Fatty Liver Disease -- It's More Than Alcohol and Obesity

Heiner Wedemeyer, MD, Michael P. Manns, MD

Disclosures

July 23, 2003

In This Article

Treatment

The primary treatment strategies for NASH are weight loss and physical activity.[23,24] In 1997, the results of one study demonstrated the beneficial effect of restricted diet and exercise in obese patients with fatty liver.[25] These data were confirmed by results of a study presented during this year's meeting proceedings by a group from Japan.[26] Seventeen patients with NASH followed a program of restricted diet and exercise (walking or jogging for 40 minutes per day) for 3-6 months. Liver biopsies taken after treatment showed that body mass index, aspartate aminotransferase (AST) and ALT levels, and histologic findings such as steatosis, lobular inflammation, and lipogranuloma, improved significantly. However, there was no significant difference in the degree of fibrosis -- thus this conservative approach seems to require more time to induce regression of liver fibrosis in patients with NASH. These small trials and others summarized by Dr. Bugianesi[23] suggest that even in the absence of randomized controlled trials, obese patients with NASH should be advised to lose weight by calorie restriction and with increased exercise. However, weight loss should not exceed 1 kg per week because more rapid weight loss may cause exacerbation of liver disease. In some cases, pharmacologic regimens may be considered for markedly obese patients, as was recently reported.[27]

As mentioned above, insulin resistance is thought to play a key role in the pathogenesis of steatosis and is almost a universal finding in patients with NASH. Results of pilot trials investigating the use of insulin-sensitizing agents not only in diabetic patients but also in nondiabetic patients have recently been published. Metformin,[28] thiazolidinediones,[29] and IKK [I-kappaB kinase] inhibitors appear to show promise in this setting.

During this year's EASL meeting, more data supporting the concept of using insulin-sensitizing agents in NASH were presented. One such report, presented by Tahan and colleagues,[30] explored the effect of rosiglitazone, an oral antidiabetic agent, in a rat model of NASH. The study authors showed that short-term (only 4 weeks) use of rosiglitazone significantly attenuated liver inflammation and reduced ALT levels in the MCDD (methionine and choline-deficient diet) rat model of NASH.

In another study, 64 patients were randomized to receive either rosiglitazone 4 mg/day, metformin 1000 mg/day, or neither of these agents (ie, were followed by diet); the study authors presented an interim analysis of their results.[31] Rosiglitazone was found to improve ALT activities and insulin resistance (as determined by the HOMA-R [homeostasis model assessment of insulin resistance] formula) in patients with NASH after 3 months of therapy. Metformin was found to decrease serum AST levels, but did not affect insulin resistance or ALT levels. We now await the longer follow-up data for these patients and especially anticipate the results of liver rebiopsy after treatment.

Antioxidants may represent an alternative approach for treating patients with severe NASH, as there is accumulating evidence supporting a role for oxidant stress in the pathogenesis of this disorder.[32] Recently, probucol, a lipid-lowering agent with strong antioxidant properties, was successfully explored in a first pilot trial conducted in patients with NASH.[33] Data from several other trials were presented during EASL 2003 that also suggested that antioxidants and vitamins C and E may be of benefit in NASH.

A study from Italy investigated the relation of diet to insulin resistance and liver disease in 25 nonobese, nondiabetic patients with NASH.[34] It is interesting to note that the study authors found a highly significant negative correlation between steatosis and intake of polyunsaturated fat, vitamin C, and vitamin E.

A group from Turkey investigated oxidative modification of low-density lipoprotein (ox LDL) immunohistochemically in liver tissues of patients with NASH.[35] Ox LDL was found to occur at high degrees in liver tissue samples taken from patients with various liver injuries due to NASH, chronic viral hepatitis, and alcoholic hepatitis -- thus providing indirect evidence that oxidative stress indeed is present in the liver of these patients.

Perlemuter and colleagues[36] from France investigated antioxidant enzyme activities (cytosolic and mitochondrial superoxide dismutases; glutathione peroxidase) in liver tissue from obese patients with NASH. They found these antioxidant enzymes to have higher activities in the liver, but not in plasma or erythrocytes. Therefore, oxidative stress may be particularly present in the liver, but not in other compartments in these patients studied.

Finally, in a pilot study from Ankara, Turkey, 16 patients with NASH were treated with vitamin E 400 mg/day.[37] Of note, the investigators found that vitamin E treatment improved biochemical (ALT, AST), histologic (steatosis, inflammation), and ultrasonographic parameters after 6 months of treatment. However, no improvement was achieved in fibrosis stage after this short-term treatment. Thus, additional studies including larger populations are needed to clarify the role of vitamin E in the treatment of patients with NASH.

Additional alternative therapeutic options were summarized by Dr. Bugianesi[23] during the President's premeeting. Among the options discussed were N-acetylcysteine and antiendotoxin/cytokine therapies.[38] Anti-TNF-alpha antibodies have been used to treat severe alcoholic steatohepatitis, but thus far, there is no indication for the use of these drugs in patients with NASH outside the setting of clinical trials. Ursodeoxycholic acid (UDCA) may have antiapoptotic and immunomodulatory effects,[39] and it has been tested in several smaller trials of patients with NASH.[24] In this setting, UDCA was found to result in normalization of ALT levels and, in 1 study, to also lead to a reduction in the amount of intrahepatic fat. However, randomized controlled trials are also lacking for UDCA in NASH. Thus, no final recommendation regarding the utility of this drug in patients with NASH can be made at present.

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