Treating Nonalcoholic Steatohepatitis (NASH) With Metformin
Condition: Hepatitis
MeSH terms: Hepatitis; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Metformin
Intervention description: After complete medical evaluation and liver biopsy, patients who qualified for therapy were started on metformin in an initial dose of 500 mg once daily. After 2 weeks, the dose was increased to 500 mg twice daily and after 4 weeks to the full dose of 1000 mg twice daily. Subsequent dose reductions were carried out based on tolerance, with particular attention to gastrointestinal upset and abdominal bloating. Patients were seen in the out-patient clinic, had a brief medical history and examination and routine blood tests at 2 and 4 weeks after enrolment and every 4 weeks thereafter. The oral and intravenous glucose tolerance tests were repeated after 40 and 44 weeks respectively and liver biopsy and imaging tests at 48 weeks. Metformin was discontinued after 48 weeks in patients without diabetes on the pre-treatment evaluation.
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Insulin; Obesity; Fatty Liver; Diabetes; Cirrhosis; Metformin; Insulin Resistance; Nonalcoholic Steatohepatitis; Hepatitis; NASH

Summary:

      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.
    

Eligibility criteria:

        -  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.