Approach and Hepatitis to JaundiceApproach and Hepatitis to Jaundicepp ppp p

Teerha Piratvisuth, M.D.NKC Institute of Gastroenterology and HepatologyNKC Institute of Gastroenterology and Hepatology

Prince of Songkla University,Thailand

Liver Function TestsLiver Function TestsLi f i ll d ll f iLiver function tests usually do not tell true function of the liverN l l d “ l”Normal values do not mean “normal”eg. normal ALT is Mean+ 2 SD and was set as early as 1950s

l f b l d fl bLevel of abnormality does not reflect severity but may help in differential diagnosis

f h l d iDecrease of the value does not mean improvement

PEG IFN/RibavirinSerum ALT Activity  According to Virological Response

Group A (24 Weeks of Treatment) Group B (48 Weeks of Treatment)

32

36Patients with an SVR (n = 62) Virological nonresponders (n = 56)Virological relapsers (n = 94) 32

36Patients with an SVR (n = 107) Virological nonresponders (n = 57)Virological relapse after EOT (n = 46)

ity

(IU

/L)

24

28

ity

(IU

/L)

24

28

m A

LT A

ctiv

i

12

16

20

m A

LT A

ctiv

i

12

16

20

Seru

m

4

8

12

Treatment Follow-up

Seru

m4

8

12

Treatment Follow-up

Study Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 720

Study Week

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 720

Study Week Study Week

The vertical arrows indicate the end of treatment

Zeuzem S, AALSLD 2003

Mild Elevation is nonspecific andusually normal when repeated

Test Normal Mild Moderate Marked

AST 11-40 <2-3 2-3 to 20 >20

ALT 3-40 <2-3 2-3 to 20 >20

ALP 35-105 <1.5-2 1.5-2 to 5 >5

GGT 2-65 <2-3 2-3 to 10 >10

Patients of Laboratory Tests in Types ofPatients of Laboratory Tests in Types of Acute Hepatic Injury

Disease Peak ALT(x URL)

AST / ALT Ratio

Viral Hepatitis 10-40 <1

Alcoholic Hepatitis 2-8 >2

Toxic injury >40 > 1 early

Ischemic injury >40 >1 early

X- times, URL - upper reference limit

Percentage of patients with AST/ALT ratios greater than 1 and greater than 2

100 AST/ALT > 1AST/ALT > 2

60

80

NT

40

60

PER

CEN

20

0Alcoholic

Liver Disease104

Post NecroticCirrhosis 30

ChronicHepatitis

48

ObstructiveJaundice

37

ViralHepatitis

52104 48 37 52

Acute Hepatic InjuryAcute Hepatic InjuryAST/ALT

Best discriminant of AST/ALT in acute hepaticBest discriminant of AST/ALT in acute hepatic injury is 200/300 IU/L 

(Rozen P Isr J Med Sci 1970)

Uncomplicated alcoholic hepatitis rarely has level AST/ALT >8‐10 times ULN (look for paracetamol?)AST/ALT >8 10 times ULN (look for paracetamol?)

Clinical setting of the gpatient is more important than liver function tests in

symptomatic casesymptomatic case

Evolution of LFTs in acute biliary obstructionAST ALTIU/LAST ALTIU/L

1300 19/25 ptsALT > 300

16/25 ptsAST > 300

1000

500

All patients had symptoms of less than 24 hours

16/25 pts : Confirmed

CBD stone

0 24-72 0 24-72Time, h Time, h Rashmi V. et al. Arch Intern Med. 1987.

Change of ALT and Bilirubin during hepatitisChange of ALT and Bilirubin during hepatitis

ALT Bilirubin

0 7 14 21 Day

Acute Hepatitis AST/ALT > 300 IU/LAST/ALT > 300 IU/L

ALT > 3 000 IU/LALT > 3,000 IU/L

• Acute atypical viral hepatitis• Acute atypical viral hepatitis

- Herpes, Dengue

• Ischemic /shock liverIschemic /shock liver

• Heat stroke

• Toxic and drugso c a d d ugs- Paracetamol, halothane

• Acute Budd –Chiari Syndrome

• Hepatic infarction or artery ligation

• Pregnancy- Pre-eclampsia, eclampsia

ALT >300 - 3000 IU/L

ALP < 3x ULN ALP > 3x ULN

Acute viral Hepatitis

Viral seromarkers for HBV,

Drug

No drug exposure,HAV, HEV HCV

negative

g p

Non-drug Non-viralnegative

- AIH- HCV RNA

- Ischemic- Acute Budd-Chiari- Acute biliaryHCV RNA

- Wilson’sAcute biliary

obstruction- Overlapse & syndrome

negative

Occupational ToxicOccupational Toxic Systemic ; Hyperthyroid

AASLD recommendations for diagnosis and screening for Wilson's disease (WD)

Patients in the pediatric age who present a clinical picture of autoimmune hepatitis or acute severe hepatitishepatitis or acute severe hepatitisAdult patients with atypical autoimmune hepatitis or who respond poorly to standard corticosteroid therapyNonalcoholic fatty liver disease, particularly in those without clinical feature of metabolic syndromeAcute or severe hepatitis with Coombs-negative intravascular hemolysis,Acute or severe hepatitis with Coombs negative intravascular hemolysis, modest elevations in serum aminotransferases, marked hyperbilirubinemiaHepatitis with KF ring or neurological diseaseHepatitis with KF ring or neurological disease

Kaplan MM. et al. www.uptodate.com 2008; pp. 1-18.

Fulminant hepatic failure with

• Coombs-negative intra-vascular hemolytic anemia Coagulopathy unresponsive to vitamin K• Coagulopathy unresponsive to vitamin K

• Rapidly progressive renal failureS i t f t i ll l th 2 000 IU L• Serum aminotransferases typically less than 2,000 IU/L

(AST often greater than ALT)

• Normal or markedly subnormal alkaline phosphatase (<40 IU/L)

• Serum alkalaline phosphatase/bilirubin < 2

Kaplan MM. et al. www.uptodate.com 2008; pp. 1-18.

Acute or chronicAcute or chronic hepatitis

HyperglobulinemiaHyperglobulinemiaAlb / Glob < 1

PHT cirrhosis No PHT or cirrhosis

H l b li iAIH

Hypergrammaglobulinemia

↑ IgG

ALT < 400 IU/ml

AST / ALT > 2 AST / ALT > 1 AST / ALT < 1

no yes

Hemolysis Biliary obstruction - acute hepatitis C

no yes

alcoholic AIHA

no

fl i d l h li t

- acute systemic infection

hepatitis lymphoma ↑ ↑( ALP )

flare in advanced fibrosis or i h i

drug alcoholic hepatitis

acute systemic infection

cirrhosis

Marker of Severity in Acute Liver Disease

• Level of AST/ALT do not reflect severity• Severity in viral hepatitis• Severity in viral hepatitis

– Total bilirubin > 257µmol/L (15 mg/dL)PT 4 b (IIB AASLD)– PT > 4 sec above (IIB, AASLD)

– Clinically worse (hypoglycemia, HE)

• ParacetamolPersistent elevation or rising of PT more– Persistent elevation or rising of PT more than 4 days (IIB, AASLD)

Chronic hepatitis

Viral AIH MetabolicAlcoholic Drug NASHViral hepatitis B, C, D

AIH MetabolicAlcoholic Drug NASH

Negative

Toxic - SystemicChronic Seronegative HIVToxic occupational

- Systemic - Amyloidosis

Chronic biliary

Seronegative AIH

HIV

Approach to Jaundice 1

Yellow skinYellow skin

Jaundice No Jaundice- Hypercarotenaemiayp

Liver function test

Isolated Predominant CholestasisHyperbilirubinemia Transminitis

Hepatocellular

2Isolated

Indirect Direct

LiverCBC Liver

NormalAbnormal Normal color

Rotor’s Dubin-Johnson

Gilbert’s syndromeHemolysis

Crigler-Najjar

Cholestasis

Ultrasound of liver

Biliary duct dilatation

YesYes

ERCP

No

ERCP MRCP

PTCIntrahepatic

Determine cause& site of obstruction

Liver biopsy Drug? Sepsis?

E d i

Sepsis? Virus?

Endoscopic Radiologic Drainage

Surgical

I i AP

H t bili

Increase in AP

Ph i l i l B Di With t h tiHepatobiliaryDisease

Physiological

P (II/III)

Bone Disease

Paget’s disease

Without hepatic, bile or bone

Disease

Cholestatic hepatitis Alcoholic hepatitis

Pregnancy (II/III)In growing age Albumin infusion (albumin from

Paget s disease(- 30 x) Rickets

Osteomalacie Vitamin D deficiency

Hyperthyroidism Bone AP Acromegaly Bone AP Pancreatic cystadenoma Heart failure Liver APp

PBC, OSC Metastatic liver Carcinoma at the hep. Drug-induced cholestasis

(albumin from placenta)

Vitamin D deficiency ostromalacia Renal tubular osteom. (glucosural osteopathy) R l t bl id i

Heart failure Liver AP Lymphoma / leukosis

Liver and skeleton AP Malignant tumours T APDrug induced cholestasis

etc. Renal tublar acidosis Glomerular kidney insufficiencyHyperparathyroidism

Osteosarcoma

Tumour AP (Regan-isoenymes) in 10-30% of patients

Hereditary hyperphosphat-Metastasing bone tumor

Multiple myeloma Benign skeletal-affection

y yp p pasaemina (familial)

Intestinal ischaemia Ulcerative bowel disease Transient hyperphosaffection

Fraktures Aseptic bone nerosis

Transient hyperphos Phatasaemia (in children)

HepatitisHepatitis

Inflammatory damage or inflammatory necrosis of the liver

Viral Hepatitisp

Viral Hepatitisp

HAV HEVHBV HFVHCV HGVHCV HGVHDV NANG VIRUSHDV NANG VIRUS

The course of typical acute viral hepatitis

Arthritis Rash 5-15%

Fever

re

Fever

Jaundice

Expo

sur

Dark Urine

E

Anorexia

Nausea

AnorexiaAnorexiaAnorexia

Malaise

Convalescent PeriodIncubation Period Pre Icteric Icteric

1-3 Mon 3-7 Days 1-4 weeks

E trahepatic Manifestations ofExtrahepatic Manifestations of HBV Infections

• Arthralgia / Arthritis• Arthralgia / Arthritis• Rash • Peripheral Neuropathy• Polyarteritis Nodosa• Polyarteritis Nodosa• Glomerulonephritis• Essential Mixed Cryoglobulinemia

Laboratory TestsLaboratory Tests

CBCEnzyme activityEnzyme activity

Transaminase (AST&ALT): normal within 10-12 weeksAlkaline Phosphatase: usually less than 3 time of UNLAlkaline Phosphatase: usually less than 3 time of UNL

BilirubinProthrom: PT prolong > 2 sec not correctedProthrom: PT prolong > 2 sec., not corrected

by vit. K suggest severe liver injuryAlbumin GlobulinAlbumin, GlobulinAutoantibodies

Treatment of Viral HepatitisTreatment of Viral HepatitisDiet : Low fat high carbohydrateDiet : Low fat, high carbohydrateActivity : RestSupportive treatmentDrugs : Essentialg

: Antiviral: Interferon: Interferon: Levamisole

Extracorporeal hepatic devicesLiver transplantationp

Hepatitis A

Primarily young age groupEnterically transmittedClinical : Fever is common and can be abrupt onsetClinical : Fever is common and can be abrupt onset

: Jaundice is uncommon in children: Mild in severity: Acute hepatitis with self-limited: Low mortality rate (1%): Relapse hepatitis have been reported

Unusual Presentation of HAV(1)

• Cholestatic hepatitis:• ~ 5% esp. in old age, chronic hemolytic anemiap g , y• Character: marked pruritus, pale stool and

prolonged jaundice• Peak bilirubin 12-29 mg/dl and last 12-18 wks.

even more than 6 months• Do not appear to be infectious• Mechanism: unknown, probably immune basis , p y

(response for steroid)

G.I. Siriraj Hospital

Diagnosis of Hepatitis ADiagnosis of Hepatitis A

Anti-HAV antibodies: IgM for acute hepatitisHAV particles NI stoolHAV particles NI stoolHAV antigen in stool and liver

Global impact of hepatitis B

2 billion with

25–40% (75–160

2 billion with evidence

of HBV infection million) die of

cirrhosis or liver cancer

World populationWorld population= 6 billion

300–400 million with 75% in Asia!% f chronic hepatitis B ~33% of population

infected with HBV at some time in their

WHO and CDC Fact SheetAvailable at http://www.who.int and http:// www.cdc.gov Mericanet al. J Gastroenterol Hepatol 2000

life

Prevalence of Hepatitis B Infection in the Asia-Pacific Region

Country Prevalence of i f ti (%)

Chronic HBV infection (%) (million)

Australia 0.1 0.15

China 9 7 120 130China 9.7 120–130Hong Kong 8.8 0.7India 3.34 34I d i 5 10 I d iIndonesia 5–10 Indonesia

Korea 4–5 2.25–2.27

Malaysia 5.24 1.65

NZ 6

Pakistan 5 6

The Philippines 12 9 6The Philippines 12 9.6

Singapore 4 0.15

Taiwan 15–20 3

Rosmawati M et al., J. Gastroenterol. Hepatol. 2004; 19:958–969Khan SA et al., J. Gastroenterol. Hepatol. 2004; 19:S419–S430Lee D-H et al. J. Korean Med. Sci. 2002; 17:457–62

Thailand 3–6 3

Vietnam 10–20 7–14

HBV G t d S btHBV Genotypes and Subtypes

Genotype

Subtype Areas of prominence

A d 2 1 NW E USAA adw2, ayw1 NW Europe, USA, Central Africa

B adw2, ayw1 Taiwan, Japan, I d i ChiIndonesia, China,

VietnamC adw2, adrq+, adrq-, ayr E Asia, Taiwan, Korea,

China Japan VietnamChina, Japan, VietnamD ayw2, ayw3 Mediterranean area,

IndiaE 4 W Af iE ayw4 W AfricaF adw4q, adw2, ayw4 Central and S AmericaG adw2 France, USA,

Transmission of HBV infection

Transfusion (bl d bl d d ) Vertical transmission(blood, blood products) Vertical transmission

Fl id C t i t dFluids (blood, semen,

secretions)

Contaminated needles and

syringesHEPATITIS B

) y g

Organs and IntravenousOrgans and tissue

transplantation

Intravenous drugs user’

shared syringes

Mechanism of Liver Damage in Hepatitis BHepatitis B

Host immune system major mechanism

Cell -mediated immune responseresponse

Direct cytopathic

HBV Infection

Symptomatic acute hepatitis B

Asymptomatic infectionp

Recovery

Recovery Fulminant hepatitis

90% in neonate 2-10% in adult

< 1%

hepatitisChronic HBV

infection

Chronic Healthy hepatitis B

ycarrier

Danger Signals in Acute Hepatitis B

• Rapidly deepening jaundice• Repeated vomiting and confusion

C l th• Coagulopathy

Risk of Progression to chronic Hepatitis BHepatitis B

• Early age of expose to HBV• Male gender• Immunocompromised host

Fulminant Hepatitis B

• Ocurrs in < 1% of patients with acute symptomatic hepatitis Bsymptomatic hepatitis B

• Rapid deterioration of patient condition with hepatic encephalopathy necrosis of hepatichepatic encephalopathy, necrosis of hepatic parenchyma, coagulopathy, renal failure and coma

• Pre-core HBV mutants are more frequently associated with a fulminant course than the wild-type HBV

Fulminant Hepatitis B

• 15-21% of fulminant hepatitis B HBsAg is15 21% of fulminant hepatitis B HBsAg is undetectable on radio immunoassay

• unless PCR method HBV DNA is not• unless PCR method, HBV-DNA is not detectable in serum in most case of fulminant hepatitis Bhepatitis B

• mortality rate 65-88%• higher survival rate in HBsAg-negative

patients (47% vs 17% with positive HBsAg)

Possible outcomes of HBV infection

Acute hepatitis B infection

3-5% of adult-acquired infections

95% of infant-acquired infections

Chronic HBV infection

infectionsinfections

Chronic hepatitis

20-23% in 5 yearsCirrhosis

12-25% in 5 years

6-15% in 5 years

Liver failureHepatocellular carcinoma

% y

Death or Liver transplant

Chronicity of HBV Infection

Age of Exposure Chronic Infection

Neonates 90%Neonates 90%Second year of life 60%6 years of age 10%6 years of age 10%Adult 5%

Mc Mahon BJ. et al. J Infect Dis. 1991. Taylor PE. 1988.

Annual rates of progression during h i HBV i f ti

Chronic HBV infection

chronic HBV infectionChronic HBV infection

Inactive carrier state<1.0%

60-70%30-40%

Chronic hepatitis B Inactive carrier state

2-6% for HBeAg(+) hepatitis B

Chronic hepatitis B

8-10% for HBeAg(–) hepatitis B

2 3%

<0.2%

Compensated cirrhosis

D t d H t ll l

2-3%

7 8%3-5%

Decompensated cirrhosis

Hepatocellular Carcinoma

7-8%

20 50%

Death20-50%20-50%

Fattovich, et al. 2004.

Not everyone with CHB has progressive li diliver disease

CHB is a long term disease liver damage occursCHB is a long-term disease – liver damage occursprogressively over time (usually several years)

Remains inactiveRemains inactive

Normal liver Chronic hepatitisCirrhosis

Cancer (HCC)

A Number of Factors Govern Differences in the C f DiCourse of Disease

HBV factors

>4−5 log

Viral load

Host factors• Age: >40 years• Male

Other factors• Habitual alcohol

consumption

Genotype Genome mutations

>4 5 log10copies/mL• Immune status: Severity,

extent, and frequency of ALT ↑ and hepatitis activity

consumption• Habitual cigarette

smoking• Aflatoxin exposure

C HCV

T1762/A1764Pre-S

C>BD>A

y• Concurrent HCV,

HDV, HIV• Others

C i i C i

HBV-related liver disease progression ↑HCV, hepatitis C virus

HDV, hepatitis D virus

Cirrhosis

progression ↑

Liaw Y-F, et al. Liver Int. 2005;25:472−489.

Fattovich G, et al. Journal of Hepatology. 2008;48:335–352.

Kao JH. Hepatol Int. 2007.

and/or HCC

REVEAL taught us a lot about the importance of HBV DNA and disease risk

Biological gradient of HCC and cirrhosis risk across

Cumulative Incidence of HCC at50 Cumulative Incidence of Cirrhosis at

Biological gradient of HCC and cirrhosis risk acrossserum HBV DNA levels

50

%)

Cumulative Incidence of HCC at Year 13 Follow-up1 (N = 3653)

50

40

Cumulative Incidence of Cirrhosis at Year 13 Follow-up2 (N = 3582)

36.2%

50

40

atie

nts

(% 30

20

23.5%30

20

Pa

10

1 3% 1 4% 3.6%

12.2% 14.9%

4.5% 5.9%9.8%

20

10

≥1 million

100,000-999,999

Baseline HBV DNA (copies/mL) measured using the Roche COBAS assay

01.3% 1.4%

< 300 300-9999

10,000-99,999

< 300 300-9999

10,000-99,999

100,000-999,999

0≥1

millionBaseline HBV DNA (copies/mL) measured using the Roche COBAS assay

1Chen et al. JAMA 2006; 2Iloeje et al. Gastroenterology 2006

REVEAL: Cirrhosis and HCC and liver-related

3000

mortality by serum HBV DNA level at study entry

2500

3000

rate

ye

ars) Cirrhosis

HCC

1500

2000

/mor

talit

y p

erso

n-y

Liver-related death

1000

1500

ncid

ence

/er

100

,000

500

In(p

e

0<300 300–9999 10000–99999 100000–999999 ≥ 1 million

HBV DNA level, copies/mL

Adapted from Chen CJ et al. JAMA 2006; Iloeje UH et al. Gastroenterology 2006;Iloeje UH et al. Clin Gastroenterol Hepatol. 2007

HBsAg and HBV DNA are independent di t f HCCpredictors of HCC

HBeAg-negative patients without liver cirrhosis (n=2840)Follow up for 17 years

HCCGreatest influence of HBsAg level at

lower HBV DNA levels

Chen et al. Hepatology 2011

HBsAg level is an important risk factor in

ERADICATE-B

patients with low HBV DNA level (<2000 IU/mL)

5-fold risk increase5-fold risk increase by univariate analysis

Tseng, … Kao. Gastroenterology 2012; Chan HL. Gastroenterology 2012

Cumulative riskHCC risk

Cumulative Risk Scores and Projected HCC RiskRisk predictor Risk score

Cumulative risk score At 3rd year At 5th year  At 10th

year 0 0.0% 0.0% 0.0%1 0.0% 0.0% 0.1%

GenderFemale 0Male 2

Age2 0.0% 0.0% 0.1%3 0.0% 0.1% 0.2%4 0.0% 0.1% 0.3%5 0 1% 0 2% 0 5%

Age30‐34 035‐39 140‐44 2

5 0.1% 0.2% 0.5%6 0.1% 0.3% 0.7%7 0.2% 0.5% 1.2%8 0.3% 0.8% 2.0%

45‐49 350‐54 455‐59 560‐65 6

9 0.5% 1.2% 3.2%10 0.9% 2.0% 5.2%11 1.4% 3.3% 8.4%12 2 3% 5 3% 13 4%

60 65    6ALT, U/L<15 015‐44 1

12 2.3% 5.3% 13.4%13 3.7% 8.5% 21.0%14 6.0% 13.6% 32.0%15 9.6% 21.3% 46.8%

≥45 2HBeAgNegative 0Positive 2

16 15.2% 32.4% 64.4%17 23.6% 47.4% 81.6%

os t eHBV DNA level, copies/mL<300 (Undetectable) 0300‐9999 010000 99999 310000‐99999 3100000‐999999 5≥106 4 Yang et al., Lancet Oncol, 2011

High Baseline HBV DNA Associated With

Cumulative incidence of HCC at Cumulative incidence of cirrhosis at

Increased Risk of Cirrhosis and HCC

50 50

Cumulative incidence of HCC at year 13 follow-up1 (N = 3,653)

Cumulative incidence of cirrhosis at year 13 follow-up2 (N = 3,582)

30

40

nts

36.2%

30

40

nts

14.9%20

30

% o

f pat

ien

23.5%

20

30

% o

f pat

ien

12.2%

3.6%1.4%1.3%

104.5% 5.9%

9.8%10

1.4%1.3%0

<300 300-999

1000-9999

10,000-99,999

≥1million

0<300 300-

9991000-9999

10,000-99,999

≥1million

Baseline HBV DNA (copies/mL)1Chen, et al. JAMA. 2006;295:65-73. 2Iloeje, et al. Gastroenterology. 2006;130:678-686.

H t ll l C i b S HBV DNAHepatocellular Carcinoma by Serum HBV DNA Levels at Study Entry and at Last Follow-up

Level of HBV DNA, copies/mL

Adjusted HR (95% CI)†

Plus

No. ofParticipants(N 3653)*

No. of HCC

C

Median Time Between the Baseline and

Last Follow-up E i ti

Sex, Age, Cigarette

Smoking, and Alcohol

C t

Plus Seropos. for HBeAg, Liver

Cirrhosis, and ALT

L lAt Study

E t At F ll (N = 3653)* Cases Examination, y Consumpt. Level Entry At Follow-up

≥ 100 000 < 10 000 146 8 11.13.8

(1.7-8.4) 1.9

(0.8-4.4) 10 000 99 7 3 4 3

≥ 100 00010 000- 99

999 120 10 10.57.3

(3.5-15.3) 4.3

(2.0-9.3)

≥ 100 000 ≥ 100 000 537 55 9.910.1

(6.3-16.2) 5.3

(2.9-9.7) ( ) ( )Abbreviations: ALT, alanine aminotransferase; CI, confidence interval; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HR, hazard ratio.*There were 289 participants whose last follow-up serum samples were not available.†Cox proportional hazard model was used†Cox proportional hazard model was used.

Survival of HBe Ag-positive patients withSurvival of HBe Ag positive patients with compensated or decompensated cirrhosis

100

84%

60

80

l (%

) 84%

40

60

urvi

val

20

S

Compensated (n=77)

Decompensated (n=21) 14%

00 1 2 3 4 5

Decompensated (n 21) 14%

0 1 2 3 4 5Years

Jongh D. et al. Gastroenterology. 1992.

Lifetime risk of death from chronicLifetime risk of death from chronic liver disease,cirrhosis or hepatocellular carcinoma

HBV - Infection During Early Childhood 25-40 %

HBV - Infection During Adulthood 15 %HBV Infection During Adulthood 15 %

Keeffe EB. Am J Gastroenterol. 1995.

Beasley RP. et al. 1991.

Mast EE. et al. SemVirol 1993.

HBV: precore mutation in HBe minus HBVHBV: precore mutation in HBe minus HBV

HBV DNAATG ATG TAG

Precore Prot.

G to A point mutation in precore region > stop codon (TAG)

ER?Precore Prot.

Processing

ER?nucleus?

e Antigen (serum)

Core Antigen (virus) P 21

Epidemiology of Hepatitis B Infection in the Asia-Pacific Region

Country Prevalence of chronic HBV infection (%) Prevalence of HBeAg-negative disease in the g

HBsAg-positive population(%)

AustraliaChina

0.15

9 78407

40-457ChinaHong KongIndia

9.78.89

3.3410

40-45607

1812

Korea 2.83 477

MalaysiaNew Zealand

5.242

Maori 6%, Pacific Islanders 8%,Asians 7%7

4515

557

P ki t 514 N t kPakistanThe Philippines

514

5-162Not know

257

Singapore 415 4015

Taiwan 15 2017 4018TaiwanThailandVietnam

15-2017

3-67

10-207

4018

30-387

407

HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus

Mohamed R., Piratvisuth T, et al. J Gastroenterol Hepatol 2004(19); 958-969

Biochemical patterns in 164 untreated anti-pHBe positive patients with chronic hepatitis B

ALT

EASL annual meeting 1999 and reference 21

CHB: Complex natural history with several stages

ImmuneImmune ImmuneImmune

HBeAg+ HBeAg–HBeAg+

ImmuneEscape/Reactivation

Immune Tolerant

ImmuneControl

Immune Clearance

HBV-DNAHBV DNA

ALTB b htBeobachten

Cirrhosis

HCC

Cirrhosis

HCC

May lead to HBsAg clearance

Inactive CarrierStatus

HBeAg –chronic HBV

HBeAg +chronic Hepatitis B

HCC HCCclearance

Statusp

Treatment indication

Treatment indication

Goals of HBV therapypy

HBV seromarkers as treatment endpoints

To define treatment success

To indicate good long-term outcomes

Clinical and biochemical improvement

Histological improvement

Preventing disease progression to cirrhosis, decompensated cirrhosis HCC and deathdecompensated cirrhosis, HCC and death

Improve quality of life and survivalEASL. CPGs. J Hepatology 2009; 50(2): 227-242.APASL Consensus. Hepato Int. 2008. AASLD Guideline. Hepatology 2007.

When and who needs to be treated?

Indication for HBV treatment

HBeAg-positiveHBV DNA > 20,000 IU/ml

ALT > 2 x ULN

HBeAg-negativeHBV DNA > 2,000 IU/ml

ALT > 2x ULN

• Fibrosis stage 3-4• Hepatic decompensatingregardless of serum ALT levelregardless of serum ALT level

Thailand practical guideline 2012

Ch i H titi B ith i i llChronic Hepatitis B with minimally elevated ALT < 2 x ULNelevated ALT 2 x ULN

Si ifi t li di⇒ Significant liver disease• necroinflammatory HAI > 4 or Metavir > 2 y

• Fibrosis F > 2 (Metavir) or F > 3 (Ishak)• Transient elastrography > 7 KPa

Thailand practical guideline 2012

Chronic HBV with normal ALTChronic HBV with normal ALT

• Male older than 40 years oldMale older than 40 years old

• Family history of cirrhosis or HCC• Clinical feature of chronic liver disease

Liver biopsy Transient elastrograpy

Significant liver disease > 7 KPa

HBV treatmentHBV treatment

Thailand practical guideline 2012

Chronic HBV with cirrhosisChronic HBV with cirrhosis

detectable undetectableHBV DNA

HBV treatment regardless of

Liver transplantation

iti li tregardless of serum ALT level waiting list

Yes No

Monitoring every

3 6 months3-6 monthsThailand practical guideline 2012

Treatment of Chronic Hepatitis BTreatment of Chronic Hepatitis B

• cIFN 5-10 MU TIW for 6 months

• Peg IFN alfa 180 μg weekly for 12 months

• Peg IFN alfa-2b 1.5 μg/kg for 12 months

L i di 100 150 d il• Lamivudine 100-150 mg daily

• Adefovir dipivoxil 10 mg daily

• Entecavir 0.5 mg daily

• Telbivudine 600 mg daily• Telbivudine 600 mg daily

• Tenofovir 300 mg daily

HBV Treatment Peginteferon vs Nucleos(t)ide Analogues

Peginterferon Nucleos(t)ide Analogues g Nucleos(t)ide Analogues Advantages Advantages• Finite duration • Daily oral dosing• Response is more durable • Minimal adverse events in the short term• Response is more durable

post-therapy• Minimal adverse events in the short term

• Post-treatment delayed response • Safe and effective in patients with advanced liver disease and hepatic decompensation

• Higher HBeAg and HBsAg seroconversion rate

• Less expensive during first yr, possible equally or more costly with long-term therapy

Disadvantages Disadvantages• Frequent adverse events • Risk of resistance

W kl b t i j ti Li it d HB A i t• Weekly subcutaneous injections • Limited HBsAg seroconversion rate

• Less effective on-treatment HBV DNA suppression

• Response is mostly not durable post-therapy

• Initially expensive • Long term or indefinit therapy may be required

Janssen H.L.A. etal. Hepatology. 2013

• Initially expensive • Long-term or indefinit therapy may be required

Incidence of Resistance with Prolonged Oral NA Therapy in CHB PatientsOral NA Therapy in CHB Patients

1 Yr 2 Yr 3 Yr 4 Yr 5 Yr

Lamivudine1 24% 42% 53% 70% 75%

Adefovir2‐4 0% 3% 11% 18% 29%

Entecavir5,6,8

(treatment‐naïve)0% 0%  1.2% 1.2% 1.2%

Entecavir5,6Entecavir(lamivudine‐resistant)

6% 15% 36% 46% 51%

Telbivudine (HBeAg+)7,8 5% 25%* NA NA NA

Telbivudine (HBeAg‐)7,8 2% 11%* NA  NA NA

Tenofovir (HBeAg+)9 0% 0% 0% 0% 0%

f i ( )9Tenofovir (HBeAg‐)9 0% 0% 0% 0% 0%

*Novartis / Idenix data on file. 1. Liaw Y-F, et al. Gastroenterololgy. 2000;119:172-80. 6. Colonno RJ, et al. Hepatology. 2006;44:229A-230A. 2 H di i SJ t l G t t l 2006 131 1743 51 7 L i t l N E J M d 2007 357 2576 882. Hadizyannis SJ, et al. Gastroenterology. 2006;131:1743-51. 7. Lai, et al. N Eng J Med. 2007;357:2576-88.3. Hadziyannis SJ, et al. N Engl J Med. 2005;352:2673-81. 8. Zeuzem S, et al. Hepatology. 2007; 46:4(suppl 1):681A.4. Hadziyannis SJ, et al. N Engl J Med. 2003;348:800-7. 9. EMEA assessment report on Viread.5. Colonno RJ, et al. Hepatology. 2006;44:1656-65. 10. EMEA assessment report on Viread.

United States 1983 1988United States, 1983-1988

Acute hepatitis A cases death fatality rate(NO.) (NO.) (%)

All patients 115,551 381 0.015

Chronic HBV infection 2311 27 11.72

Chronic liver disease 2,3113 107 4.64

No liver disease 113,009 247 0.2

1calculated from 0.2% HBsAg carrier rate in US258.5 fold greater fatality rate than patients with no liver disease3calculated from estimated 2% prevalence of chronic liver disease in US423 f ld t f t lit t th ti t ith li di423-fold greater fatality rate than patients with no liver disease

Hadler, 1991.

Sh h i E id iShanghai Epidemic

Acute hepatitis A cases death fatality rate(NO.) (NO.) (%)

All patients 310,746 47 0.015

HBV infection 27,3461 15 0.052

No HBV infection 283,400 233 0.009

1calculated from 8.8% HBsAg carrier rate in this region China25.6-fold greater fatality rate than patients without HBV infection37patients with miscellaneous non hepatic deaths excluded37patients with miscellaneous non-hepatic deaths excluded

Yao, 1991.

Safety & Immunity of Hepatitis A vaccine i P ti t ith Ch i Li Diin Patients with Chronic Liver Disease

• > 94% of chronic liver disease (CHB, CHC, Al h li i h i ) itiAlcoholic cirrhosis) were seropositive after complete vaccinationL l i j ti it t th t• Local injection-site system were the most common reaction reported (35% of all d )doses)

Keeffe EB, et al. Hepatology 1998

73

Natural History Of HBV Reactivation During ChemotherapyChemotherapy

Recovery of Recovery of DeathChemotherapyChemotherapy

neutropeniaSteroid withdrawal

neutropeniaSteroid withdrawal

Acute liver failure

DeathChemotherapysteroids

Chemotherapysteroids

Chronic hepatitis

CirrhosisCirrhosis

ALTAcute HBV DNA 

I

hepatitis

I

0 4 8 12 16 20 24 28 32 36 52 100

RecoveryImmune rebound

Immune suppression

Weeks after exposure

0 8 6 20 8 3 36 5 00

Nunes J, et al. Acta Reumatol Port 2011;36:110‐118.

Management of HBV during pregnancy HBsAg+ve pregnant women

1st trimester check: LFTs,CBC, INR HBeAg, HBeAb, HBV DNA levels

2nd trimester (at 24 28 weeks)

if active disease or advanced fibrosis : consider treatment with tenofovir or telbivudine

Previous child HBV infection

2nd trimester (at 24-28 weeks) check: ALT , HBV DNA levels

No Yes*

HBV DNA HBV DNA Regardless of maternal<2,000,000 IU/ml

HBV DNA >2,000,000 IU/ml

monitor Consider treatment with telbivudine or

Regardless of maternalHBV DNA levels

Stopping therapy atConsider treatment with telbivudine or tenofovir at 26-32 weeks

HBIG and HBV vaccine given to newborn

Stopping therapy at 1 month post partum

NoYeswithin 12 h. and complete vaccination

oes

Breastfeeding Formula feeding

Postpartum monitoring for flare in mothersPostpartum monitoring for flare in mothers

* Individual consideration after discussion about risk and benefits with mother

Recent Advance in Management of Chronic Hepatitis CChronic Hepatitis C

Teerha Piratvisuth, M.D.NKC Institute of Gastroenterology and HepatologyNKC Institute of Gastroenterology and Hepatology

Prince of Songkla University,Thailand

Chronic Hepatitis C in Thailand

Prevalence 0 8 6%Prevalence 0.8 – 6%

Higher prevalence in male 3 2% vsHigher prevalence in male 3.2% vs1.8% in female

Increasing with age, peak at 31-40 years of ageyears of age

Luksamijarulkul 2007. Sunanchaikarn 2007Sunanchaikarn 2007. Ratanasuwan 2004. Boonmar S. 1990.

Prevalence of HCV :geographic distribution

3.8-7.5%

3.4-5.6%

1-2%

1%

Sunanchaikarn S Asian Pac J Allergy Immunol 2007Sunanchaikarn S. Asian Pac J Allergy Immunol 2007.Ratanasuwan W. Southeast Asian J Trop Med Public Health 2004.Wiwanitkit V. Viral Immunol 2002.Jittiwutikarn J. Am J Trop Med Hyg. 2006.

Risk factors for HCV infection in Thailand

Tattooing Unsafe injectionBlood

20%

Unsafe injection sharing of

razors

Blood transfusion prior 1992

32%46.7%IVDU

32%

Hansurabhanon T. 2002., Luksamijarulkul P. 2005., Sawanpanyalert 1996., Tanwandee T. 1998.

HCV genotype distributionHCV genotype distribution

III: 51% VI: 6-12%a: 96%b: 4%

a: 22% b: 78%

I: 33%II: 4%II: 4%

Sunanchaikarn S. Asian Pac J Allergy Immunol 2007.Theamboonlerts. Acta Virol 2002.Kanistanon D. J Clin Microbiol 1997.Pham DA. Asian Pac J Allergy Immunol 2009.Tokita H. Proc Natl Acad Sci USA 1994.

Good SVR rates in Asia are likely due to the highGood SVR rates in Asia are likely due to the high prevalence of the favorable IL28B CC genotype

Thomas DL, et al. Nature 2009; 461: 798–801

Natural course of chronic hepatitis CNatural course of chronic hepatitis CAcute hepatitis C

Chronic hepatitis C

~80%

Cirrhosis

20% in 20 Yrs

0.4% /yr1.1% /yr1.5% /yr 2.5% /yr

Hepatocellular carcinoma

Variceal bleeding

Ascites Hepatic encephalopathy

68% /yr40% /yr86% /yr 11% /yr

DeathButi et al. J Hepatol. 2000.

Progression of fibrosis by duration g yof infection

Marcellin F. et al. Hepatology. Nov 2002; 36(5) Suppl. 1: S47-S56.

Probability of developing cirrhosisProbability of developing cirrhosis

Marcellin F. et al. Hepatology. Nov 2002; 36(5) Suppl. 1: S47-S56.

Life expectancy in patients aged 30Life expectancy in patients aged 30 years with chronic hepatitis C

1618 16.9 yrs

1214

ed li

fe

y (y

rs)

68

10

imin

ish

pect

ancy

7.1 yrs

246D

iex

p

02

Mild chronic h titi C

Moderate chronic h titi C

Buti et al. J Hepatol. 2000

hepatitis C hepatitis C

Hepatitis C Tests andHepatitis C Tests and Diagnosis of HCVDiagnosis of HCV

O i ti f HCVStructural Nonstructural

Organization of HCV genomeStructural Nonstructural

C C1 E2 NS25’ NS3 NS5NS4 3’

c33 5-1-1

Polyproteins c22 HVRc100

Aminoacids 384-414Function

C P RNA d dCoreEnvelope

ProteasesHelicase RNA-polymerase

RNA-dependent

HCV: Antibody Tests

Two Principal Roles of Antibody Tests for HCVHCV– Screening Assay: High Sensitivity Tests

Anti-HCV EIA– Supplemental Assay: Resolve False-Supplemental Assay: Resolve False

Positive ResultsRecombinant Immunoblot Assay (RIBA)Recombinant Immunoblot Assay (RIBA)

Anti-HCV antibody tests

Assay Antibodies detected / coding regiony g g

Screening tests:

1st generation ELISA Anti-c100/NS41st generation ELISA Anti-c100/NS4

2nd generation ELISA Anti-c22/C, anti-c200/NS3/NS4

(anti c33 + anti c100)(anti-c33 + anti-c100)

3rd generation ELISA C, NS3, NS4, NS5

4 h G i ELISA C NS3 NS4 NS54th Generation ELISA C, NS3, NS4, NS5 (Murex anti-HCV version 4.0)

Sensitivity and Positive Predictive ValueSensitivity and Positive Predictive Value of Anti-HCV EIA

Positive Predictive Value

Wk. Before Sensitivity Low Hightest positive Prevalence Prevalence

EIA-1 16 70-80 50-50 70-85

EIA-2 10 92-95 50-61 88-95

EIA-3 6 8 97 25 n.d.EIA 3 6-8 97 25 n.d.

EIA-4 4-8 97 n.d. n.d.

Gretch, Hepatology, 1997

To confirm HCV infection

Anti HCV (RIBA Assay )( y )HCV RNA qualitativeHCV RNA qualitative

quantitative

Response-guided therapy in genotype 1 patients

Baseline HCV genotype 1

HCV RNA neg HCV RNA posWk 4 45% 55%

HCV RNA neg HCV RNA pos(>2 log10)Wk 12 HCV RNA pos

(<2 log10)42%

Wk 24 HCV RNA posHCV RNA neg

Peg-IFN/RBVfor 48 weeks

Stop treatmentPeg-IFN/RBVfor 72 weeks?

Peg-IFN/RBV for 24 weeks, only if LVL* at baseline

Omata, et al. Hepatol Int 2012; [Epub ahead of print]* LVL = Low viral load, HCV RNA <400 000 IU/ml

96% 70% 50%Overall SVR 70%

Response-guided therapy inResponse-guided therapy in genotype 2/3 patients

HCV genotype 2/3Baseline

HCV RNA neg HCV RNA posWk 4

HCV RNA neg

HCV RNA pos(>2 log10) but

negative th ft

Wk 12 HCV RNA pos(<2 log10)

or positive at k 24thereafter week 24

Treatment for 24 weeks

Stop treatmentTreatment for 48 weeks

Treatmentfor 16 weeks*

Omata, et al. Hepatol Int 2012; [Epub ahead of print]* Genotype 2 patients only

Overall SVR 80%

HCV Life Cycle and DAA Targets

Receptor bindingand endocytosis Transport

and releaseFusion

and uncoating

ER l(+) RNA Virionassembly

LDER lumen

LD

Translation andpolyprotein processing

RNA replicationMembranous

webER lumen

LDNS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotideNucleoside/nucleotideNonnucleoside

NS5A* inhibitors

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

*Role in HCV life cycle not well defined

Hepatitis Delta Virus (HDV)

A defective single-stranded RNA virusg

Requires for HBV for replication

Using HBV surface coat proteins to provide a shellprovide a shell

Outcome and natural history ofOutcome and natural history of HDV infection

Co-infection SuperinfectionCo infection Superinfection

Fulminant Recovery Chronicity FulminantRecoveryChronicity

% % % % % %

Ci h i

2-20% 90-95% 2-7% 70-95% 5-10% 10-20%

0 80%Cirrhosis 70-80%

Hepatocellularcarcinoma?G.I. Siriraj Hospital.

Hepatitis E

• Endemic in Middle East part of Africa China• Endemic in Middle East, part of Africa, China,

Mexico, India

• Water - Borne epidemic

• Faeco - Oral transmission

• Incubation period about 2 6 weeks• Incubation period about 2-6 weeks

East-AfrMed-J 1996. May.

Hepatitis E

• Age of infection : 15 - 40 years oldAge of infection : 15 40 years old

• Acute icteric hepatitis

• Self - Limiting

• Mortality ratey

- General population 0.5 - 3%

%- Pregnant women 14 - 20%

Am-J. Trop-Med-Hyg. 1994. Oct.

Annu- Rev-Med. 1996.

Diagnosis of HEV Infection

Anti HEV Antibodies IgMAnti-HEV Antibodies - IgM

- IgG persist > 4 years

HEV particled in stool

HEV RNA in stool and serum

HEV Ag hepatocyte and stool