Metabolic Factors / NAFLD Metabolic Factors / NAFLD on the Natural History of on the Natural History of

Chronic Hepatitis B or C in Chronic Hepatitis B or C in AsiaAsia

Pei-Jer ChenPei-Jer ChenNational Taiwan University & HosNational Taiwan University & Hos

pitalpital

Insulin Insulin resistanceresistance

Metabolic FactoMetabolic Factorsrs

HBV or HHBV or HCVCV

Hepatic Hepatic steatosissteatosis

23820 cohort members (11973 males and 11847 females), recruited in 1991

4155 HBsAg sero-positive (2445 males and 1710 fem

ales)

19665 HBsAg sero-negative (9528 males and 10137 fem

ales--- anti HCV assay

Flow chart of the REVEAL cohortFlow chart of the REVEAL cohort

HBV DNA

TG.Chole.

HCV RNA

DM

Cross-Section Study: CHB/CHC Cross-Section Study: CHB/CHC versus Control in terms of versus Control in terms of

Metabolic FactorsMetabolic Factors

A study of base-line data in the A study of base-line data in the REVEAL cohortREVEAL cohort

Metabolic factors:Metabolic factors:ObesityObesity

Central obesity: waist circumferences >90 cm for menCentral obesity: waist circumferences >90 cm for men and >80 cm for women.and >80 cm for women.

Body Mass Index: Body Mass Index: normal weightnormal weight BMI< 23 kg/m BMI< 23 kg/m22

overweightoverweight 23 23 << BMI < 25 kg/m BMI < 25 kg/m22

obeseobese 25 25 << BMI < 30 kg/m BMI < 30 kg/m22

morbid obesemorbid obese BMI BMI >> 30 kg/m 30 kg/m22

HypercholesterolemiaHypercholesterolemia: : total cholesterol total cholesterol >> 240 240

mg/dLmg/dL

HypertriglyceridemiaHypertriglyceridemia: TG : TG >> 150 mg/dL 150 mg/dL

History of DMHistory of DMHistory of hypertensionHistory of hypertension

Risk Factors OR (95% CI)* OR (95% CI)* Triglyceride > 150 vs. < 150 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 1.06 (0.97 – 1.16) 25 – 29.9 vs. <23 1.09 (1.00 – 1.19) > 30 vs. <23 1.21 (1.01 – 1.45) P for trend 0.01

1.13 (1.04 – 1.23)

Central obesity Yes vs. No

1.30 (0.98 – 1.74) 1.32 (0.99 – 1.75)

History of DM Yes vs. No

0.98 (0.8 – 1.19) 0.98 (0.80 – 1.19)

History of hypertension Yes vs. No

Table . Multivariate-adjusted odds ratios of being HBsAg seropositive in relation to selected metabolic factors

HBV Infection does not Correlates with HBV Infection does not Correlates with the Development of NAFL or IR (1)the Development of NAFL or IR (1)

AuthorAuthor SettingSetting PopulatioPopulationn

ResultsResults RemarksRemarks

Moucari Moucari (2008)(2008)

Cross-Cross-sectionalsectional

500 CHC, 500 CHC, 100 CHB100 CHB

IR: 5% in CHB and 35% in CHCIR: 5% in CHB and 35% in CHC Not matchedNot matched

Wang Wang (2007)(2007)

Health Health examinatioexaminationn

50 CHB 50 CHB and 457 and 457 controlscontrols

HBV carriers not associated with IR or HBV carriers not associated with IR or FLFL

Small sample Small sample sizesize

MohammaMohammadd (2006) (2006)

Case Case controlcontrol

60 CHC 60 CHC and 40 and 40 CHBCHB

HOMA-IR associated with fibrosis in HOMA-IR associated with fibrosis in CHC, but not in CHBCHC, but not in CHB

Selection Selection bias, small bias, small sizesize

TsochatziTsochatziss (2007) (2007)

Case Case seriesseries

213 eAg-v213 eAg-ve CHBe CHB

Hepatic steatosis less frequent in CHB tHepatic steatosis less frequent in CHB than in CHC; associated with metabolic fhan in CHC; associated with metabolic factorsactors

Selection Selection bias, not bias, not representativerepresentative

Cindoruk Cindoruk (2007)(2007)

Treatment Treatment cohortcohort

140 CHB140 CHB Presence of steatosis not associated witPresence of steatosis not associated with HBV loadh HBV load

Selection Selection bias, not bias, not representativerepresentative

Demir (2Demir (2007)007)

Case Case seriesseries

49 eAg-ve 49 eAg-ve CHBCHB

NAFLD: most common cause of NAFLD: most common cause of elevated ALT in patients with CHBelevated ALT in patients with CHB

Selection Selection bias, small bias, small sizesize

Moucari et al, Gastroenterology 2008; Wang et al, JGH 2007; Mohammad et al, Indian J GastrMoucari et al, Gastroenterology 2008; Wang et al, JGH 2007; Mohammad et al, Indian J Gastroenterol 2006; Tsochatzis et al, Dis Liver Dis 2007; Lin et al, WJG 2007; Cindoruk et al, J Clin oenterol 2006; Tsochatzis et al, Dis Liver Dis 2007; Lin et al, WJG 2007; Cindoruk et al, J Clin Gastroenterol 2007; Demir et al, Ann Hepatol 2007Gastroenterol 2007; Demir et al, Ann Hepatol 2007

AuthorAuthor SettingSetting PopulatioPopulationn

ResultsResults RemarksRemarks

Persico Persico (2009)(2009)

CohortCohort 726 CHC, 726 CHC, 126 CHB126 CHB

Age and BMI correlate with steatosis in CAge and BMI correlate with steatosis in CHBHB

Selection Selection biasbias

Yun (200Yun (2009)9)

Liver Liver biopsy biopsy seriesseries

86 young 86 young male CHB male CHB

Steatosis associated with TG level and HSteatosis associated with TG level and HOMA IROMA IR

Small Small sample sizesample size

Imazeki Imazeki (2008)(2008)

Case Case seriesseries

544 CHC, 544 CHC, 286 CHB, 286 CHB, 122 122 controlscontrols

IR in CHB (36%) similar to controls IR in CHB (36%) similar to controls (36%), but lower than in CHC (54%)(36%), but lower than in CHC (54%)

Selection Selection bias, not bias, not matchedmatched

KumarKumar (2009)(2009)

Case Case controlcontrol

69 CHC 69 CHC and 50 and 50 healthy healthy controlscontrols

HOMA-IR associated with BMI, but not HOMA-IR associated with BMI, but not CHB itselfCHB itself

Selection Selection bias, small bias, small sizesize

Persico et al, World J Gastroenterol 2009; Yun et al, Liver Int 2009; Kumar et al, Am J GastroPersico et al, World J Gastroenterol 2009; Yun et al, Liver Int 2009; Kumar et al, Am J Gastroenterol 2009; Imazeki et al, Liver Int 2008enterol 2009; Imazeki et al, Liver Int 2008

HBV Infection does not Correlates with HBV Infection does not Correlates with the Development of NAFL or IR (2)the Development of NAFL or IR (2)

SummarySummary

Obesity, history of diabetes : Prevalence Obesity, history of diabetes : Prevalence not increase in HBsAg sero-positive subjenot increase in HBsAg sero-positive subjects cts

TGTG>>150: in HBsAg sero-positive cases150: in HBsAg sero-positive cases

Metabolic factors and Hepatitis Metabolic factors and Hepatitis C infectionC infection

Relationship with anti-HCV status and Relationship with anti-HCV status and HCV RNA levels cross-sectionHCV RNA levels cross-section

Risk Factors OR (95% CI)* OR (95% CI)* Triglyceride > 150 vs. < 150 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 0.95 (0.80 – 1.12) 25 – 29.9 vs. <23 1.07 (0.92 – 1.25) > 30 vs. <23 1.18 (0.89 – 1.56) P for trend 0.01

1.13 (0.98 – 1.30)

Central obesity Yes vs. No

1.56 (1.05 – 2.33) 1.59 (1.06 – 2.37)

History of DM Yes vs. No

1.13 (0.85 – 1.51) 1.13 (0.85 – 1.51)

History of hypertension Yes vs. No

Table . Multivariate-adjusted Odds Ratios of being anti-HCV seropositive relation to selected risk factors

SummarySummary

Obesity, Diabetes : Increased in anti-HCV Obesity, Diabetes : Increased in anti-HCV seropositive cases. seropositive cases.

TG<150: anti-HCV seropositiveTG<150: anti-HCV seropositive

Serum triglyceride level, total cholesterol lSerum triglyceride level, total cholesterol level and body mass index are inversely coevel and body mass index are inversely correlated with HCVRNA viral load rrelated with HCVRNA viral load

NATURE CELL BIOLOGY 2007; 9:961-9

Huh-7 cells transfected with JFH1 RNACore recruits NS proteins to LDs

HCV and LipidsHCV and Lipids

Negro and Sanyal. Liver Int 2009;29:26Negro and Sanyal. Liver Int 2009;29:26

23820 cohort members (11973 males and 11847 females)

4155 HBsAg sero-positive (2445 males and 1710 fem

ales)

19665 HBsAg sero-negative (9528 males and 10137 fem

ales)

18541 anti-HCV seronegative

Flow chart of the REVEAL cohortFlow chart of the REVEAL cohort

3931 anti-HCV seronegative 218 anti-HCV ser

opositive

1095 anti-HCV seropositive

HCC n=187LC n=429

LC death n=57Liver death n=212

HCC n=51LC death n=16

Liver death n=74 HCC n=53

LC death n=61Liver death n=108

10 years follow-up

Metabolic factors and Incident HMetabolic factors and Incident Hepatocellular Carcinoma (HCC)epatocellular Carcinoma (HCC)

HBsAg (+) and anti-HCV (-) (N=3931; HCC=187)

Risk Factors RR (95% CI)* RR (95% CI)* 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 1.40 (0.97 – 2.02) 25 – 29.9 vs. <23 1.17 (0.81 – 1.69) > 30 vs. <23 1.36 (0.64 – 2.89) P for trend 0.317

1.33 (0.96 – 1.85)

Central obesity Yes vs. No

2.27 (1.10 – 4.66) 2.41 (1.17 – 4.95)

History of DM Yes vs. No

0.43 (0.16 – 1.18) 0.45 (0.16 – 1.21)

History of hypertension Yes vs. No

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)

Risk Factors RR (95% CI)* RR (95% CI)* 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 1.05 (0.41 – 2.73) 25 – 29.9 vs. <23 3.02 (1.48 – 6.14) > 30 vs. <23 4.13 (1.38 – 12.4) P for trend <0.001

2.16 (1.19 – 3.92)

Central obesity Yes vs. No

3.25 (1.0 – 8.85) 3.52 (1.29 – 9.24)

History of DM Yes vs. No

0.91 (0.31 – 2.67) 0.83 (0.28 – 2.44)

History of hypertension Yes vs. No

Table. Multivariate-adjusted relative risks of HCC in relation to selected risk factors stratified by HBV and HCV infection status

Serum Hepatitis Markers Status

Metabolic Factors Relative Risk (95% CI)

HBsAg (-) anti-HCV (-)* BMI<30 1.00 HBsAg (-) anti-HCV (-) BMI>30 2.50 (0.99 – 6.32) HBsAg (+) anti-HCV (-) BMI<30 19.9 (14.3 – 27.6) HBsAg (+) anti-HCV (-) BMI>30 22.0 (10.3 – 46.9) HBsAg (-) anti-HCV (+) BMI<30 15.7 (10.4 – 23.8) HBsAg (-) anti-HCV (+) BMI>30 34.5 (13.5 – 87.6) HBsAg (-) anti-HCV (-)¥ DM (-) 1.00 HBsAg (-) anti-HCV (-) DM (+) 3.49 (1.08 – 11.3) HBsAg (+) anti-HCV (-) DM (-) 18.7 (13.6 – 25.9) HBsAg (+) anti-HCV (-) DM (+) 43.5 (20.5 – 92.3) HBsAg (-) anti-HCV (+) DM (-) 15.0 (9.95 – 22.5) HBsAg (-) anti-HCV (+) DM (+) 60.3 (23.6 – 153.6)

Table. Relative risks of HCC by HBsAg, anti-HCV serological status, obesity and history of diabetes mellitus (DM)

Table. Relative risks of HCC by HBsAg, anti-HCV serological status, obesity and history of diabetes mellitus (DM)

Serum Hepatitis Markers Status

Metabolic Factors Relative Risk (95% CI)

HBsAg (-) anti-HCV (-)? BMI<30 DM (-) 1.00 HBsAg (-) anti-HCV (-) BMI>30 DM (-) 2.81 (1.11 – 7.12) HBsAg (-) anti-HCV (-) BMI<30 DM (+) 4.39 (1.35 – 14.3) HBsAg (-) anti-HCV (-) BMI>30 DM (+) --? HBsAg (+) anti -HCV (-) BMI<30 DM (-) 20.6 (14.7 – 29.0) HBsAg (+) anti -HCV (-) BMI>30 DM (-) 20.4 (9.13 – 45.6) HBsAg (+) anti -HCV (-) BMI<30 DM (+) 43.0 (19.3 – 96.1) HBsAg (+) anti -HCV (-) BMI>30 DM (+) 264.7 (35.2 – 1993) HBsAg (-) anti-HCV (+) BMI<30 DM (-) 15.7 (10.2 – 24.1) HBsAg (-) anti-HCV (+) BMI>30 DM (-) 33.6 (12.0 – 94.2) HBsAg (-) anti-HCV (+) BMI<30 DM (+) 63.6 (22.6 – 179) HBsAg (-) anti-HCV (+) BMI>30 DM (+) 134.5 (17.5 – 1035)

Summary I:Summary I:Obesity:Obesity:

– Anti-HCV positive:Anti-HCV positive:

Central obesity: 2-fold increased risk Central obesity: 2-fold increased risk

BMI BMI >> 30 kg/m 30 kg/m22 : 4-fold increased risk : 4-fold increased risk– HBsAg positive:HBsAg positive:

Central obesity: 33% increased riskCentral obesity: 33% increased risk

BMI: no associationBMI: no association

DMDM– Anti-HCV positive:Anti-HCV positive:

3 to 4 fold increased risk3 to 4 fold increased risk– HBsAg positive:HBsAg positive:

2-fold increased risk2-fold increased risk

Summary II:Summary II:

Combine HBV, HCV serological status witCombine HBV, HCV serological status with obesity and DMh obesity and DMCompare to HBsAg (-) + anti-HCV (-) + DM (-) + Compare to HBsAg (-) + anti-HCV (-) + DM (-) + BMI <30 kg/mBMI <30 kg/m22

– HBsAg(+) + DM(+) + BMI HBsAg(+) + DM(+) + BMI >>30 kg/m30 kg/m22 RR=265 (95% CI = 35 – 1993)RR=265 (95% CI = 35 – 1993)– Anti-HCV(+) + DM(+) + BMI Anti-HCV(+) + DM(+) + BMI >>30 kg/m30 kg/m22 RR=135 (95% CI=18 – 1035)RR=135 (95% CI=18 – 1035)

Synergistic effects of metabolic factors and Synergistic effects of metabolic factors and hepatitis infections on HCChepatitis infections on HCC

Fatty Liver and Incident HepatoFatty Liver and Incident Hepatocellular Carcinoma (HCC)cellular Carcinoma (HCC)

ResultsResults

Hazard ratios for incident HCCHazard ratios for incident HCC– 1.48 in overweight (BMI 25.0~29.9 kg/mm) 1.48 in overweight (BMI 25.0~29.9 kg/mm) – 1.96 in obese (BMI≥30.0) 1.96 in obese (BMI≥30.0) – compared with normal-weight (BMI 18.5~24.9) mcompared with normal-weight (BMI 18.5~24.9) m

en en

Liver-related mortality had Liver-related mortality had – adjusted hazard ratios 1.74 in overweight and 1.5adjusted hazard ratios 1.74 in overweight and 1.5

0 in obese men 0 in obese men

Excess BMI associated with the occurrence Excess BMI associated with the occurrence of fatty liver and cirrhosisof fatty liver and cirrhosis

SummarySummary (I) (I)

In patients with CH-B,In patients with CH-B,

Prevalence of hepatic steatosis similar in pts Prevalence of hepatic steatosis similar in pts with CHB vs. in general populationwith CHB vs. in general population

HBsAg carriage not associated with IRHBsAg carriage not associated with IR

Metabolic derangement rather than viral factorMetabolic derangement rather than viral factors more closely associated with the developmes more closely associated with the development of steatosisnt of steatosis

Concurrent metabolic syndrome may acceleraConcurrent metabolic syndrome may accelerate the progression of CHBte the progression of CHB

Summary (II)Summary (II)

HCV infection may induce IR and liver steatosis.HCV infection may induce IR and liver steatosis.

HCV life cycle is closed linked to lipid metabolismHCV life cycle is closed linked to lipid metabolism

Concurrent metabolic factors (increased BMI, DM) Concurrent metabolic factors (increased BMI, DM) accelerate the progression of CHCaccelerate the progression of CHC

In Patients with CHC:

Conclusions and PerspectivesConclusions and PerspectivesAfter controlling for the virus effect, obesity consiAfter controlling for the virus effect, obesity consistently shows to be associated with higher risk of stently shows to be associated with higher risk of different spectrum of liver diseases: from hepatitidifferent spectrum of liver diseases: from hepatitis to liver diseases related death.s to liver diseases related death.Hypertriglyceridemia: maybe an indication (biomHypertriglyceridemia: maybe an indication (biomarker) for better liver function? Mechanism remaarker) for better liver function? Mechanism remains unknown?ins unknown?The role of fatty liver in the relationship between The role of fatty liver in the relationship between metabolic factors and end stage liver diseases rmetabolic factors and end stage liver diseases remains unknownemains unknownLong term follow up of NAFLD patients without hLong term follow up of NAFLD patients without hepatitis is neededepatitis is needed

Metabolic Factors

NAFLD Cirrhosis HCC

HBV, HCV ?

HBV, HCV ?

HBV? HBV? HBV?

HCV? HCV? HCV?

BackgroundBackground

HBVHBV