Body mass index, hepatic fibrosis and inflammation in chronic
hepatitis C: a retrospective study
El- Badawy RM. MD, Abdo S.A MD, Glalal Mawad MD,
Magdy A. Gad, Entesar H. El-Sharqawy MD,
Amin H. MD, Aza A. Senna MD,
Dept. pf heptology, gastroenterology and Clinical pathology Department
Benha Faculty of Medicine – Zagazig University
Abstract:
The factors that contribute to histological progression of liver disease in HCV
are still under investigation. The aim of this study is to evaluate the impact of "Body
Mass Index" (BMI) as a measure of obesity on the outcome of chronic HCV infection.
The present study retrospectively included 30 consecutive patients from the
department of hepatology, gastroenterology and infectious disease at Benha university
hospitals between June 2003 and April 2004. Patients included 24 ♂ and 6 ♀ with age
range from 25-70 years and BMI between 20-36 kg/m2. The patients were grouped
into 2 groups not obese and obese (13/30 and 17/30) respectively. Three factors were
identified as independently influencing prognosis: age, BMI and serum ALT. The
relative risk of developing advanced fibrosis in obese group is 13 folds the non-obese
patients. In conclusion despite the limitations of cross sectional studies, the relative
risk of fibrosis progression related to BMI in our analysis as well as in the literature is
probably indisputable. However, further longitudinal cohort studies are needed to
confirm the current consensus.
Introduction:
The majority of cases of
primary hepatitis C virus (HCV)
infection result in persistent viraemia.
Progression to cirrhosis marks the
onset of risk for complications such as
liver failure and hepatocellular
carcinoma. However, while liver
disease progression appears more
indolent than previously reported, it is
highly variable (2). Identifying factors
that influence outcome is important in
order to counsel individuals regarding
prognosis and facilitate decisions
related to clinical management. A
number of factors have been proposed
as promoting HCV-related liver
fibrosis. These include: host ethnicity,
gender, obesity, alcohol consumption,
smoking, age at infection, mode of
HCV acquisition, serum transaminase
levels,
histological
grade
of
inflammation,
co-infection
with
hepatitis B virus (HBV) or HIV, HCV
genotype, viral load and quasi species
diversity (1).
The aim of the present study is
to evaluate the impact of "Body Mass
Index" (BMI) as a measure of obesity
on the outcome f chronic hepatitis C
virus infection and to compare this
impact with that of other pertinent
historical, biochemical and virological
parameters.
Patients and methods
Patient selection:
The
present
study
retrospectively
included
30
consecutive
patients
from
the
Department
of
hepatology
gastroenterology
and
infectious
diseases at Benha University hospitals
between June 2003 and April 2004.
Patients were included in the study if:
(1) positive for HCV RNA reverse
transcription polymerase chain reaction
(RT-PCR); (2) a liver biopsy is
available; (3) had no history of alcohol
use; (4) negative serology for hepatitis
B surface antigen; (5) absence of other
causes of prior anti-HCV treatment;
and (6) no history of hepatic
decompensation defined as the
presence of ascites, jaundice (total
bilirubin > 3 mg/dL), variceal
bleeding, or hepatic encephalopathy (3).
Methods and data collection:
Data collected included age,
gender, risk factors for acquiring HCV
infection
(specifically:
blood
transfusion, dental treatment, previous
surgical operations) and BMI. Patients
with a BMI between 25 and 29.9 kg/m2
were categorized as overweight, and
patients with a BMI >30 kg/m2 were
categorized as obese (9).
Quantitative HCV RNA PCR
was performed in all patients, and
HCV genotyping was carried out (22).
Routine laboratory data included
complete blood counts, albumin,
alanine
aminotransferase
(ALT),
aspartate aminotransferase (AST) and
prothrombin time (PT). All patients
underwent abdominal ultrasonography
to rule out hepatocellular carcinoma. In
all patients, ultrasonography was used
to measure spleen size; a maximal
spleen dimension of more than 13 cm
indicated splenomegaly.
Hepatic histology
Hematoxylin-eosin
and
trichrome stainings were used for
histology
assessment.
Knodell's
scoring system was used to stage
hepatic fibrosis (16). While stage 0
represented the absence of hepatic
fibrosis, stage III/IV represented
advanced hepatic fibrosis. HAI (i.e.
total Knodell score-fibrotic score) was
used to grade activity of CHC (16). In
the present study, an HAI of more than
7 was considered active liver injury (5,
12 & 19)
.
Statistical analysis
The descriptive data were
presented as percentage or mean with
standard deviation or range. Either
Chi-square test, Fisher's Exact Test.
Student's t-test, or analysis of variance
test was used to compare frequencies
or means, respectively. Both univariate
test was used to compare frequencies
or means, respectively. Both univariate
and multivariate analysis were used
and the odds ratios were calculated by
using Logistic regression model.
Multiple univariate analysis were
carried out to determine the risk factors
for and association of CHC activity
with BMI. A P value of < 0.05 was
considered as statistically significant.
Results
Baseline demographic findings
The baseline demographic data are summarized in Table 1. Of the 30 patients
with recorded BMI, the mean BMI was 28.4 ± 4.9 (20-36) kg/m2. Obesity was seen in
17/30 (56.7%) patients. Overall, 23/30 (76.7%) patients were overweight or obese.
Histologically, 10 (33.3%) had stages III or IV fibrosis, while 20 (66.7%) had
stages I and II fibrosis. In the present study, patients with stages III and IV fibrosis
were combined as a group with advanced firbrosis; and patients with stages I and II
were combined as a group with mild fibrosis. Of the 30 patients with recorded HAI,
the median grade was 2. Seven (23.3%) had HAI grade I; 14 (46.7%) had HAI grade
II; 7 (23.3%) grade III and 2 (6.7%) had grade IV.
Table (1): Features of 30 enrolled patients
46.6 ± 8.2 (25-58)
24:6
28.8 ± 4.9 (20-36)
17 (56.7%)
23 (76.7%)
1.15±0.4mg/dL (0.7-2.1)
4.1±0.4g/dL (3.2-5.0)
98.9±54.1 IU/L (45-271)
70.2±27.9 IU/L (30-130)
12.9±0.8s (11-15)
11 (36.7%)
9 (30.0%)
5 (16.7%)
5 (16.7%)
Age, yr (mean ± SD) (Range)
Sex (M:F)
BMI (mean ± SD) (Range)
Obesity (BMI>30)%
Overweight (BMI>25) (%)
Bilirubin (mean ± SD) (Range)
Albumin (mean ± SD) (Range)
ALT (mean ± SD) (Range)
AST (mean ± SD) (Range)
PT (mean ± SD) (Range)
Fibrosis
1
2
3
4
Necro-inflammation
1
2
3
4
Genotype
Type 1
Type 4
Viral Load (mean ± SD) (Range)
7 (23.3%)
14 (46.7%)
7 (23.3%)
2 (6.7%)
1 (3.3%)
29 (96.7%)
751710.1±1155749.1 (1000-4401000)
Table (2): Comparison between the MILD and ADVANCED fibrosis groups.
AGE
HB
WBCS
PLATELET
BILIRUBIN
ALBUMIN
PT
ALT
AST
PCR
BMI
FIBROSIS
N
Mean
SD
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
Mild
Advanced
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
38.85
50.30
14.02
14.25
7175.00
6810.00
240450
200100
1.06
1.34
4.22
3.92
12.66
13.27
83.20
130.40
63.65
83.20
764669.00
725792.30
27.05
32.40
8.67
4.62
1.16
1.87
2351.46
2786.26
65630
39515
0.41
0.33
0.44
0.41
0.76
0.82
53.45
41-88
25.79
28.66
1296386.82
868913.18
4.807
2.413
P Value
0.001
0.681
0.709
0.086
0.066
0.089
0.052
0.021
0.070
0.933
0.003
Patients with advanced fibrosis had higher age mean, ALT and BMI (Table 2).
Table (3): Logistic univariate regression analysis of all variables for the prediction
of advanced fibrosis
AGE
BMI
ALT
PT
BILIRUBIN
AST
PLATELET
ALBUMIN
HB
WBCS
PCR
OR (95% CI)
P Value
1.43 (1.06-1.47)
1.44 (1.07-1.94)
1.02 (1.00-1.04)
2.78 (0.93-8.31)
6.37 (0.82-49.74)
1.03 (0.99-1.06)
1.00 (0.99-1.001)
0.19 (0.02-1.38)
1.13 (0.65-1.97)
0.99 (0.98-1.00)
1.00 (0.99-1.001)
0.007
0.016
0.046
0.067
0.077
0.082
0.094
0.099
0.669
0.698
0.929
Table (3) summarizes results of univariate regression analysis of eleven
clinical virological, and biochemical parameters as possible risk factors for advanced
hepatic fibrosis. It revealed that being overweight/obese (i.e. BMI >25 kg/m2) with
elevated ALT eventually constitutes with the advancement in age a statistically
significant risk factor for the development of grades III/IV hepatic fibrosis. Unvariate
analysis (Table 3) did not reveal association of the level of viral load with hepatic
fibrosis. In this study, the number of cases with genotype other than 4 was not
statistically adequate to draw any conclusions as regards the role of genotyping in the
development of irreversible stages of chronic liver disease.
Table (4) showing the distribution of cases with advanced (Stages III/IV)
fibrosis among obese and non-obese patients. It is clear that the difference is
statistically significant. Moreover, from the same table it is possible to calculate the
relative risk of developing advanced fibrosis in an obese patient with HCV as 2.25
(95% CI of 1.27-3.99). In contrast, the relative risk in a non-obese patient is only 0.17
(95% CI of 0.008-0.704) (P < 0.05).
Table (4): Comparison between obese and non-obese patients as regards the stage
of hepatic fibrosis:
Mild Fibrosis
Advanced Fibrosis
Total (%)
Not Obese
Obese
Total (%)
P Value
12
1
13 (43.3%)
8
9
17 (56.7%)
20 (66.7%)
10 (33.3%)
0.0268
Table (5): Comparison between obese and non-obese patients the grade of hepatic
necro-inflammation (HAI):
Mild
Severe
Total (%)
Not Obese
Obese
Total (%)
P Value
12
1
13 (43.3%)
9
8
17 (56.7%)
21 (70%)
9 (30%)
0.0417
Furthermore, obesity was also significantly associated with a higher HAI
(Table 5), a histological indicator of active CHC (14). These data indicate that in
patients with CHC, a higher BMI is more associated with an active and progressive
CHC.
Discussion:
This study examined factors
associated with progression to cirrhosis
in people with chronic HCV infection.
Following statistical analysis of factors
associated with disease progression,
three were identified as independently
influencing prognosis: age, BMI, and
serum ALT level (Table 2 and 3).
Age of the patient at the time of
infection has consistently been
associated with more rapid progression
to cirrhosis in patients with chronic
HCV infection. A number of studies
have demonstrated that subjects
infected at an older age develop
cirrhosis over a shorter period (6). In a
high endemicity area like Egypt, a
major proportion of the population at
risk are exposed to infection early in
their life.
Therefore, more advanced liver
disease is significantly more prevalent
among older age groups (Table 2 and
3). Children with chronic HCV
infection have been shown to have
disproportionably low rates of fibrosis
progression (11). Serum transaminase
levels fluctuate significantly in patients
with chronic HCV infection and poorly
predict the extent of liver damage (17).
However,
recent
studies
have
demonstrated
slower
disease
progression rates for chronic HCVinfected patients with persistently
normal ALT levels compared to
patients with elevated ALT levels (10).
The results of the present study support
an independent association between
elevated serum ALT levels and
increased risk of progression to
cirrhosis (Table 2 and 3).
It is unclear whether viral
factors, such as virulence of the
infecting viral genotype, viral load and
quasi species diversity, impact on the
development of HCV-related cirrhosis,
Infection with HCV genotype I,
particularly subtype 1b- has been
reported to increase the rate of
progression to HCV- related cirrhosis
(22)
. Rather than a direct effect
attributable to HCV genotype, it may
be that genotype prevalence is
changing,
other
genotypes
are
becoming more common and patients
with genotype 1b have simply been
infected for longer. Studies that have
considered other factors related to
disease progression have typically
failed to find any association between
HCV genotype and cirrhosis (10). The
analysis reported here was unable to
examine the impact of viral genotype
on
HCV-related
liver
disease
progression because only one patient
had genotype 1.
Progression to cirrhosis has
also been associated with higher serum
viral load in some studies (4). In the
analysis reported here, viral load
showed no identifiable impact on
disease progression. This is in
agreement with recent evidence
suggesting that viral load does not
influence disease progression in
chronic HCV infection (18).
In the present study, BMI
proved to be an independent risk factor
for the development of hepatic fibrosis
(Tables 2, 3 and 4). The relative risk of
developing advanced fibrosis in an
obese patient with HCV is 13 folds the
relative risk in non-obese patient. The
mechanism
by
which
obesity
contributes to HCV progression is
unclear.
Several
pathogenetic
mechanisms might be involved,
including steatosis, steatohepatitis,
leptin, insulin resistence and genetic
factors. Steatosis is a common
histological finding occurring in more
than 50% of patients with chronic
hepatite C. In patients with viral
genotype 3, steatosis may be a
cytopathic effect of the virus (7). In at
least a proportion of patients with
HCV the pathogenesis of steatosis
appears to be the same as for patients
with non-alcoholic fatty liver disease,
i.e., related to visceral adiposity and
elevated to visceral adiposity and
elevated circulating insulin levels. A
highly significant relationship between
steatosis and body mass index (BMI)
in patients with untreated chronic HCV
was established in previous studies (12 &
19)
. These studies also revealed a
significant
relationship
between
steatosis
and
hepatic
fibrosis,
suggesting that in chronic HCV,
steatosis plays a role in disease
progression. In support of this
Hichman(7) showed that weight loss is
associated with an improvement in
liver histology and biochemistry in
patients with chronic HCV (14). In
conditions such as non-alcoholic
steatohepatitis and alcoholic liver
disease, steatosis is associated with the
development of acinar inflammation
(7)
. In this work, obesity was also found
to be significantly associated with
hepatic necro-inflammation (Table 5).
Similar to alcohol-related liver disease,
steatosis is associated with an
increased production of reactive
oxygen species resulting in lipid
peroxidation and activation of hepatic
stellate cells. The mechanism for this is
not precisely known although recently,
steatosis has been shown to alter the
expression of mitochondrial membrane
proteins, including uncoupling protein2 (6). This protein has been implicated
in the generation of reactive oxygen
species and lipid metabolism (3). Other
studies have suggested a role for leptin
and insulin in the relationship between
obesity and fibrosis. Serum levels of
these hormones are increased in the
circulation of obese individuals.
Exogenous leptin enhanced the
inflammatory
and
profibrogenic
responses in the liver caused by
hepatotoxic chemicals (15). In another
study, insulin significantly stimulated
connective tissue growth factor
(CTGF) mRNA in hepatic stellate cells
(20)
CTGF is a factor involved in the
fibrogenic process of various tissues,
and is up-regulated in patients with
obesity-related fatty liver disease.
Despite the limitations of crosssectional studies, the relative risk of
fibrosis progression related to BMI in
our analysis as well as in the literature
is probably indisputable.
However,
further
models
particularly based upon longitudinal
cohort studies are needed to confirm
the current consensus and predict
future risk of disease progression.
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‫دراسة زمنية لمعدل وزن كتلة الجسم والتليف وااللتهاب الكبدى فى حاالت االلتهاب‬
‫الفيروسى المزمن (سى)‬
‫رضا البدوى‪ ،‬صبرى أنيس عبده‪ ،‬جالل معوض محمد‪ ،‬مجدى جاد‪،‬‬
‫انتصار الشرقاوى‪ ،‬حسام أمين‪ ،‬عزة أبو سنة*‬
‫قسم أمراض الكبد والجهاز الهضمى واألمراض المعدية و قسم الباثولوجيا اإلكلينيكية*‬
‫كلية طب بنها – جامعة الزقازيق‬
‫إن الطبيعة المرضية لفيروس (سى) وكذلك العوامل التى تؤدى إلى تقدم الفيروس فى أنسجة الكبدد غيدر‬
‫معروفة ومازالت قيد البحث‪ .‬وقد قام قسم الكبد والجهاز الهضمى واألمراض المعدية بكلية طد‬
‫بنهدا بعمدل د ارسدة‬
‫عن ذلك‪ ،‬ووجدد مدن نتداال البحدث أن ‪ 3‬عوامدل‪ :‬هدى عمدر المدرعض عندد إهدابتف بدالفيروس ووزندف ومعدد ارتفدا‬
‫خمداار الكبددد ‪ ،ALT‬هدى العوامددل الثةثددة التددى لهددا عةقددة وثيقددة بتليددو الكبددد وتقدددم الحالددة المرضددية ولددذا نوهددى‬
‫بعمل المزعد من الدراسات للتأكد من ذلك واكتشاف المزعد من العوامل األخرى‪.‬‬