L.A. LesmanaDepartment of Medicine, University of Indonesia , Jakarta

HEPATITIS VIRAL INFECTION and NON-ALCOHOLIC FATTY LIVER DISEASE

(NAFLD) : AN UPDATE

NALFD – AASLD definition 2012 Evidence of hepatic steatosis, by imaging or

by histology,No causes for secondary hepatic fat

accumulation

Chalasani N, et al. Gastroenterology 2012;142:1592-1609.

Prevalence of NAFLD in the Asia-Pacific region

Country Percentage of NAFLD

Japan 9 – 30%China 5 – 18%Korea 18 %India 5 – 28%Indonesia 30%Malaysia 17 %Singapore 5%

Amarapurkar. Asia Pacific Working Party on NAFLD 2006

Insulin Resistance and Hepatitis

Hep B Hep C Cleared Hep C

0

10

20

30

40

50

60

IR

%

p<0.005 p<0.005

Imazeki et al. Liver Int 2008:355-62

Chronic Hepatitis B (CHB) and NAFLDCurrent Evidence

Prevalence of steatosis in CHBStudies Year Country Number of

casessPrevalence of steatosis (%)

Altlparmak et al.

2005 Turkey 164 39

Gordon et al. 2005 Australia 17 76

Thomopulos et al.

2006 Greece 233 18

Bondini et al 2007 USA 153 32

Peng et al 2008 China 153 27

Rastogi et al 2011 India 350 34

Lesmana et al 2012 Indonesia

174 30Thomopoulos KC, et al. Eur J Gastroenterol Hepatol 2006;18:233-7Altlparmak E, et al. World J Gastroenterol 2005;11:3056-9.Gordon A, et al. J Hepatol 2005;43:38-44.Peng D, et al. J Gastroenterol Hepatol 2008;23:1082-8.

Bondini S, et al. Liver Int 2007;27:607-11.Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9.Lesmana LA, et al. Acta Med Indones 2012;44:35-9.

Factors associated with FL in CHBFatty Liver (-)

(n=100)Fatty Liver (+)

(n=64)p-value

Mean age (years) 33.2 + 11.70 37.9 + 10.09 0.006

Mean BMI (kg/m2) 25.3 + 3.93 27.8 + 3.70 0.000

Male sex, n(%) 60 (53.1) 53 (46.9) 0.008

Mean AST (U/L) 76.5 + 56.14 70.0 + 54.61 0.469

Mean ALT (U/L) 131.6 + 109.39 113.5 + 68.19 0.686

Mean cholesterol (mg/dL) 162.2 + 38.8) 184.9 + 34.5 0.000

Mean triglyceride (mg/dL) 102.5 + 44.66 133.7 + 65.96 0.004

HBeAg positive, n(%) 42 (41.4) 17 (27.0) 0.059

Mean viral load (pg/mL) 1,628.24 781.55 0.067

Fibrosis stage 2-3, n(%) 20 (20) 11 (17.2) 0.754

HAI 9-17, n(%) 36 (36) 23 (35.9) 0.772

Altlrmak E , et al. World J Gastroenterol 2005;11:3056-9.

Insulin Resistance in CHBHOMA-IR

<1.64(n=35)

HOMA-IR > 1.64

(n=34)

p-value

Mean BMI (kg/m2) 21.8 + 3.7 24.0 + 4.4 0.029

Mean waist circumference (cm)

80.1 + 8.6 85.1 + 10.2 0.089

Median triglyceride (mg/dL) 90.0 110.0 0.016

Median fasting insulin (μU/mL)

5.0 11.7 <0.001

Fasting glucose (mg/dL) 85 53 <0.001

Fibrosis F2-F4, n(%) 21 (60.0) 15 (54.2) 0.232

HAI >6, n(%) 11 (31.4) 10 (29.4) 0.717

Steatosis grade 1-2 20 (57.2) 21 (61.8) 0.873

Median HBV-DNA (log copies/mL)

5.14 6.2 0.324

HBeAg positive, n(%) 13 (37.1) 13 (38.2) 1.000Kumar M, et al. Am J Gastroenterol 2009;104:76-82.

Demographic FactorsVariable Steatosis (+)

(n=118)Steatosis (-)

(n=232)p value

Mean age 35.5 + 10.5 27.9 + 14.0 <0.001

Male : Female 108 : 10 192 : 40 0.045

Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9.

Variable Steatosis (+)

(n=52)

Steatosis (-)

(n=122)

p value OR(95%CI)

Mean age 42.6 + 10.5

40.0 + 11.2 0.150 -

Male : Female (%)

73.1 : 26.9 49.2 : 50.8 0.004 2.81 (1,38-5,69)

Medistra Hospital. Unpublished data 2007-2009

Biochemical and Viral FactorsVariable Steatosis

(+)(n=118)

Steatosis (-)(n=232)

p value

Median ALT (U/mL) 62 68 0.620

HBeAg positive (%) 48.8 57.2 0.106

Median DNA (copies/mL)

69 x 104 750 x 104 0.025

HBV genotypes (n=80):ABCDA+CA+DA+C+D

12.6%00

81.2%3.1%3.1%

0

14.5%2.1%2.1%64.6%2.1%12.5%2.1%

0.567

Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9.

Metabolic Parameters Variable Steatosis

(+)(n=118)

Steatosis (-)(n=232)

p value

Mean BMI (kg/m2) 25.2 + 4.8 20.4 + 3.5 <0.01

Mean FBS (mg/dL) 94.1 + 19.6 86.9 + 13.9 0.091

Mean TG (mg/dL) 138.8 + 62.1 88.0 + 27.9 0.002

Mean cholesterol (mg/dL)

171.8 + 43.5 139.3 + 37.6 0.017

Mean insulin (IU/L) 13.0 + 9.1 9.1 + 6.0 0.027

Median HOMA-IR 2.7 (0.96-11.75)

1.9 (0.19-6.7) 0.048

Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9.

BMI: body mass index; FBS: fasting blood sugar; TG: triglycerides;HOMA-IR: Homeostatic Model of Assessment – Insulin Resistance

Histological Features

Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9.

Variable Steatosis (+)(n=118)

Steatosis (-)(n=232)

p value

Mean HAI score 4.8 + 2.6 4.5 + 2.9 0.286

Mean fibrosis score 1.7 + 1.1 1.5 + 1.1 0.170

HAI: histological activity index

Data in Medistra HospitalVariable Steatosis

(+)(n=118)

Steatosis (-)(n=232)

p value

Mean BMI (kg/m2) 25.1 + 3.7 22.7 + 3.3 <0.001

Waist circumference (cm)

88.3 + 11.0 79.0 + 10.1 <0.001

Mean ALT (U/L) 49.8 + 26.7 71.7 + 102.9 0.132

Log HBV-DNA (copies/mL)

5.92 + 1.99 6.07 + 2.08 0.675

Liver stiffness (kPa) 8.3 + 6.3 9.5 + 10.2 0.468

HBeAg-positive (%) 42.3 45.1 0.736

Genotype C (%) 32.4 19.8 0.138

Lesmana LA, et al. Acta Med Indones 2012;44:35-9.

Histological FeaturesFibrosis stage Inflammatory grade

F0-F1 F2-F40

102030405060708090

100

FL(+) FL(-)

% o

f case

s

A0-A1 A2-A30

20

40

60

80

100

FL(+) (FL-)

% o

f case

s

p = 0.849 p = 0.624

Lesmana LA, et al. Acta Med Indones 2012;44:35-9.

Predictors of Steatosis in CHBCountr

yN Steatos

isPredictors

Altlparmak, et al (2005)

Turkey 164

39% Older age, BMI, high cholesterol and triglyceride

Gordon, et al (2005) Australia

17 76% Waist circumference, FPG, C-peptide

Thomopoulos, et al (2006)

Greece 233

18% FPG, BMI> 25 kg/m2

Bondini, et al (2007) USA 64 19% Obesity, waist circumference, hypergension, dyslipidemia, older age

Cindoruk, et al (2007) Turkey 140

34% BMI, total cholesterol, hypertriglyceridemia

Peng, et al (2008) China 153

27% BMI, Age ALT

Rastogi, et al (2011) India 350

34% Triglyceride

Lesmana, et al (2012) Indonesia

174

30% Waist circumference

Fatty Liver vs. SVR Rates

Cindoruk M, et al. J Clin Gastroenterol 2007;41:513-7.

HBeAg (-) HBeAg (+)0%

10%

20%

30%

40%

36.20%39.60%

31.50% 33.30%

With steatosis Without steatosis

FL did not affect IFN-based treatment outcomes (p > 0.005)

ALT

HBeAg+

HBV DNA

Immune Escape/Reactivation

Inactive Carrier Status

HBeAg – Chronic HBV

HBeAg +Chronic Hepatitis B

Immune Tolerant

ImmuneControl

Immune Clearance

Immune control – treatment not required

Immune control – inactive disease

HBeAg–

Summary: NAFLD in CHBNAFLD is commonly found in about one-third of

patients.NAFLD in CHB is strongly associated with

metabolic factors, e.g.: body mass index (BMI), obesity, insulin resistance, dyslipidemia.

NAFLD is not associated with liver fibrosis or histological activity index.

NAFLD may not affect treatment response.In patients with CHB and NAFLD with elevated

ALT in clinical practice is not easy to distinguish whether the high ALT is due to CHB or NAFLD.

Chronic Hepatitis C (CHC) and NAFLDCurrent Evidence

Risk factors of FL in Chronic Hep C

Parameter HCV (n=75) HCV+ FL (n=69)

p value

Obesity 25 52 <0.05

Diabetes 8 21 <0.05

Hypertension 14 25 <0.05

Hypertriglyceridemia 15 33 <0.05

Metabolic syndrome 28 63 <0.001

Fatty liver is associated with features of metabolic syndrome in patients

with chronic hepatitis C virus infection.

Sanyal AJ, et al. Am J Gastroenterol 2003;98:2064-71

IR and Liver Fibrosis in CHC

F0-F1 F2-F40

102030405060708090

100

9

91

33

67

HOMA-R >2.5HOMA-R <2.5

% o

f case

s

Taura N, et al. Am J Gastroenterol 2006;101:2752-9.

Insulin resistance is associated with more advanced fibrosis in patients with chronic hepatitis C virus infection

p = 0.002

HCV GENOTYPE DISTRIBUTION

1a 1b 1c 2a 2e 2f 3a 3k0

5

10

15

20

25

30

35

40

45

50

6.7

47.3

18.7

105.3

0.7 0.7

10.7

HCV genotype 1b is predominant in Indonesia

Utama A, et al. Liver Int 2010;30:1152-60.

Subjects: 68 chronic hepatitis, 48 cirrhosis, and 34 HCCMethod: core sequence analyses

%

Relapse rate are higher in patients infected with HCV genotype 3 who have an RVR

RVR SVR Relapse0

102030405060708090

86.7 84.3

10.1

79.6 79.2

15.6

Genotype 2 (n=427)Genotype 3 (n=505)

Resp

on

ders

(%

)

Shah SR, et al. Clin Gastroenterol Hepatol 2011;9:688-93.

RVR: rapid virologic response (HCV RNA <43 IU/mL at week-4 ) SVR: sustained virologic response (HCV RNA <15 IU/mL at week-48

p=0.001

Steatosis is the strongest independent predictor of relapse in patients infected with HCV

genotype 3 who have an RVR

Shah SR, et al. Clin Gastroenterol Hepatol 2011;9:688-93.

OR: 3.0; 95%CI: 1,5-6.1; p=0.003 Steatosis vs. no steatosis

HCV RNA > vs. < 400.000 IU/mL

BMI > vs < 30 kg/m2

Age > vs <45 years

GGT > vs < ULN

OR: 2.5; 95%CI: 1,0-6.3; p=0.04

OR: 2.2; 95%CI: 1,0-4.8; p=0.04

OR: 2.2; 95%CI: 1,2-4.2; p=0.02

OR: 2.1; 95%CI: 1,1-4.1; p=0.03

-2 -1 0 1 2 3 4 5 6 7 8

HCV infection and Metabolic Syndrome

There is no evidence for association between HCV infection and metabolic syndrome.

The 2 conditions occur together at a higher rate than would occur by chance, although HCV infection has been associated with type2 diabetes mellitus.

The serum lipid profile of patients with HCV infections is characterized by decreased level of cholesterol and sometimes triglycerides,in contrast to metabolic syndrome

Negro F. Gastroenterology 2012;142:1288-92

HCV and Lipid Metabolism that may lead to steatosis of hepatocytes

Negro F. Gastroenterology 2012;142:1288-92.

HCV might affect insulin signaling in hepatocytes contributing to Insulin Resistance

Negro F. Gastroenterology 2012;142:1288-92.

Possible Clinical Outcomes Insulin resistance in CHC

have substantial impact on the morbidity and mortality :Accelerated progression

of liver fibrosis Increase type 2 diabetesReduced virological

response to antiviral therapy

Increase incidence of cardiovascular events need further study

Bugianesi E, et al. J Hepatol 2012;56(Suppl ):S56-S65

Summary: NAFLD in CHCNAFLD is frequently found in CHCIts present is genotype specific, mostly

genotype 1 and 3Alcohol, central obesity, raised BMI are

associated with more activity and more severe fibrosis

Obesity reduces response to IFN-based treatment

NAFLD may increase relapse rate among previously rapid virologic responders

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