Treating Nonalcoholic Steatohepatitis (NASH) With Metformin
Treating Nonalcoholic Steatohepatitis (NASH) With Metformin
Nonalcoholic Steatohepatitis (NASH) is associated with progressive liver disease, fibrosis,
 and cirrhosis. Although the cause of NASH is unknown, it is often associated with obesity,
 type 2 diabetes, and insulin resistance. At present, there are no approved treatments for
 NASH patients, but an experimental approach has focused on improving their insulin
 sensitivity. Metformin is one of the most commonly used medications for the treatment of
 diabetes.

 The purpose of this study is to determine whether the medical problems of NASH patients,
 specifically liver damage, improves when their insulin sensitivity is enhanced with
 metformin.

 The study will last 3 to 5 years and will enroll up to 30 patients. Participants will undergo
 a complete medical examination, a series of lab tests, and a liver biopsy. They will then
 start taking a single 500-mg tablet of metformin once a day for 2 weeks, then the same dosage
 twice a day for 2 more weeks, if they tolerate the first dosage. The dosage will increase to
 1,000 mg twice a day for the remaining 44 weeks of the study. After 1 year, participants will
 undergo a repeat medical examination and liver biopsy.
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from
 simple fatty liver (steatosis) to steatosis with inflammation and necrosis to cirrhosis, that
 occurs in persons who drink little or no alcohol. Nonalcoholic steatohepatitis (NASH)
 represents the more severe end of this spectrum and is associated with progressive liver
 disease, fibrosis and cirrhosis. The etiology of NASH is unclear, but it is often associated
 with obesity, type 2 diabetes, hyperlipidemia and insulin resistance. We have recently
 conducted a study of a 48-week course of pioglitazone in 21 non-diabetic patients with NASH.
 Serum aminotransferase levels and liver histology improved in most patients and the
 improvements correlated with changes in insulin sensitivity. These results are promising, but
 pioglitazone is associated with significant weight gain, is quite expensive, and its
 long-term safety is yet to be proven. In contrast, metformin is inexpensive, extremely well
 tolerated, and of proven long-term safety in patients with diabetes and pre-diabetes.

 In this study, we propose to treat 20 non-diabetic patients with NASH with metformin for
 48-weeks. After an initial evaluation for insulin sensitivity, fat distribution and liver
 biopsy, patients will receive gradually increasing doses of metformin orally to a maximum of
 2000 mg daily. Patients will be monitored at regular intervals for symptoms of liver disease,
 side effects of metformin and serum biochemical and metabolic indices. At the end of
 48-weeks, patients will have a repeat medical evaluation and liver biopsy. Pre and post
 treatment liver histology, fat distribution and insulin sensitivity will be compared. The
 primary end point of successful therapy will be improvement in hepatic histology as
 determined by reduction of at least three points in NASH activity score. Secondary end points
 will be improvement in insulin sensitivity, body fat distribution, and liver biochemistry.
-  INCLUSION CRITERIA:

 1. Age at entry at least 18 years.

 2. Serum alanine (ALT) or aspartate (AST) aminotransferase activities that are above
 the upper limits of normal.

 3. Evidence of steatohepatitis on liver biopsy done within the previous 12 months
 with a NASH activity score of at least 4 (of a total possible score of 16)
 including a score of at least 1 each for steatosis, hepatocellular injury and
 parenchymal inflammation. Histological criteria of steatohepatitis include: (1)
 macrovesicular steatosis, (2) acinar zone 3 hepatocellular injury (ballooning
 degeneration), (3) parenchymal and (4) portal inflammation. Additionally helpful,
 but not required, features include the presence of (5) Mallory's hyaline and (6)
 pericellular and/or sinusoidal fibrosis that predominantly involves zone 3.

 4. Written informed consent.

 EXCLUSION CRITERIA:

 1. Evidence of another form of liver disease.

 1. Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).

 2. Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.

 3. Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or
 greater and liver histology consistent with autoimmune hepatitis or previous
 response to immunosuppressive therapy.

 4. Autoimmune cholestatic liver disorders as defined by elevation of alkaline
 phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver
 histology consistent with primary biliary cirrhosis or elevation of alkaline
 phosphatase and liver histology consistent with sclerosing cholangitis.

 5. Wilson disease as defined by ceruloplasmin below the limits of normal and liver
 histology consistent with Wilson disease.

 6. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than
 normal and liver histology consistent with alpha-1-antitrypsin deficiency.

 7. Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy
 and homozygosity for C282Y or compound heterozygosity for C282Y/H63D.

 8. Drug-induced liver disease as defined on the basis of typical exposure and
 history.

 9. Bile duct obstruction as shown by imaging studies.

 2. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day)
 in the previous 10 years, or history of alcohol intake averaging greater than 10
 gm/day (1drink per day: 7 drinks per week) in the previous one year.

 3. Contraindications to liver biopsy: platelet counts less than 75,000/mm(3) or
 prothrombin time greater than 16 seconds.

 4. Decompensated liver disease, Child-Pugh score greater than or equal to 7 points.

 5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce
 hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate,
 tetracycline or amiodarone in the previous 6 months.

 6. Presence of diabetes mellitus as defined by: fasting plasma glucose of greater than or
 equal to 126 mg/dl on two separate occasion, or diabetic symptoms with a random plasma
 glucose of greater than or equal to 200 mg/dl (34).

 7. Use of anti-diabetic drugs, including insulin, biguanides, sulfonylureas, or
 thiazolidinediones in the previous 6 months.

 8. Significant systemic or major illnesses other than liver disease, including congestive
 heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease
 with hypoxia, renal failure, organ transplantation, serious psychiatric disease,
 malignancy that, in the opinion of the investigator would preclude treatment with
 metformin and adequate follow up.

 9. Positive test for anti-HIV.

 10. Active substance abuse, such as alcohol, inhaled or injection drugs within the
 previous one year.

 11. Pregnancy or inability to practice adequate contraception in women of childbearing
 potential.

 12. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml
 and/or liver mass on imaging study that is suggestive of liver cancer.

 13. Any other condition, which, in the opinion of the investigators would impede
 competence or compliance or possibly hinder completion of the study.

 14. History of hypersensitivity reactions to metformin.

 15. Serum creatinine greater than 1.5 mg/dl in men and greater than 1.4 mg/dl in women.