Race, Insulin Resistance and Hepatic Steatosis in
Chronic Hepatitis C
Hari S. Conjeevaram,1 David E. Kleiner,2 Jay E. Everhart,3 Jay H. Hoofnagle,3 Steven Zacks,4 Nezam H. Afdhal,5 and
Abdus S. Wahed6 for the Virahep-C Study Group
Hepatic steatosis is common in chronic hepatitis C and has been linked to concurrent obesity,
insulin resistance, diabetes, disease severity, and poor response to therapy. Racial differences in
rates of obesity and diabetes may contribute to racial differences in hepatic steatosis and treat-
ment response. The aim of the present study was to compare hepatic steatosis and its associations
between African American (AA) and Caucasian American (CA) patients with chronic hepatitis C,
genotype 1, participating in a prospective study of peginterferon and ribavirin therapy. Liver
biopsy results were available from 194 AA patients and 205 CA patients. The 2 groups were
compared for anthropometric, clinical, andbiochemical features and insulin resistance estimated
by the homeostasis model assessment index (HOMA-IR). Sixty-one percent of the AA patients
and65%of theCApatients hadhepatic steatosis (P
0.38). Inunivariable analysis, steatosiswas
associated with HOMA-IR, body mass index, waist circumference, serum triglycerides, amino-
transferase level, and histological scores for inflammation and fibrosis. After adjusting for these
features, AA patients had a lower risk of steatosis than did CA patients (OR 0.54, 95% CI
0.32-0.91, P
0.02). Insulin resistance but not steatosis was associated with a lower rate of
sustained virological response when adjusted for known factors that predict response (relative
risk 0.87, 95%CI0.77-0.99, P
0.028).Conclusion: After adjusting for the higher prevalence of
features associated with hepatic steatosis, AA patients had a lower prevalence of hepatic steatosis
thandidCApatientswith chronic hepatitisC, genotype 1. Insulin resistance but not steatosiswas
independently associated with lower sustained virological response. (HEPATOLOGY 2007;45:80-87.)
Hepatic steatosis is a common histological findingin chronic hepatitis C virus (HCV) infection,found in 40%-70% of patients.1-3 In the largest
series reported, the prevalence of steatosis was 65%, and
its presence was associated with more advanced disease,
especially in patients with genotype 1 infection.4 The
mechanisms of hepatic steatosis in HCV are thought to be
multifactorial.5-14 Several possibilities have been proposed
including the presence of insulin resistance. Insulin resis-
tance is a key factor in the development of steatosis in
nonalcoholic fatty liver disease (NAFLD) and has been
observed in individuals with HCV, especially in HCV,
genotype 1 infection (referred to as metabolic steatosis).15
Compared to other racial groups, African Americans
(AA) appear to have a lower prevalence of fatty liver,16,17
despite a higher prevalence of risk factors for NAFLD.
Clinical series have also found an unexplained low repre-
sentation of African Americans among patients with non-
alcoholic steatohepatitis (NASH), the most severe form of
NAFLD.18 There have been no large studies of African
Americans and Caucasian Americans (CA) designed to
compare risk factors for and the presence of NAFLD de-
termined by histopathology. Among patients with HCV,
the relationship between race and the presence or severity
of steatosis is unknown in genotype 1 infection, which is
the predominant type found among both AA and CA.
The aim of this study was to compare the prevalence and
severity of hepatic steatosis according to anthropometry
and other measures of insulin resistance among a large
cohort of AA and CA with chronic hepatitis C, genotype
From the 1University of Michigan, Ann Arbor, MI; 2National Cancer Institute,
National Institutes of Health, Bethesda, MD; 3National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; 4Uni-
versity of North Carolina at Chapel Hill, Chapel Hill, NC; 5Beth Israel Deaconess
Medical Center, Boston, MA; and the 6University of Pittsburgh, Pittsburgh, PA.
Received June 12, 2006; accepted October 4, 2006.
Supported as a cooperative agreement by the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) with co-support from the National Center on
Minority Health and Health Disparities (NCMHD) and the Intramural Research
Program of the National Cancer Institute (NCI) with further support under a Cooper-
ative Research and Development Agreement (CRADA) with Roche Laboratories, Inc.
(grant numbers U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344,
U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345,
U01 DK60309, U01 DK60346, U01 DK60349, and U01 DK60341); and Na-
tional Center for Research Resources (NCRR) General Clinical Research Centers Pro-
gram (grantsM01RR00645 [NewYorkPresbyterian],M02RR000079 [University of
California, San Francisco], M01 RR16500 [University of Maryland], M01
RR000042 [University of Michigan], M01 RR00046 [University of North Carolina]).
Address reprint requests to: Hari Conjeevaram, M.D., M.S., Division of Gas-
troenterology, University of Michigan, 3912 Taubman Center, 1500 East Medical
Center Drive, Ann Arbor, MI 48109-0362. E-mail: omsairam@umich.edu; fax:
(734) 936-7392.
Copyright © 2006 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.21455
Potential conflict of interest: Dr. Zacks is on the speakers’ bureau of Roche. He
also received grants from Salix Pharmaceuticals.
80

1, enrolled in a trial of antiviral therapy. We also wanted
to assess whether the presence and severity of hepatic ste-
atosis and/or insulin resistance were important factors to
predict virological response in this population.
Patients and Methods
Patient Population. The Virahep-C study was a
multicenter study of combination peginterferon and riba-
virin therapy of chronic hepatitis C designed to assess the
rates and predictors of response among AA and CA with
genotype 1 infection and to identify reasons for nonre-
sponse to therapy. The design and primary outcomes of
the Virahep-C trial have been reported.19 Eight clinical
centers across the United States participated. Adult pa-
tients 18 years and older who were treatment naive, in-
fected with genotype 1, had detectable HCV RNA, and
had histologic evidence of chronic HCV were eligible to
participate. Patients with a history of alcohol consump-
tion of more than 2 drinks or the equivalent (
20 g) per
day or evidence of alcohol abuse in the preceding 6
months were excluded. All patients had undergone liver
biopsy within 18 months of enrollment. The study was
designed to enroll at least 400 patients, equally divided
between AA and CA. Patients were classified by race as
either African American or Caucasian race and by ethnic-
ity as either Hispanic or non-Hispanic based on self-re-
port. All participants were required to have been born in
the United States. Between July 2002 and December
2003, a total of 401 patients were enrolled and started on
therapy.
Study Design. Baseline anthropometric measure-
ments, including height and weight to calculate body
mass index (BMI) and waist circumference and waist-hip
ratio to assess truncal obesity, were recorded at screening.
Fasting glucose and insulin were obtained at baseline, and
insulin resistance (IR) was assessed by the homeostasis
model assessment index (HOMA): {fasting insulin [
U/
ml]  (fasting glucose [mg/dl]/18)}/22.5.20,21 Other
baseline blood tests included serum alanine aminotrans-
ferase (ALT), aspartate aminotransferase (AST), and fast-
ing triglycerides. All patients were questioned about
history of diabetes, hypertension, hyperlipidemia, and
medication use for these conditions.
All patients were required to have had liver biopsies
performed within 18 months of screening, which were
read by a central pathologist for whom all clinical infor-
mation including race was masked. All biopsies were as-
sessed for severity of hepatitis C by grading the
inflammation and staging the fibrosis using the modified
histologic activity index (HAI) scoring system described
by Ishak et al.22 In addition, 2 other histological features,
steatosis and features of steatohepatitis, were scored. Ste-
atosis was graded on a scale from 0 to 4 according to the
percentage of cells with fat, with 0 none, 0.5 (trace)
5%, 1 5% to25%, 2 25% to50%, 3 50%
to 75%, and 4  75% to 100%. Because few patients
had marked steatosis, those with steatosis grades 2, 3, and
4 were combined for analysis. Three specific features of
steatohepatitis were recorded as either present or absent:
zone 3 ballooning degeneration, zone 3 perisinusoidal fi-
brosis, and Mallory bodies. A biopsy was considered to
show steatohepatitis if 2 of the 3 features were present in
addition to a steatosis grade of 1 or above. HOMA is used
routinely to assess longitudinal changes including assess-
ment of the effects of treatment.20,21 In general a HOMA
index value of more than 1.5 is considered abnormal
based on repeat testing measurements performed by both
HOMA assessment and by euglycemic clamp technique
and is considered representative of decreased insulin sen-
sitivity. Although insulin secretion is pulsatile, the corre-
lation between HOMA computed from repeat sampling
(using a mean of 3 samples taken at 5-minute intervals to
compute HOMA) and the value obtained from a single
basal sample to determine insulin sensitivity has been
shown to be near perfect, even in patients with type 2
diabetes (r  0.99, P  0.0001).21 In this study we de-
cided to use a HOMA index value of more than 2.0 as the
criterion to represent insulin resistance.
Patients received peginterferon alfa-2a (Pegasys, Roche
Pharmaceuticals, Nutley, NJ) in a dose of 180
g weekly
and ribavirin (Copegus, Roche Pharmaceuticals, Nutley,
NJ) in a dose of 1000-1200 mg daily for at least 24 weeks.
The study was designed such that patients who became
HCV RNA negative by week 24 continued treatment for
a total of 48 weeks, whereas those who remained HCV
RNA positive stopped treatment. The primary endpoint
of the trial was a sustained virological response, defined as
the absence of detectable HCV RNA for at least 24 weeks
after stopping therapy. HCV RNA testing was done at a
central laboratory (SeraCare BioServices, Gaithersburg,
MD) using the Cobas Amplicor Assay (sensitivity 50 IU/
ml: Roche Molecular Diagnostics, Alameda, CA). Se-
lected samples were tested for HCV RNA levels by Cobas
Amplicor Monitor Assay and for HCV RNA genotype by
Versant HCV Genotype Assay (Bayer, Tarrytown, NY).
The design and details of this study were approved by
the institutional review boards of the participating insti-
tutions and by a central Data Safety and Monitoring
Board assembled by the National Institute of Diabetes
and Digestive and Kidney Diseases to oversee and moni-
tor the trial. All patients gave written informed consent
for participation.
Statistical Analysis. Prevalence and severity of steato-
HEPATOLOGY, Vol. 45, No. 1, 2007 CONJEEVARAM ET AL. 81