| |
|
Note: Tables and figures
of the article can be access and seen in the PDF file.
Background
It
is estimated that, worldwide, the number of people with
positive hepatitis C antibody is 170 million with a
prevalence of 3% (Violante and Nunez-Nateras, 2007), its
progression leads to chronic hepatitis, cirrhosis and
eventually to hepatocellular carcinoma; and endstage
liver disease (Murray and Carithers, 2005). There is a
significant regional variation in prevalence, with the
highest occurring in North Africa and the Middle East
(more than 3%) (Armstrong et al., 2002).
A
number of concomitant viral and host-related factors
such as HCV genotype, viral load, age, gender, alcohol
consumption, obesity, iron overload, stage of fibrosis
and coinfection with hepatitis B virus are considered to
have an impact on disease progression and response to
antiviral treatment (Afdhal, 2004; Guidi et al., 2005;
Marcellin et al., 2002; Poynard et al., 2001; Seeff,
2002; Shiffman, 2003; Sulkowski et al., 2000).
Nonalcoholic fatty liver disease (NAFLD) encompasses a
continuum that ranges from simple hepatic steatosis to
nonalcoholic steatohepatitis (NASH). NAFLD are common
features in patients with chronic hepatitis C, detected
in 30–70% of patients (Lonardo, 2004; Ramesh &
Sanyal, 2004). However, HCV infection may also play a
direct pathogenic role, influencing lipoprotein
metabolism and insulin sensitivity (Petit et al., 2003;
Rubbia-et al., 2000; Serfaty et al., 2001; Shintani,
2004).
Both
host and viral factors contribute to the complex link
between NAFLD and chronic hepatitis C (CHC) infection
and appear to have genotypic influences. Host dependent
factors include alcohol use, visceral obesity, body mass
index (BMI), hyperlipidaemia and genetic background (Adinolfi
et al., 2005).
NASH describes a subtype of NAFLD that shows hepatic
steatosis associated with hepatocyte injury (ballooning
degeneration, parenchymal inflammation, Mallory bodies
and fibrosis). Some patients with NASH can progress to
cirrhosis or end stage liver disease (Hubscher ,2006
).Current estimates make the prevalence of NASH 23% in
the general population (Falck
Ytter et al.,2001).
While there is growing evidence that steatosis
contributes to the progression of fibrosis (Adinolfi et
al., 2005;
Rubbia-Brandt et al.,
2000). Its impact on the
response to antiviral treatment remains controversial (Adinolfi
et al., 2001; Hourigan et al., 1999; Patton et al.,
2004; Rubbia-Brandt et al.,
2000;
Westin et al., 2002).
Aim of
the study
To
estimate the association of NAFLD with CHC and to
evaluate the effect of steatosis and NASH on the end
treatment virologic response of combined antiviral
therapy in CHC.
Patients and methods
One
hundred and twenty naive (no history of previous
antiviral therapy) HCV patients referred to tropical
medicine outpatient clinic, Mansoura University
Hospital, were initially enrolled in this study during
the period from January 2006 to January 2008.
Inclusion criteria included anti-HCV and HCV-RNA
positivity, elevated ALT and AST levels at least twice
for 6 months, chronic inflammation on liver histology,
no alcohol consumption and no contraindications to
interferon and ribavirin administration.
Exclusion criteria included patients below 20 or above
60 years old, patients with liver cirrhosis (fibrosis
stage V and VI in liver biopsy), patients with Diabetes
Mellitus (DM), patients with concomitant chronic
hepatitis B infection or obese patients with BMI more
than 35. Thirty one such patients (19 male and 12
female) fulfilling the above mentioned criteria were
excluded. Finally the study was conducted on only 89
patients.
Clinical and demographic information, including age,
gender, weight, height, BMI (calculated as weight in
kilograms divided by height in meters squared),
laboratory data (complete blood picture, bilirubin,
alanine transferase (ALT), aspartate transferase (AST),
albumin, alkaline phosphatase, gamma glutamyl
transferase (γ-GT), serum glucose, serum cholesterol,
serum triglyceride and HCV-RNA level) were recorded at
the time of liver biopsy. Informed consent was obtained
from each patient and this study was approved from
Mansoura Ethical Committee.
Every
patient in this study was subjected to history taking,
physical examination, abdominal ultrasound and
histological assessment. Laboratory data were
periodically monitored for all studied patients during
the course of the antiviral combination therapy.
The
presence of HCV infection was diagnosed by the use of
enzyme linked immunosorbent assay (ELISA) (Murex
anti-HCV kit, version 3.0) to detect HCV antibodies,
which was confirmed by the use of reverse transcription
polymerase chain reaction (PCR) to detect HCV-RNA.
HCV-RNA levels were done before treatment and at 12, 24
and 48 weeks after initiation of the antiviral
combination therapy.
HCV genotyping was not performed for these patients as
multiple previous studies revealed that HCV genotype 4
is the most dominant genotype in Egypt (Chamberlain
et al.,
1997; Ray et
al., 2000;
Simmonds
et al., 1993).
Blood sample was withdrawn from every subject in this
study. The separated serum was divided into two
aliquots. The first aliquot was used for estimation of
liver functions (serum bilirubin, albumin, ALT, AST,
alkaline phosphatase and
γ-GT)
using automatic autoanalyzer Hitachi 902, Roche
Diagnostics. The second aliquot was stored at –70°C
until time of assay of RTPCR.
Detection and quantification of HCV-RNA
in serum:
Detection of HCV-RNA in serum was
performed by automated RT-PCR assay (COBAS AMPLICOR HCV
Test, version 2.0; Roche Diagnostics, Molecular
Division). The amplicor HCV monitor test V 2.0 is based
on five major processes (Ming-Lung
et al.,
2000);
specimen preparation, reverse transcriptase of target
RNA to generate complementary DNA, PCR amplification of
target DNA using HCV complementary primers,
hybridization of the amplified products to
oligonucleotide probes specific to the targets and
detection of the probe – bound amplified products by
colorimetric determination.
Histopathological assessment:
Liver
biopsy specimens were reviewed by a single pathologist,
who was blinded to the patients’ clinical information.
For each liver biopsy specimen, hematoxylin and eosin,
Masson’s trichrome, reticuline stains were available.
The histological activity (grade) and degree of fibrosis
(stage) of the viral hepatitis were assessed according
to the modified histological activity index (HAI) of
Ishak (Ishak et al., 1995).
The
histopathological diagnosis of associated NAFLD was
determined by the presence of steatosis which was graded
according to the Brunt grading system, based on
percentage of hepatocytes involved: grade 0 none
involved, grade 1(mild) up to 33%, grade 2 (moderate) up
to 66% and grade 3 (severe) more than 66% (Brunt et al.,
1999). NASH was diagnosed according to previous reports
by presence of pericentral steatosis, hepatocellular
ballooning degeneration and Mallory hyaline, mixed
neutrophilic and lymphocytic intralobular infiltrate and
pericellular fibrosis in zone 3 (Younossi et al., 1998).
Treatment regimens: All patients were treated with a
combination therapy and underwent subcutaneous pegylated
interferon
α 2a (180
μg
weekly) and ribavirin, administered orally from 800 to
1200 mg/day, according to body weight (less than 65 kg,
800 mg/day; 65–85 kg, 1000 mg/day; more than 85 kg, 1200
mg/day). The duration of treatment was 48 weeks. Optimal
adherence to treatment regimens were monitored during
the course of treatment.
Patients were classified as nonresponders, if there is
failure for 2 log. reduction of the viral load after 12
weeks of treatment or if HCV RNA was detectable at end
of therapy and end of treatment responders if there is
undetectable HCV RNA at the end of therapy.
Analysis of data: The statistical analysis of data was
used by using SPSS program (Statistical Package for
Social Science) Version 10. The parametric data was
summarized using mean ± standard deviation;
nonparametric data was summarized using median
(minimum-maximum) and number& percentage for qualitative
data.
To test
statistical significant difference between groups,
independent sample t-test was used to compare between
two groups for parametric data, Mann-Whitney test was
used in non-parametric data. Chi-Square test was used
for qualitative data (number & percentage), Multivarate
regression analysis was used using significant data in
univarate analysis to know the predictors of the
response to treatment, Odds ratios and 95% of confidence
intervals were calculated. Probability (P) value < 0.05
was considered significant.
Results
Eighty-nine patients with chronic HCV infection were
included in this study after exclusion of patients with
fibrosis stage V and VI in liver biopsy, patients with
DM or BMI more than 35.
Table 1 summarizes the clinical and histopathologic
characteristics of the patients. Forty-four patients
(49.4%) had no hepatic steatosis (grade 0) on the liver
biopsy, while NAFLD was seen in 45 patients (50.6%)
among which 19 (21.4%) had grade 1 steatosis, 13 (14.6%)
grade 2, two (2.2%) grade 3 (Fig. 1) and 11(12.4%) had
NASH. The histological diagnosis of superimposed
steatohepatitis was reported by the presence of
hepatocellular ballooning degeneration and Mallory
hyaline, mixed neutrophilic and lymphocytic intralobular
infiltrate in addition to steatosis by hematoxylin and
eosin (Fig. 2) and pericellular fibrosis demonstrated by
Masson’s trichrome stain (Fig. 3). The patients with
superimposed NASH (11 cases) were 5 males and 6 females,
with a mean BMI of 30.6 ± 2.1 kg/m2.
The histological activity
in liver biopsy of these cases were moderate and severe
activity (7,2 cases ) vs 2cases showing mild activity
Out of patients with superimposed NASH, 8 patients
showed stage III and IV fibrosis.
The
clinical and histopathologic parameters are summarized
in Table 2, according to the presence of NAFLD. Patients
with NAFLD differed from those without NAFLD by having
significant higher serum levels of AST (61.4 ± 35.1 vs.
40.2 ± 24.3, P<0.001) and ALT (98.5 ± 31.4 vs. 47.7 ±
16.6, P <0.001), with an AST/ALT ratio <1 in both
groups. In addition, Gamma glutamyl transferase was
higher in patients with NAFLD (87.0 vs. 34.0, P=0.003).
Moreover, the rate of higher histological activity
(moderate activity 31 vs. 23, severe activity 5 vs. 1,
P=0.018) and more advanced fibrosis stage (stage III 14
vs. 9, stage IV 7 vs. 2, P=0.020) in patients with NAFLD
were higher than in those without NAFLD. Patients with
or without hepatic steatosis had insignificant
difference in levels of serum cholesterol, serum
triglyceride, serum albumin, serum alkaline phosphatase
and bilirubin (Table 2).
Sixty
six cases showed two or more log. reduction of HCV RNA
after 12 weeks with no detectable level after 24 week of
therapy, but there were breakthrough in 5 cases with
reappearance of HCV RNA in serum just after the end of
treatment (48 weeks). The overall end treatment
virologic response was achieved in 61 cases (68.54%)
while 28 cases (31.46%) were nonresponders. Table 3
demonstrated the presence of the end treatment virologic
response in relation to different clinical and
histopathologic parameters. Cases with BMI more than 30
kg/m2 were significantly associated with lower chances
for end treatment virologic response (46.2%) compared
with those with BMI less than 30 kg/m2 (77.8%,
P=0.011).
End
treatment virologic response was significantly higher
(86.36%) in patient not affected by NAFLD compared with
51% in group affected by NAFLD (P=0.000). In patients
presented with associated NASH, only 3 out of 11 (27.3%)
showed undetectable HCV-RNA at the end of therapy (Fig.
4).
A
significant decreases in end treatment virologic
response to antiviral therapy is noticed with the
increase in the extent of fibrosis (stage) although
advanced stages (Stage V and VI) were excluded from this
study (P= 0.012).
No
significant effect on response to therapy was exerted by
demographic data (age and gender) and histopathologic
activity (Table 3).
Applying the model of logistic regression analysis in
all variables in relation to end treatment virologic
response revealed that NAFLD can be considered as
independent risk factor for poor response to combined
pegylated Interferon α 2a plus ribavirin treatment (odds
ratio 3.81(95%CI{0.72-22.38}), P=0.002).
Discussion
Chronic
HCV infection is commonly associated with hepatic
steatosis (Adinolfi et al., 2001; Fiore et
al., 1996; Giannini et al., 1999; Hourigan et al., 1999;
Hwang et al., 2001; Sharma et al., 2004). In this study
the association of hepatic steatosis among patients with
chronic active hepatitis C was 50.6%, this data confirms
the high prevalence of steatosis in chronic HCV
infection in the previous studies, especially in active
forms of chronic disease.
Several investigators suggested a pathogenic link
between HCV infection and this metabolic disorder, two
distinct forms of hepatocellular steatosis can be seen
in patients with CHC infection (Castera et al., 2005;
Hui et al., 2002) Classical metabolic risk factors of
hepatocellular steatosis account for the vast majority
of cases. In contrast a direct cytopathic and
steatogenic effect of HCV genotype 3 has been clearly
demonstrated (Rubbia-Brandt et al., 2000). There is a
growing body of observations indicating that HCV core
and NS5A proteins influence intracellular lipid
metabolism, increasing triglycerides synthesis and
impairing very low density lipoprotein secretion (Shi et
al., 2002; Tsutsumi et al., 2002). In addition, there is
experimental and clinical evidence that HCV enhances
reactive oxygen species production and lipid
peroxidation (Farinati et al., 1995; Okuda et al.,
2002), and promotes insulin resistance
(Shintani et al.,
2004). The
assignment of either of the two types of steatosis
(viral and metabolic) to a specific viral genotype is
not so clear cut (Negro, 2006).
The
impact of NAFLD on natural history and response to
treatment of CHC has been extensively studied. Steatosis
is a well known independent factor enhancing the rate of
fibrosis progression (Adinolfi et al., 2001; Hourigan et
al., 1999; Patton et al., 2004; Westin et al., 2002),
whereas its impact on the response rate to antiviral
therapy is a matter of debate (Bressler et al.,
2003; Fabris et al., 2005; Harrison et al., 2005; Lam
et al., 1994; Patton et al., 2004; Poynard et al., 2003;
Zeuzem et al., 2004; Ziol et al., 1996).
In the present study, we selected a cohort of patients
with no confounding factors (morbid obesity, diabetes
mellitus, alcohol consumption and advanced fibrosis)
with homogeneous therapeutic schedules; pegylated
interferon
α 2a was given in association
with ribavirin. The overall end treatment virologic
response to combined antiviral treatment was achieved in
61 cases (68.54%). Previous studies reported lower
response rates that range between 41% and 62.8% as they
assess the sustained virologic response (SVR) with
exclusion of relapsers (Fabris et
al., 2005; Harrison et al., 2005;
Patton et al., 2004;
Zeuzem et al., 2004;
Ziol et al., 1996).
On the other
hand, we assess the end treatment virologic response in
patients with mild to moderate stage of fibrosis (I-IV).
Our study confirms the previously reported association
between the extent of fibrosis, higher index of
pathohistological activity and the severity of steatosis
and steatohepatitis. The degree of hepatic steatosis may
be an important cofactor in both accelerating fibrosis
and increasing liver necroinflammatory activity in CHC
(Adinolfi et al., 2001). The severity of fat
accumulation correlates with activation of hepatic
stellate cells, thus steatosis per se may activate
fibrogenesis
(Poynard et al., 2003;
Ramesh
and Sanyal, 2004).
The
overall end treatment virologic response was
significantly higher (86.36%) in patients not affected
by NAFLD compared with 51% in group affected by NAFLD
(P=0.000) moreover, most of CHC patients with associated
NASH were nonresponders 72.72%.
In
accordance with previous reports, patients with HCV and
significant steatosis or steatohepatitis (NASH) have a
significantly reduced SVR to interferon (IFN)
monotherapy or combination therapy with IFN and
ribavirin (Fabris et al., 2005; Patton et al., 2004;
Zeuzem et al., 2004; Ziol et al., 1996). In a large
cohort of CHC patients, steatosis was found to be an
independent factor that reduces early virological
response, and lack of steatosis was associated with
higher likelihood of SVR (Fujie et al., 1999).
Appling the model of logistic regression analysis in
this study, NAFLD can be considered as independent risk
factor for poor response to combined pegylated
interferon
α 2a
plus ribavirin treatment (odds ratio 0.039, P=0.002).
At
variance with findings of the present study, other
authors reported the presence of steatosis did not alter
the response rate to standard antiviral therapy in
patients with hepatitis C, irrespective of its severity
(Bressler et al., 2003; Lam et al., 1994; Poynard et
al., 2001; Poynard et al., 2003).
In this
study, patients with hepatitis C and NAFLD have
significantly higher levels of aminotransferases (with
an AST/ALT ratio <1), some previous studies reported
similar results (Adinolfi et al., 2001; Fujie et al.,
1999; Giannini et al., 1999).
Cases
with BMI more than 30 kg/m2 were significantly
associated with lower chances for end treatment
virologic response (46.2%) compared with those with BMI
less than 30 kg/m2 (77.8%, P=0.011). It has been
hypothesized that the two intertwined factors obesity
and steatosis act independently on viral clearance.
Recent data indicates that both fat within hepatocytes
and BMI, better still, visceral obesity appear to
influence treatment response (Bressler et al., 2003;
Lonardo et al.,2004; Okuda et al., 2002).
CHC and
steatosis are common entities that can have interactive
synergistic effect on the liver. Steatosis is frequently
observed in CHC and seems to have a significant impact
on the natural history of the disease with respect to
development of fibrosis and reduction of virologic
response to current therapy (Patel et al., 2005).
In
summary, hepatic steatosis is detected in nearly one
half of studied patients with CHC, even when confounding
factors such as overweight, diabetes mellitus or alcohol
intake were excluded. Irrespective of its grade, NFALD
in hepatitis C is associated with a more severe disease
and reduced response rate to combined antiviral therapy.
Moreover, most of CHC patients with associated NASH were
nonresponders: raising a question about the value of
screening NASH prior to initiation of antiviral therapy.
References
Adinolfi LE,
Durante-Mangoni E, Zampino R, Ruggiero G. Review
article: hepatitis C virus-associated steatosis
pathogenic mechanisms and clinical implications. Aliment
Pharmacol Ther 2005; 22(S2): 52–5.
Adinolfi LE, Gambardella
M, Andreana A, Tripodi MF, Utili R, Ruggiero G.
Steatosis accelerates the progression of liver damage of
chronic hepatitis C patients and correlates with
specific HCV genotype and visceral obesity. Hepatology
2001 Jun; 33(6): 1358–64.
Afdhal NH. The natural
history of hepatitis C. Semin Liver Dis 2004; 24(Suppl.
2): 3–8.
Armstrong GL, Wasley A,
Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The
prevalence of hepatitis C virus infection in the United
States, 1992 through 2002. Ann Intern Med 2006 May;
144(10): 705–14.
Bressler BL, Guindi M,
Tomlinson G, Heathcote J. High body mass index is an
independent risk factor for nonresponse to antiviral
treatment in chronic hepatitis C. Hepatology 2003;38:
639–44. 37.
Brunt EM, Janney CG, Di
Bisceglie AM, Neuschwander-Tetri BA, Bacon BR.
Nonalcoholic steatohepatitis: a proposal for grading and
staging the histological lesions. Am J Gastroenterol
1999; 94: 2467-2474.
Castera L, Chouteau P,
Hezode C, Zafrani ES, Dhumeaux D, Pawlotsky JM.
Hepatitis C virus-induced hepatocellular steatosis. Am J
Gastroenterol 2005 Mar; 100(3): 711–5.
Chamberlain RW, Adams N,
Saeed AA, Simmonds P, Elliott RM Complete nucleotide
sequence of a type 4 hepatitis C virus variant, the
predominant genotype in the Middle East. J Gen Virol
1997;.78, 1341–1347.
Fabris P, Floreani A,
Carlotto A, Baldo V, Bozzola L, Giordani M. T., Negro
F, Rassu M, Tramarin A, de Lalla F. Impact of liver
steatosis on virological response in elderly Italian
patients with chronic hepatitis C treated with
peg-interferon alpha-2b plus ribavarin. Aliment
Pharmacol Ther 2005 Apr; 21(9): 1173–8.
Falck Ytter Y, Younossi
ZM, Marchesini G,
McCullough AJ. Clinical features and natural
history of nonalcoholic steatosis syndromes. Semin Liver
Dis 2001;21(1):17-26.
Farinati F, Cardin R, De
Maria N,
Della
Libera G,
Marafin C,
Lecis
E,
Burra
P,
Floreani A,
Cecchetto A,
Naccarato R. Iron storage, lipid peroxidation
and glutathione turnover in chronic anti-HCV positive
hepatitis. J Hepatol 1995 Apr; 22(4): 449–56.
Fiore G, Fera G, Napoli N,
Vella F, Schiraldi O. Liver steatosis and chronic
hepatitis C: a spurious association? Eur J Gastroenterol
Hepatol 1996 Feb.; 8(2): 125–9.
Fujie H, Yotsuyanagi H,
Moriya K,
Shintani Y,
Tsutsumi T,
Takayama T,
Makuuchi M,
Matsuura Y,
Miyamura T,
Kimura
S,
Koike
K. Steatosis and intrahepatic hepatitis C
virus in chronic hepatitis. J Med Virol 1999 Oct; 59(2):
141–5.
Giannini E, Ceppa P, Botta
F,
Fasoli
A,
Romagnoli P,
Cresta
E,
Venturino V,
Risso
D,
Celle
G,
Testa
R. Steatosis and bile duct damage in chronic
hepatitis C: distribution and relationships in a group
of Northern Italian patients. Liver 1999 Oct; 19(5):
432–7.
Guidi M, Muratori P,
Granito A, Muratori L, Pappas G, Lenzi and Bianchi F.
Hepatic steatosis in chronic hepatitis C: impact on
response to anti-viral treatment with peg-interferon and
ribavirin. Aliment Pharmacol Ther 2005; 22: 943–949.
Harrison SA, Brunt EM,
Qazi RA,
Oliver
DA,
Neuschwander-Tetri BA,
Di
Bisceglie AM,
Bacon
BR. Effect of significant histologic
steatosis or steatohepatitis on response to antiviral
therapy in patients with chronic hepatitis C. Clin
Gastroenterol Hepatol 2005 Jun; 3(6): 604–9.
Hourigan LF, Macdonald
GA, Purdie D Whitehall VH, Shorthouse C, Clouston A,
Powell EE. Fibrosis in chronic hepatitis C correlates
significantly with body mass index and steatosis.
Hepatology 1999 Apr; 29(4): 1215–9.
Hubscher SG. Histological
assessment of non-alcoholic fatty liver disease.
Histopathology 2006 Nov., 49(5), 450–465.
Hui JM, Kench J, Farrell
GC,
Lin R,
Samarasinghe D,
Liddle
C,
Byth K,
George
J. Genotype-specific mechanisms for hepatic
steatosis in chronic hepatitis C infection. J
Gastroenterol Hepatol 2002 Aug; 17(8): 873–81.
Hwang SJ, Luo JC, Chu CW,
Lai CR,
Lu CL,
Tsay
SH,
Wu JC,
Chang
FY,
Lee SD.
Hepatic steatosis in chronic hepatitis C virus
infection: prevalence and clinical correlation. J
Gastroenterol Hepatol 2001 Feb;16(2): 190–5.
Ishak K, Baptista A,
Bianchi L,
Callea
F,
De
Groote J,
Gudat
F,
Denk H,
Desmet
V,
Korb G,
MacSween RN. Histological grading and staging
of chronic hepatitis. J Hepatol 1995 Jun.; 22(6): 696–9.
Lam NP, DeGuzman LJ,
Pitrak D, Layden TJ. Clinical and histologic predictors
of response to interferon-alpha in patients with chronic
hepatitis C viral infection. Dig Dis Sci 1994; 39:
2660–4.
Lonardo A, Adinolfi LE,
Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and
hepatitis C virus: mechanisms and significance for
hepatic and extrahepatic disease. Gastroenterology 2004
Feb.; 126(2): 586–97.
Lonardo a, Loria P,
Adinolfi LE, Ruggiero G, Carulli N. Fat in HCV: does it
matter? Monothematic Conference”Non-alcoholic
steatohepatitis: from cell biology to clinical practice”
EASL (ed), Estoril, 2004: 56-60.
Marcellin P, Asselah T,
Boyer N. Fibrosis and disease progression in hepatitis
C. Hepatology 2002; 36: S47–S56.
Ming-Lung Yu, Wan-Long
Chuang L, Chia-Yen DAI, Shinn-Cherng Chen L, Zu-Yau Lin,
Ming-Yuh Hsieh, Liang-Yen Wang , Wen-Yu Chang. Clinical
Evaluation of the Automated COBAS Amplicor HCV monitor
test Version 2.0 for Quantifying Serum Hepatitis C Virus
RNA and Comparison to the Quantiplex HCV Version
2.0 Test. J Clin Microbiol. 2000 Aug; 38 (8): 2933–39.
Murray KF, Carithers RL
Jr. AASLD practice guidelines: evaluation of the patient
for liver transplantation. Hepatology 2005 Jun; 41(6):
1407–32.
Negro F: Mechanisms and
significance of liver steatosis in hepatitis C virus
infection. World J Gastroenterol 2006; 12: 6756–6765.
Okuda M, Li K, Beard MR,
Showalter LA; Scholle F; Lemon SM; Weinman SA.
Mitochondrial injury, oxidative stress, and antioxidant
gene expression are induced by hepatitis C virus core
protein. Gastroenterology 2002 Feb.; 122(2): 366–75.
Patel K, Zekry A,
McHutchison JG: Steatosis and chronic hepatitis C virus
infection: mechanisms and significance. Clin Liver Dis
2005; 9: 399–410.
Patton HM, Patel K,
Behling C,
Bylund
D,
Blatt
LM,
Vallée
M,
Heaton
S,
Conrad
A,
Pockros PJ,
McHutchison JG. The impact of steatosis on
disease progression and early and sustained treatment
response in chronic hepatitis C patients. J Hepatol 2004
Mar; 40(3): 484–90.
Petit JM, Benichou M,
Duvillard L,
Jooste
V,
Bour
JB,
Minello A,
Verges
B,
Brun
JM,
Gambert P,
Hillon
P. Hepatitis C virus-associated
hypobetalipoproteinemia is correlated with plasma viral
load, steatosis, and liver fibrosis. Am J Gastroenterol
2003 May; 98(5): 1150–4.
Poynard T, Ratziu V,
Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates
and risk factors of liver fibrosis progression in
patients with chronic hepatitis C. J Hepatol 2001 May;
34(5): 730–9.
Poynard T, Ratziu V,
McHutchison J,
Manns
M,
Goodman Z,
Zeuzem
S,
Younossi Z,
Albrecht J. Effect of treatment with
peginterferon or interferon alfa-2b and ribavirin on
steatosis in patients infected with hepatitis C.
Hepatology 2003 Jul; 38(1): 75–85.
Ramesh S, Sanyal AJ.
Hepatitis C and nonalcoholic fatty liver disease. Semin
Liver Dis 2004; 24: 399–413.
Ray SC, Arthur RR, Carella
A, Bukh J, Thomas DL Genetic epidemiology of hepatitis
C virus throughout Egypt. J Infect Dis 2000;.182,
698–707.
Rubbia-Brandt L, Quadri R,
Abid K,
Giostra E,
Malé
PJ,
Mentha
G,
Spahr
L,
Zarski
JP,
Borisch B,
Hadengue A,
Negro
F. Hepatocyte steatosis is a cytopathic
effect of hepatitis C virus genotype 3. J Hepatol 2000
Jul; 33(1): 106–15.
Seeff LB. Natural history
of chronic hepatitis C. Hepatology 2002; 36: S35–S46.
Serfaty L, Andreani T,
Giral P, Carbonell N, Chazouilleres O, Poupon R.
Hepatitis C virus induced hypobetalipoproteinemia: a
possible mechanism for steatosis in chronic hepatitis C.
J Hepatol 2001 Mar.; 34(3): 428–34.
Sharma P, Balan V,
Hernandez J,
Rosati
M,
Williams J,
Rodriguez-Luna H,
Schwartz J,
Harrison E,
Anderson M,
Byrne
T,
Vargas
HE,
Douglas DD,
Rakela
J. Hepatic steatosis in hepatitis C virus
genotype 3 infection: does it correlate with body mass
index, fibrosis, and HCV risk factors? Dig Dis Sci 2004
Jan; 49(1): 25–9.
Shi ST, Polyak SJ, Tu H,
Taylor DR, Gretch DR, Lai MM. Hepatitis C virus NS5A
colocalizes with the core protein on lipid droplets and
interacts with apolipoproteins. Virology 2002; 292:
198–210.
Shiffman ML. Natural
history and risk factors for progression of hepatitis C
virus disease and development of hepatocellular cancer
before liver transplantation. Liver Transpl 2003; 9:
S14–S20.
Shintani Y, Fujie H,
Miyoshi H,
Tsutsumi T,
Tsukamoto K,
Kimura
S,
Moriya
K,
Koike
K. Hepatitis C virus infection and diabetes:
direct involvement of the virus in the development of
insulin resistance. Gastroenterology 2004 Mar.; 126(3):
840–8.
Simmonds P, Holmes EC, Cha
TA, Chan SW, McOmish F, Irvine B, Beall E, Yap PL,
Kolberg J, Urdea MS Classification of hepatitis C virus
into six major genotypes and a series of subtypes by
phylogenetic analysis of the NS-5 region. J Gen Virol
1993; 74, 2391–2399.
Sulkowski MS, Mast EE,
Seeff LB, Thomas DL. Hepatitis C virus infection as an
opportunistic disease in persons infected with human
immunodeficiency virus. Clin Infect Dis 2000; 30(Suppl.
1): S77–S84.
Tsutsumi T, Suzuki T,
Shimoike T,
Suzuki
R,
Moriya
K,
Shintani Y,
Fujie
H,
Matsuura Y,
Koike
K,
Miyamura T. Interaction of hepatitis C virus
core protein with retinoid X receptor alpha modulates
its transcriptional activity. Hepatology 2002 Apr;
35(4): 937–46.
Violante MD and
Nunez-Nateras R:Epidemiology of Hepatitis Virus B & C.
Archives of Medical Research 2007;38:606 – 611.
Westin J, Nordlinder H,
Lagging M, Norkrans G, Wejstal R. Steatosis accelerates
fibrosis development over time in hepatitis C virus
genotype 3 infected patients. J Hepatol 2002 Dec; 37(6):
837–42.
Younossi ZM, Gramlich T,
Liu YC,
Matteoni C,
Petrelli M,
Goldblum J,
Rybicki L,
McCullough AJ. Nonalcoholic fatty liver
disease: assessment of variability in pathologic
interpretations. Mod Pathol 1998 Jun; 11(6): 560–5.
Zeuzem S, Hultcrantz R,
Bourliere M,
Goeser
T,
Marcellin P,
Sanchez-Tapias J,
Sarrazin C,
Harvey
J,
Brass
C,
Albrecht J. Peginterferon alfa- 2b plus
ribavirin for treatment of chronic hepatitis C in
previously untreated patients infected with HCV
genotypes 2 or 3. J Hepatol 2004 Jun; 40(6): 993–9.
Ziol M, Nhieu JT,
Roudot-Thoraval F,
Métreau JM,
Deugnier Y,
Dhumeaux D,
Zafrani ES. A histopathological study of the
effects of 6-month versus 12-month interferon alpha-2b
therapy in chronic hepatitis C. J Hepatol 1996 Dec;
25(6): 833–41. |
|
|
