Metabolic Factors / NAFLD
on the Natural History of
Chronic Hepatitis B or C in
Asia
Pei-Jer Chen
National Taiwan University &
Hospital
HBV or
HCV
Hepatic
steatosis
Insulin
resistance
Metabolic
Factors
Flow chart of the REVEAL cohort
23820 cohort members (11973 males
and 11847 females), recruited in 1991
4155 HBsAg sero-positive
(2445 males and 1710
females)
HBV
DNA
TG.
Chole.
19665 HBsAg sero-negative
(9528 males and 10137
females--- anti HCV assay
HCV
RNA
DM
Cross-Section Study: CHB/CHC
versus Control in terms of
Metabolic Factors
A study of base-line data in the
REVEAL cohort
Metabolic factors:
Obesity
Central obesity: waist circumferences >90 cm for men
and >80 cm for women.
Body Mass Index: normal weight BMI< 23 kg/m2
overweight 23 < BMI < 25 kg/m2
obese 25 < BMI < 30 kg/m2
morbid obese BMI > 30 kg/m2
Hypercholesterolemia: total cholesterol > 240
mg/dL
Hypertriglyceridemia: TG > 150 mg/dL
History of DM
History of hypertension
Table . Multivariate-adjusted odds ratios of being HBsAg seropositive in
relation to selected metabolic factors
Risk Factors
Triglyceride
> 150 vs. < 150
OR (95% CI)*
0.61 (0.55 – 0.66)
0.60 (0.55 – 0.66)
Total cholesterol
> 240 vs. < 240
0.92 (0.81 – 1.05)
0.92 (0.81 – 1.05)
Body Mass Index
23 – 24.9 vs. <23
25 – 29.9 vs. <23
> 30 vs. <23
P for trend
OR (95% CI)*
1.06 (0.97 – 1.16)
1.09 (1.00 – 1.19)
1.21 (1.01 – 1.45)
0.01
Central obesity
Yes vs. No
1.13 (1.04 – 1.23)
History of DM
Yes vs. No
1.30 (0.98 – 1.74)
History of hypertension
Yes vs. No
0.98 (0.8 – 1.19)
1.32 (0.99 – 1.75)
0.98 (0.80 – 1.19)
HBV Infection does not Correlates with
the Development of NAFL or IR (1)
Author
Setting
Populatio
n
Results
Remarks
Moucari
(2008)
Crosssectional
500 CHC,
100 CHB
IR: 5% in CHB and 35% in CHC
Not matched
Wang
(2007)
Health
examinatio
n
50 CHB
and 457
controls
HBV carriers not associated with IR or
FL
Small sample
size
Mohamma
d (2006)
Case
control
60 CHC
and 40
CHB
HOMA-IR associated with fibrosis in
CHC, but not in CHB
Selection bias,
small size
Tsochatzi
s (2007)
Case
series
213 eAgve CHB
Hepatic steatosis less frequent in CHB
than in CHC; associated with metabolic
factors
Selection bias,
not
representative
Cindoruk
(2007)
Treatment
cohort
140 CHB
Presence of steatosis not associated
with HBV load
Selection bias,
not
representative
Demir
(2007)
Case
series
49 eAg-ve
CHB
NAFLD: most common cause of
elevated ALT in patients with CHB
Selection bias,
small size
Moucari et al, Gastroenterology 2008; Wang et al, JGH 2007; Mohammad et al, Indian J
HBV Infection does not Correlates with
the Development of NAFL or IR (2)
Author
Setting
Populatio
n
Results
Remarks
Persico
(2009)
Cohort
726 CHC,
126 CHB
Age and BMI correlate with steatosis in
CHB
Selection
bias
Yun
(2009)
Liver
biopsy
series
86 young
male CHB
Steatosis associated with TG level and
HOMA IR
Small
sample size
Imazeki
(2008)
Case
series
544 CHC,
286 CHB,
122
controls
IR in CHB (36%) similar to controls (36%), Selection
but lower than in CHC (54%)
bias, not
matched
Kumar
Case
control
69 CHC
and 50
healthy
controls
HOMA-IR associated with BMI, but not
CHB itself
(2009)
Selection
bias, small
size
Persico et al, World J Gastroenterol 2009; Yun et al, Liver Int 2009; Kumar et al, Am J
Gastroenterol 2009; Imazeki et al, Liver Int 2008
Summary
Obesity, history of diabetes : Prevalence
not increase in HBsAg sero-positive
subjects
TG>150:
in HBsAg sero-positive cases
Metabolic factors and Hepatitis
C infection
Relationship with anti-HCV status and
HCV RNA levels cross-section
Table . Multivariate-adjusted Odds Ratios of being anti-HCV seropositive
relation to selected risk factors
Risk Factors
Triglyceride
> 150 vs. < 150
OR (95% CI)*
0.60 (0.51 – 0.70)
0.60 (0.51 – 0.70)
Total cholesterol
> 240 vs. < 240
0.89 (0.71 – 1.10)
0.89 (0.71 – 1.10)
Body Mass Index
23 – 24.9 vs. <23
25 – 29.9 vs. <23
> 30 vs. <23
P for trend
OR (95% CI)*
0.95 (0.80 – 1.12)
1.07 (0.92 – 1.25)
1.18 (0.89 – 1.56)
0.01
Central obesity
Yes vs. No
1.13 (0.98 – 1.30)
History of DM
Yes vs. No
1.56 (1.05 – 2.33)
1.59 (1.06 – 2.37)
History of hypertension
Yes vs. No
1.13 (0.85 – 1.51)
1.13 (0.85 – 1.51)
Summary
Obesity, Diabetes : Increased in anti-HCV
seropositive cases.
TG<150:
anti-HCV seropositive
Serum triglyceride level, total cholesterol
level and body mass index are inversely
correlated with HCVRNA viral load
Huh-7 cells transfected with JFH1
RNA
NATURE CELL BIOLOGY 2007; 9:961-9
HCV and Lipids
Negro and Sanyal. Liver Int 2009;29:26
Flow chart of the REVEAL cohort
23820 cohort members (11973
males and 11847 females)
4155 HBsAg sero-positive
(2445 males and 1710
females)
218 anti-HCV
seropositive
3931 anti-HCV
seronegative
19665 HBsAg sero-negative
(9528 males and 10137
females)
1095 anti-HCV
seropositive
18541 anti-HCV
seronegative
10 years follow-up
HCC n=187
LC n=429
LC death n=57
Liver death n=212
HCC n=51
LC death n=16
Liver death n=74
HCC n=53
LC death n=61
Liver death n=108
Metabolic factors and Incident
Hepatocellular Carcinoma (HCC)
Table. Multivariate-adjusted relative risks of HCC in relation to selected
risk factors stratified by HBV and HCV infection status
HBsAg (+) and anti-HCV (-)
(N=3931; HCC=187)
RR (95% CI)*
RR (95% CI)*
Risk Factors
Triglyceride
> 150 vs. < 150
0.60 (0.40 – 0.89)
0.60 (0.40 – 0.90)
Total cholesterol
> 240 vs. < 240
1.14 (0.68 – 1.91)
1.13 (0.67 – 1.91)
Body Mass Index
23 – 24.9 vs. <23
25 – 29.9 vs. <23
> 30 vs. <23
P for trend
1.40 (0.97 – 2.02)
1.17 (0.81 – 1.69)
1.36 (0.64 – 2.89)
0.317
Central obesity
Yes vs. No
1.33 (0.96 – 1.85)
History of DM
Yes vs. No
2.27 (1.10 – 4.66)
2.41 (1.17 – 4.95)
History of hypertension
Yes vs. No
0.43 (0.16 – 1.18)
0.45 (0.16 – 1.21)
Table. Multivariate-adjusted relative risks of HCC in relation to selected
risk factors stratified by HBV and HCV infection status
HBsAg (-) and anti-HCV (+)
(N=1095; HCC=51)
RR (95% CI)*
RR (95% CI)*
Risk Factors
Triglyceride
> 150 vs. < 150
0.63 (0.30 – 1.32)
0.61 (0.29 – 1.28)
Total cholesterol
> 240 vs. < 240
0.16 (0.02 – 1.20)
0.17 (0.02 – 1.25)
Body Mass Index
23 – 24.9 vs. <23
25 – 29.9 vs. <23
> 30 vs. <23
P for trend
1.05 (0.41 – 2.73)
3.02 (1.48 – 6.14)
4.13 (1.38 – 12.4)
<0.001
Central obesity
Yes vs. No
2.16 (1.19 – 3.92)
History of DM
Yes vs. No
3.25 (1.0 – 8.85)
History of hypertension
Yes vs. No
0.91 (0.31 – 2.67)
3.52 (1.29 – 9.24)
0.83 (0.28 – 2.44)
Table. Relative risks of HCC by HBsAg, anti-HCV serological status, obesity
and history of diabetes mellitus (DM)
Serum Hepatitis Markers
Status
HBsAg (-) anti-HCV (-)*
HBsAg (-) anti-HCV (-)
HBsAg (+) anti-HCV (-)
HBsAg (+) anti-HCV (-)
HBsAg (-) anti-HCV (+)
HBsAg (-) anti-HCV (+)
¥
HBsAg (-) anti-HCV (-)
HBsAg (-) anti-HCV (-)
HBsAg (+) anti-HCV (-)
HBsAg (+) anti-HCV (-)
HBsAg (-) anti-HCV (+)
HBsAg (-) anti-HCV (+)
Metabolic Factors
Relative Risk
(95% CI)
1.00
2.50 (0.99 – 6.32)
19.9 (14.3 – 27.6)
22.0 (10.3 – 46.9)
15.7 (10.4 – 23.8)
34.5 (13.5 – 87.6)
BMI<30
BMI>30
BMI<30
BMI>30
BMI<30
BMI>30
DM (-)
DM (+)
DM (-)
DM (+)
DM (-)
DM (+)
1.00
3.49 (1.08 – 11.3)
18.7 (13.6 – 25.9)
43.5 (20.5 – 92.3)
15.0 (9.95 – 22.5)
60.3 (23.6 – 153.6)
Table. Relative risks of HCC by HBsAg, anti-HCV serological status,
obesity and history of diabetes mellitus (DM)
Serum Hepatitis Markers
Status
HBsAg (-) anti-HCV (-)?
HBsAg (-) anti-HCV (-)
HBsAg (-) anti-HCV (-)
HBsAg (-) anti-HCV (-)
HBsAg (+) anti -HCV (-)
HBsAg (+) anti -HCV (-)
HBsAg (+) anti -HCV (-)
HBsAg (+) anti -HCV (-)
HBsAg (-) anti-HCV (+)
HBsAg (-) anti-HCV (+)
HBsAg (-) anti-HCV (+)
HBsAg (-) anti-HCV (+)
Metabolic Factors
BMI<30
BMI>30
BMI<30
BMI>30
BMI<30
BMI>30
BMI<30
BMI>30
BMI<30
BMI>30
BMI<30
BMI>30
DM (-)
DM (-)
DM (+)
DM (+)
DM (-)
DM (-)
DM (+)
DM (+)
DM (-)
DM (-)
DM (+)
DM (+)
Relative Risk
(95% CI)
1.00
2.81 (1.11 – 7.12)
4.39 (1.35 – 14.3)
?
-20.6 (14.7 – 29.0)
20.4 (9.13 – 45.6)
43.0 (19.3 – 96.1)
264.7 (35.2 – 1993)
15.7 (10.2 – 24.1)
33.6 (12.0 – 94.2)
63.6 (22.6 – 179)
134.5 (17.5 – 1035)
Summary I:
Obesity:
– Anti-HCV positive:
Central obesity: 2-fold increased risk
BMI > 30 kg/m2 : 4-fold increased risk
– HBsAg positive:
Central obesity: 33% increased risk
BMI: no association
DM
– Anti-HCV positive:
3 to 4 fold increased risk
– HBsAg positive:
2-fold increased risk
Summary II:
Combine HBV, HCV serological status
with obesity and DM
Compare to HBsAg (-) + anti-HCV (-) + DM (-) +
BMI <30 kg/m2
– HBsAg(+) + DM(+) + BMI >30 kg/m2
 RR=265 (95% CI = 35 – 1993)
– Anti-HCV(+) + DM(+) + BMI >30 kg/m2
 RR=135 (95% CI=18 – 1035)
Synergistic effects of metabolic factors
and hepatitis infections on HCC
Fatty Liver and Incident
Hepatocellular Carcinoma (HCC)
Results
Hazard ratios for incident HCC
– 1.48 in overweight (BMI 25.0~29.9 kg/mm)
– 1.96 in obese (BMI≥30.0)
– compared with normal-weight (BMI 18.5~24.9)
men
Liver-related mortality had
– adjusted hazard ratios 1.74 in overweight and
1.50 in obese men
Excess BMI associated with the occurrence
of fatty liver and cirrhosis
Summary (I)
In patients with CH-B,
Prevalence of hepatic steatosis similar in pts
with CHB vs. in general population
HBsAg carriage not associated with IR
Metabolic derangement rather than viral
factors more closely associated with the
development of steatosis
Concurrent metabolic syndrome may
accelerate the progression of CHB
Summary (II)
In Patients with CHC:
HCV infection may induce IR and liver steatosis.
HCV life cycle is closed linked to lipid metabolism
Concurrent metabolic factors (increased BMI, DM)
accelerate the progression of CHC
Conclusions and Perspectives
After controlling for the virus effect, obesity
consistently shows to be associated with higher
risk of different spectrum of liver diseases: from
hepatitis to liver diseases related death.
Hypertriglyceridemia: maybe an indication
(biomarker) for better liver function? Mechanism
remains unknown?
The role of fatty liver in the relationship between
metabolic factors and end stage liver diseases
remains unknown
Long term follow up of NAFLD patients without
hepatitis is needed
Background
HBV, HCV ?
HBV?
Metabolic
Factors
HBV?
HCC
Cirrhosis
NAFLD
HCV?
HBV?
HCV?
HBV
HBV
HBV, HCV ?
HCV?