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
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
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
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
- 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.
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 dxefined 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 immunosuppresive therapy.
4. Autoimmune cholestatic liver disordersas 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
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
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.