Recombinant Leptin Therapy for Treatment of Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic Steatohepatitis: is Leptin an Etiological Factor (Phase 2).

Nonalcoholic steatohepatitis (or NASH) is known to be caused by deposition of fat in the liver and development of scarring. This condition occurs more frequently in overweight and obese persons. It is often associated with resistance to the actions of insulin hormone. Fat cells secrete a hormone called leptin. Recently, we have learned that obese or overweight persons make too much leptin, which may contribute to insulin resistance. Paradoxically, patients who do not have any fat cells, also have insulin resistance. In these patients, insulin resistance is caused by the absence of leptin and leptin replacement significantly improves insulin resistance and fat deposition in the liver. In an earlier study, we determined the leptin levels in patients with NASH and how these levels are related to body fat levels as well as responsiveness to insulin. We saw that a subgroup of patients with NASH have relatively low levels of leptin in contrast to the amount of body fat they had. We now would like to see if restoring leptin levels to normal will improve the disease process in these patients. Our study patients will be male patients, aged between 18 and 65 (inclusive), who do not have any other cause for their liver disease. We have put some restrictions in body size such that a spectrum of patients from normal weight to obese range would be included. They will also demonstrate low leptin levels (levels similar to only 25% of normal population). We will use a genetically engineered form of leptin manufactured by Amylin Inc. given via injections under the skin. We plan to continue therapy for a period of one year and evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic parameters and body composition characteristics that we examined in our earlier study. We expect that patients with low blood leptin levels will show improvement in their liver disease and insulin resistance when their blood leptin levels are restored to normal.

Inclusion Criteria:

• Biopsy proven NASH
• Circulating fasting leptin <9 ng/mL (staggered criteria for different BMI levels)

Exclusion Criteria:

• Presence of advanced liver disease (as evidenced by abnormal synthetic function, abnormal prothrombin time or albumin)
• Presence of clinical lipodystrophy
• Presence of other liver disease
• Presence of clinical diabetes (fasting >126 mg/dL or 2 hour post 75 g-glucose >200 mg/dL or random glucose >200 mg/dL with presence of diabetes symptoms or known history of diabetes)
• Any medication for treatment of NASH or obesity
• Presence of HIV
• Inability to give informed consent
• Presence of end-stage renal disease, any type of active cancer, or >class 2 congestive heart failure ((New York Heart Association Functional Classification System), based on medical history and physical examination
• Presence of any other condition that limits life expectancy to <2 years
• Active infection (may be transient)
• Any other condition in the opinion of the investigators that may impede successful data collection