believe that statins are relatively safe to use in patients with NAFLD who need cholesterol-lowering agents. Nevertheless, clinical monitoring of these patients for potential hepatic toxicity is recommended.
Other medications
Other medications, such as pentoxifylline (Pentoxil, Trental), probiotics, and angiotensin-converting enzyme inhibitors, have been used in small studies of patients with NASH, with encouraging but inconclusive results.
Although a number of pilot studies of agents for treating NAFLD have been proposed, they are small and open-label. With the tremendous recent gains in clinical investigation, functional genomics, and proteomics, it is expected that our understanding of NASH and its treatment will be broadened.
In summary, despite the relatively large number of agents tested for the treatment of NAFLD, most of the data are preliminary. Thus, in 2008, there is no established, evidence-based treatment for patients with NASH.
