This study will evaluate the effectiveness of pioglitazone, a new diabetes medicine, on
decreasing insulin resistance and improving liver disease in patients with nonalcoholic
steatohepatitis (NASH). NASH is a chronic liver disease with unknown cause that involves
fat accumulation and inflammation in the liver, leading to liver cirrhosis in 10 to 15
percent of patients and significant liver scarring in another 30 percent. Although similar
to a condition that affects people who drink excessive amounts of alcohol, NASH occurs in
people who drink only minimal or no alcohol. It is most often seen in patients with insulin
resistance. Pioglitazone decreases insulin resistance and improves blood lipid (fat)
levels, so that it may improve liver disease in NASH.
Patients with NASH 18 years of age or older may be eligible for this study. Candidates will
be screened with a medical history and physical examination and routine blood tests. They
will see a dietitian for counseling on diet and weight reduction, if needed. They will stop
taking any medications for liver disease and take a daily multivitamin pill. After 2
months, those eligible for participation will be enrolled in the study.
Participants will be admitted to the Clinical Center for 2 to 3 days for a complete medical
history, physical examination, blood tests, urinalysis, chest X-ray, electrocardiogram,
abdominal ultrasound and a liver biopsy. After the diagnosis of NASH is confirmed, the
following procedures will be performed:
- Echocardiography - imaging test using sound waves shows the heart structure and
- Resting metabolic rate - measures amount of oxygen (and calories) used to maintain body
functions at rest. While lying down, the patient wears a clear plastic hood over the
head for 20 minutes while the amount of oxygen used is measured.
- Magnetic resonance imaging (MRI) scans - shows the size of the liver and other organs.
The patient lies on a table in a metal cylinder that contains a magnetic field (the
scanner) for no more than 30 minutes while the organs are imaged.
- Dual energy X-ray absorptiometry (DEXA) scan measures whole body composition, including
amount of fat. The patient lies under an X-ray scanning machine for about 2 minutes.
- Oral glucose tolerance test (OGTT) - measures blood sugar and insulin levels. The
patient drinks a very sweet drink containing glucose (sugar), after which blood samples
are collected at various intervals during the 3-hour test. The blood is drawn through
a catheter (thin plastic tube) placed in the arm before the test begins.
- Intravenous glucose tolerance test (IVGTT) - determines how the tissues respond to
insulin and glucose. Glucose is injected into a vein, followed by a short infusion of
insulin. Blood samples are collected through a catheter at various intervals during
the 3-hour test.
When the above procedures are completed, patients start taking pioglitazone by mouth once a
day for 48 weeks, keeping track of the medication and any side effects. They will be seen
at the clinic every 2 weeks for the first month and then every 4 weeks for the rest of the
treatment period. The visits will include an interview and examination by a physician and
blood draw for laboratory tests. Female patients will have a pregnancy test at each clinic
visit. At the end of the treatment period patients will be admitted to the Clinical Center
for a repeat medical evaluation that will include the procedures described above.
Nonalcoholic steatohepatitis (NASH) is a clinicopathological entity that is being recognized
more frequently in recent years. It is characterized by histologic changes that are similar
to alcoholic hepatitis, but in the absence of excessive alcohol consumption. It is
typically associated with type 2 diabetes mellitus, obesity and dyslipidemia and insulin
resistance. It may progress and cause severe hepatic fibrosis and cirrhosis in significant
numbers of patients. Currently, there is no effective therapy for this condition. In this
pilot, open label study, we propose to treat 30 patients with nonalcoholic hepatitis with
pioglitazone for 48 weeks. Pioglitazone has been shown to improve insulin sensitivity, the
possible underlying mechanism of nonalcoholic steatohepatitis. Pioglitazone is an
antidiabetic drug that belongs to thiazolidinedione group. The mechanism of action is
thought to be mediated by activation of peroxisome proliferator-activated receptors-gamma
(PPAR-gamma). After an initial evaluation of insulin sensitivity, fat distribution and
liver biopsy, patients will receive 30 mg of pioglitazone, orally for 48 weeks. Patients
will be monitored at regular intervals for symptoms of liver disease, side effects of
pioglitazone, serum biochemical and metabolic indices. At 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, reduction in visceral fat, liver volume and liver biochemistry.
Age at entry of at least 18 years.
Serum alanine or aspartate aminotransferase activities that are above the upper limit of
Evidence of chronic steatohepatitis, on liver biopsy done within the previous 12 months.
Histologic criteria of steatohepatitis: diffuse, chronic liver disease characterized by
(1) macrovesicular steatosis, (2) inflammation or evidence of hepatocellular drop-out, and
(3) acinar zone 3 hepatocellular injury (ballooning degeneration). Additionally helpful,
but not required, features include the presence of Mallory's hyalin and
pericellular/sinusoidal fibrosis that predominantly involves zone 3.
Absence of other forms of liver disease.
Absence of significant alcohol consumption (less than 7 drinks per week during the
Written informed consent.
Evidence of another form of liver disease.
Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).
Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.
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
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.
Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology
consistent with Wilson disease.
Alpha-1-antitrypsin deficiency as defined by alpha-1 antitrypsin level less than normal
and liver histology consistent with alpha-1-antitrypsin deficiency.
Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and
homozygosity for C282Y or compound heterozygosity for C282Y/H63D.
Drug-induced liver disease as defined on the basis of typical exposure and history.
Bile duct obstruction as shown by imaging studies.
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 (1
drink per day: 7 drinks per week) in the previous one year.
Contraindications to liver biopsy: platelet counts less than 75,000/mm(3) or prothrombin
time greater than 16 seconds.
Decompensated liver disease, Child-Pugh score greater than or equal to 7 points.
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.
Presence of diabetes mellitus as defined by: fasting plasma glucose of greater than or
equal to 126 mg/dl or diabetic symptoms with a random plasma glucose of greater than or
equal to 200 mg/dl.
Use of antidiabetic drugs, including insulin, biguanides, sulfonylureas, or
thiazolidinediones in the previous 6 months.
Significant systemic or major illnesses other than liver disease, including congestive
heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease, renal
failure, organ transplantation, serious psychiatric disease, malignancy that, in the
opinion of the investigator would preclude treatment with pioglitazone and adequate follow
Positive test for anti-HIV.
Active substance abuse, such as alcohol, inhaled or injection drugs within the previous
Pregnancy or inability to practice adequate contraception in women of child-bearing
Evidence of hepatocellular carcinoma: alphafetoprotein levels greater than 200 ng/ml
and/or liver mass on imaging study that is suggestive of liver cancer.
Any other condition which, in the opinion of the investigators would impede competence or
compliance or possibly hinder completion of the study.
History of hypersensitivity reactions to thiazolidinediones.