Progression of Fibrosis in Hepatitis C With and
Without Schistosomiasis: Correlation with
Serum Markers of Fibrosis
Sanaa M. Kamal,
Ahmed Al Tawil,
Margaret James Koziel,
and Nezam H. Afdhal
Serial liver biopsies are the gold standard by which the progression of ﬁbrosis is evaluated. This
longitudinal cohort study assessed the different rates in the progression of ﬁbrosis using serial
liver biopsies and serum ﬁbrosis markers YKL-40 and PIIINP and the cytokines, transforming
growth factor beta (TGF-
) and tumor necrosis factor alpha (T⌵F؊
). A 10-year cohort study
was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis.
Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two
liver biopsies (at entry and end of follow-up), and true rates in the progression of ﬁbrosis were
calculated per year. Serum YKL-40, N-terminal propeptide of collagen III (PIIINP), TGF-
were measured, as well as the expression of TGF-
, and YKL-40 mRNA in liver
tissue. A signiﬁcant increase in the progression rates of ﬁbrosis occurred in the coinfected group
(0.61 ؎ 0.13) compared with the HCV monoinfection group (0.1 ؎ 0.06; P < .001)). The
progression of ﬁbrosis rate/year had a direct linear correlation for YKL-40 (r ؍ 0.892, P < .001)
and for PIIINP (r ؍ 0.577, P < .01). YKL-40 showed a linear correlation with TGF-
0.897, P < .001). Hepatic mRNA levels of YKL-40 and TGF-
correlated with the serum levels,
conﬁrming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and
ﬁbrosis markers can accurately determine the rate at which ﬁbrosis is progressing, identifying
both those with rapid ﬁbrosis and those with stable disease. Supplementary material for this
article can be found on the H
epatitis C virus (HCV) infection is character-
ized by silent onset in most infected individuals,
a high rate of viral persistence, and the potential
for development of chronic liver disease, ranging from
chronic hepatitis to cirrhosis and hepatocellular carcino-
However, the progression of ﬁbrosis in chronic
hepatitis C is highly variable, and the natural history of
the disease usually extends over several decades.
idemiological studies of chronic HCV infection, age, du-
ration of infection, alcohol consumption, male sex, and
coinfection with HIV, hepatitis B virus, or schistosomia-
sis have been related to histological severity.
kines secreted in response to cell injury such as tumor
necrosis factor-alpha (TNF-
) and transforming growth
factor beta-1 (TGF-
1) have been implicated in the de-
velopment of liver inﬂammation and ﬁbrosis.
has been shown to modulate hepatic stellate cell activation
as well as synthesis of some extracellular matrix proteins
and proteins involved in matrix degradation.
Serial liver biopsies are the current gold standard to
evaluate the progression of ﬁbrosis.
A number of sero-
logical and urinary compounds such as procollagens, tis-
sue inhibitors of metalloproteinases (TIMP), type IV S
collagen, hyaluronic acid, and laminin and mediators of
extracellular matrix production such as TGF-
Abbreviations: HCV, hepatitis C virus; TNF-
, tumor necrosis factor alpha;
, transforming growth factor beta; TIMP, tissue inhibitors of metallopro-
teinases; ALT, alanine aminotransferase; PCR, polymerase chain reaction; PIIINP,
aminoterminal propeptide of type III procollagen; AST, aspartate aminotransferase;
ECM, extracellular matrix.
Liver Center, Beth Israel Deaconess Medical Center, Harvard Med
ical School, Boston, MA;
Division of Gastroenterology and Hepatology, Depart
ment of Internal Medicine, University of Ain Shams, Cairo, Egypt;
Pathology, University of Basel, Switzerland; and the
Department of Pathology,
University of of Ain Shams, Cairo, Egypt.
Received April 22, 2005; accepted January 23, 2006.
Supported by Espinosa Fibrosis Fund, BIDMC to NHA and NIH grants NIAID
R29A141563 and R21 A1054887 to MJK and SK respectively.
Address reprint requests to: Nezam H. Afdhal M.D., Liver Center, Beth Israel
Deaconess Medical Center, 110 Francis street, Boston, MA 02215. E-mail:
email@example.com; fax: 617-632-1066.
Copyright © 2006 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conﬂict of interest: Nothing to report.