ACUTE VIRAL HEPATITISDIAGNOSIS & MANAGEMENT

I DEWA NYOMAN WIBAWADIV.GASTROENTERO-HEPATOLOGYDEPT. INTERNAL MED UDAYANA UNIV./ SANGLAH HOSPITAL, DENPASAR.

Curicullum Vitae• Nama : Prof. DR.Dr I Dewa Nyoman Wibawa, SpPD-KGEH• Tempat/Tgl Lahir : Klungkung, 17 November 1952• Riwayat Pendidikan :

– Pendidikan dokter : FK Unud Tahun 1979– Spesialisasi : FK Undip Tahun 1986– Konsultan : Tahun 1997 dari Organisasi PPHI, PGI, PEGI– Doktor : Tahun 2000 FK Unair– Guru Besar : Tahun 2002 FK Unud– Pendidikan tambahan : di Jepang Tahun 1995 sampai tahun 1996

• Jabatan : – Kepala Divisi Gastroentero-Hepatologi FK Unud/RS Denpasar; – Ka LitBang FK Unud; – Ka Unit Epid Klinik FK Unud.– Ketua Organisasi PPHI, PGI, PEGI Cabang Denpasar

ACUTE HEPATITIS

Definition:• Any disease process characterized by a

– diffuse inflammatory infiltrate of liver tissue,– with or without a degree of hepatocellular necrosis and local fibrosis.

• Etiology– Infectious, Chemical, Toxic and Autoimmune

Viral Hepatitis

• Viral infection of the Liver caused by– viruses with specific Hepatotrophic replication

Or– systemic viral infections involving hepatocytes

• The major biochemical marker is ALT

AA“ Infectious”

“ Serum”

Viral hepatitis

Entericallytransmitte

d

Parenteraly

transmittedF, G, TTV

? other

EE

NANBNANB

BB DD CC

Viral Hepatitis - Historical Perspectives

Source ofvirus

feces blood/blood-derived

body fluids

blood/blood-derived

body fluids

blood/blood-derived

body fluids

feces

Route oftransmission

fecal-oral percutaneouspermucosal

percutaneouspermucosal

percutaneouspermucosal

fecal-oral

Chronicinfection

no yes yes yes no

Prevention pre/post-exposure

immunization

pre/post-exposure

immunization

blood donorscreening;

risk behaviormodification

pre/post-exposure

immunization;risk behaviormodification

ensure safedrinking

water

Type of Hepatitis

A B C D E

Acute Viral Hepatitis• Asymptomatic infection

– Inappearance• Symptomatic infection

– Prodromal illness (Flu like)– Vomiting– Aversion to alcohol and cigarettes– RUQ discomfort– Pale faeces and dark urine– Jaundice

Hepatitis A Infection

Hepatitis A Virus

Hepatitis A

• Symptomatic Illness– Symptomatic in 80% of adults but not children (<3%)– Malaise, Vomiting and jaundice prominent

• Transmission patterns– Person to person contact– Common source outbreaks especially seafood

• At risk groups– Family contacts– People in institutional settings– Partners of gay men and IVDUs

Hepatitis A Virus (HAV)

• Virion– Non-enveloped 27-32nm virion– Hepatovirus of Picornaviridae– Linear ss+RNA genome of 7500 nm– Single open reading frame with VPg at 5’end of RNA– Encodes 4 structural and several non-structural proteins

Possible enterohepatic cycling of HAV

Cuthbert JA., Clin Microbiol Rev 2001, 14: 38-58.

HAV Pathogenesis

• Ingested orally• Resistant to stomach acid• Reaches the liver via the intestine• Replicates in hepatocyte cytoplasm• Secreted in the bile and excreted in faeces• Cell mediated immune clearance

and cyto-pathology• Symptoms last 2-3 weeks

Clinical Manifestations

• Incubation period 2 – 6 weeks• May be asymptomatic• Overt illness in 5%• Present as three stages, 1 Preicteric 2 Icteric 3 Recovery

FecalHAV

Symptoms

0 1 2 3 4 5 6 12

24

Hepatitis A Infection

Total anti-HAV

Titer ALT

IgM anti-HAV

Months after exposure

Typical Serological Course

Treatment• No specific antiviral drug is available• Treatment is symptomatic• Specific passive prophylaxis by pooled normal

human immunoglobulin given before exposure or in early incubation period can prevent or attenuate clinical illness.

Vaccination for HAV• Hepatitis A vaccination is recommended for all

children starting at age 1 year, travellers to certain countries, and others at risk.

• A safe and effective formalin inactivated alum conjugated vaccine containing HAV grown in human diploid cell culture is available

• A full course containing two intramuscular injections of the vaccine

• Protection starts after 4 weeks after injection and lasts for 10 – 20 years

Prevention of Hepatitis A Infection

• Pre-exposure– travelers to intermediate and high

HAV-endemic regions

• Post-exposure (within 14 days)Routine– household and other intimate contactsSelected situations– institutions (e.g., day care centers)– common source exposure (e.g., food prepared by infected

food handler)

Hepatitis B Infection

Hepatitis B Virus• Blumberg in 1965

discovers, names as Australia antigen.

• 1968 identified with association in serum hepatitis.

• Surface component of HBV called as surface antigen.

Acute Hepatitis B

• Symptoms & signs– 70% sub-clinical and 30% icteric– Flu-like or serum sickness– Constitutional symptoms with Jaundice

• Laboratory finding– AST / ALT increased and may rise 1000 IU/ml– High bilirubin– HBs Ag (+), HBc IgM (+) and HBV –DNA (+)

Pathogenesis of HBV infection• Disease is Immune mediated• Hepatocytes carry viral antigen• Immune response subject to antibody dependent.• N K cell and cytotoxic T cell attack• In the absence of adequate immune response HBV infection

may not cause hepatitis.• But lead to carrier state.• Infection – Immunodeficient person are likely to because

asymptomatic carrier followed infection

Incubation period: Average 60-90 days Range 45-180 days

Clinical illness (jaundice): <5 yrs, <10% 5 yrs, 30%-50%

Acute case-fatality rate: 0.5%-1% Chronic infection: <5 yrs, 30%-90%

5 yrs, 2%-10% Premature mortality from

chronic liver disease: 15%-25%

Hepatitis B - Clinical Features

What are the clinical symptoms of Hepatitis B ??

The Clinical Outcomes of HBV Infection

Chronic infection

Cirrhosis

HCC Decompensation

Inactive carrier state

Adult acute infection Recovery

Fulminant hepatitis

95%

< 1%30–90%

5–50 years

Transplantor

Death

Perinatal/childhoodacute infection Recovery

10–70%

< 5%

Mild, moderate or severe chronic hepatitis

1*

Adapted from EASL Consensus Statement. J. Hepatol. 2003; 39 (S1):S3–25

0.1*

2–10*

4* 3* 2–8*

* per 100 patient-years

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBsHBsAg

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

Acute Hepatitis B Virus Infection with Recovery

Typical Serologic Course

Weeks after Exposure

Titre

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(6 months)

HBeAg

Chronic(Years)

anti-HBe

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

Weeks after Exposure

Titre

Progression to Chronic Hepatitis B Virus InfectionTypical Serologic Course

Diagnosis• A battery of serological tests are used for the diagnosis of

acute and chronic hepatitis B infection.• HBsAg - used as a general marker of infection.• HBsAb - used to document recovery and/or immunity to

HBV infection. • anti-HBc IgM - marker of acute infection.• anti-HBcIgG - past or chronic infection.• HBeAg - indicates active replication of virus and

therefore infectiveness.• Anti-Hbe - virus no longer replicating. However, the

patient can still be positive for HBsAg which is made by integrated HBV.

• HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

Treatment • Patients with Hepatitis needs supportive

treatment• Hepatotrophic agent is considerable

treatment.• IN ACUTE EXCACERBATION CASES ORAL ANTI

VIRAL IS IMPORTANT.

Hepatitis C Infection

HCV Virology• The virus is not been grown

in culture• The virus is 50- 60 nm with

linear single stranded RNA genome surrounded by an enveloped carrying glycoprotein spikes

• Now classified as Hepacivirus in the family of Flaviviridae

• Six genotypes are identified, with high mutability

Incubation period: Average 6-7

wksRange 2-26 wks

Clinical illness (jaundice): 30-40% (20-30%)

Chronic hepatitis: 70%

Persistent infection: 85-100%

Immunity: No protective antibody

response identified

Hepatitis C - Clinical Features

Symptoms

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4

Hepatitis C Virus InfectionTypical Serologic Course

Titre

Months Years

Time after Exposure

Acute HCV

Liver TransplantCandidates

Chronic HCV

60%-85%

Cirrhosis

20%-50%

HepaticFailure

~ 20%

Liver Cancer

~ 20%

NIH Consensus Development Conference Statement. Hepatology. 2002;36(suppl. 1):S3.

Davis GL et al. Gastroenterol Clin North Am. 1994;23:603.Koretz RL et al. Ann Intern Med. 1993;119:110.

Takahashi M et al. Am J Gastroenterol. 1993;88:240.

Disease Progression ofHepatitis C Virus (HCV)

Adapted from Brown RS. Epidemiology and Natural History of Hepatitis C. Presented at: ACG Clinical Implications meeting; April 6, 2000; Dallas, TX.

two of three:

1.seroconversion (prefer < 1 year)

2.marked elevation in ALT (> 10 x ULN)

3.wide fluctuations in HCV VL (> 1 log)characteristic of acute HCV infection

Cohort Case Definition for Acute HCV Infection

Acute HCV Infection•first 6 months of infection •no specific diagnostic test•spontaneous clearance can occur•treatment highlyeffective

Chronic HCV Infection•after 6 months of infection•less responsive to treatment•cause of almost all HCV-related liver damage

Outcome of Acute HCV InfectionOutcome of Acute HCV Infection

Gerlach JT et al. Gastroenterology. 2003;125:80.

24 cleared (52%),24 cleared (52%),all within 16 wksall within 16 wks

46 symptomatic46 symptomatic

None clearedNone cleared

9 asymptomatic9 asymptomatic

54 cases observed for 3 months without treatment

First 12 Weeks Are ImportantFirst 12 Weeks Are Important• If symptoms develop, 50% chance of spontaneous If symptoms develop, 50% chance of spontaneous

viral clearance by 12 weeksviral clearance by 12 weeks• If no symptoms in first 12 weeks, little chance of If no symptoms in first 12 weeks, little chance of

spontaneous clearancespontaneous clearance• If PCR still positive at 5-6 weeks, little chance of If PCR still positive at 5-6 weeks, little chance of

spontaneous clearancespontaneous clearance• Transition from acute to chronic infection probably Transition from acute to chronic infection probably

occurs between 12 and 16 weeksoccurs between 12 and 16 weeks• Nearly 100% cure rate if antiviral treatment Nearly 100% cure rate if antiviral treatment

started by 12 weeksstarted by 12 weeks

Gerlach JT et al. Gastroenterology. 2003;125:80.Jaeckel E et al. N Engl J Med. 2001;345:1452.

Pimstone NR et al. Ann Int Med. 2004;141:W-91.PCR, polymerase chain reaction

Acute HCV: Treatment StudiesAcute HCV: Treatment Studies

NNTime toTime toRx (wk)Rx (wk) TreatmentTreatment

SVRSVR(%)(%)

1.1. 20202020

12121212

PEG (180 or 1.5/kg)PEG (180 or 1.5/kg)PEG + RibavirinPEG + Ribavirin

80808585

2.2. 15151515

885252

IFN 6MU/d x 4 wksIFN 6MU/d x 4 wks

6MU TIW x 20 wks6MU TIW x 20 wks

1001005353

3.3. 2626 12-2412-24 IFN or PEG x 24-52 wksIFN or PEG x 24-52 wks 8080

4.4. 4444 4-164-16 IFN 5MU TIWIFN 5MU TIW 9898

1. Kamal SM et al. Hepatology. 2004;39:1721.2. Nomura H et al. Hepatology. 2004;39:1213.

3. Gerlach JT et al. Gastroenterology. 2003;125:80.4. Jaeckel E et al. N Engl J Med. 2001;345:1452.Rx, treatment

Acute HCV: Management SummaryAcute HCV: Management SummaryALT normal, anti-HCV negative

PCR weekly x 2

Negative Positive(Get viral load)

Repeat at 12 weeksRepeat at 12 weeksFlu sx/JaundiceFlu sx/Jaundice

PCR at 12 weeksPCR at 12 weeks

AsymptomaticAsymptomatic

PCR at 6 weeksPCR at 6 weeks

(+)(+) (-)(-) (+)(+) (-)(-)

DoneDonePEG-IFN x 24 weeks

(-)(-) (+)(+)

DoneDonesx, symptoms

Time After Exposure

Symptoms +/-

Tit

er

Anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4[Years][Months]

Adapted from CDC Hepatitis Slide Kit. http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/. Accessed 10/1/04.

Serologic Pattern of Acute HCV Infection With Progression to Chronic Infection

HCV RNA

Acute HCV Infection: SummaryAcute HCV Infection: Summary

1.1. Symptomatic patients may clear HCVSymptomatic patients may clear HCV2.2. Spontaneous clearance usually Spontaneous clearance usually

occurs by 6 weeks, almost always by 12 occurs by 6 weeks, almost always by 12 weeksweeks

3.3. Start treatment for Start treatment for asymptomatic asymptomatic infections infections at 6 weeksat 6 weeks

4.4. Start treatment for Start treatment for symptomatic symptomatic infections if infections if still positive at 12 weeksstill positive at 12 weeks

5.5. Standard dose of PEG-IFN weekly x 24 weeks Standard dose of PEG-IFN weekly x 24 weeks will achieve SVR in 85%-100%will achieve SVR in 85%-100%

Hepatitis D Infection

Acute hepatitis D

Coinfection– severe acute disease.– low risk of chronic infection.

Superinfection– usually develop chronic HDV infection.– high risk of severe chronic liver disease.– may present as an acute hepatitis.

Hepatitis D - Clinical

Features

Percutanous exposures

injecting drug use

Permucosal exposuressex contact

Hepatitis D Virus Modes of Transmission

anti-HBs

Symptoms

ALT Elevated

Total anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV CoinfectionTypical Serologic Course

Time after Exposure

Titre

Jaundice

Symptoms

ALTTotal anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV SuperinfectionTypical Serologic

Course

Time after Exposure

Titre

Hepatitis EInfection

Hepatitis E Virus

• Calicivirus-like viruses• unenveloped RNA virus, 32-34 nm in diameter• +ve stranded RNA genome, 7.6 kb in size.• very labile and sensitive• Can only be cultured recently

Incubation period: Average 40 days

Range 15-60 days Case-fatality rate: Overall, 1%-3%

Pregnant women, 15%-25%

Illness severity: Increased with age

Chronic sequelae: None identified

Hepatitis E - Clinical Features

Symptoms

ALT IgG anti-HEV

IgM anti-HEV

Virus in stool

0 1 2 3 4 5 6 7 8 9 10

11

12

13

Hepatitis E Virus InfectionTypical Serologic Course

Titer

Weeks after Exposure

MANAGEMENT

• No specific therapy.• Bed rest, high calory & protein diet.• Special treatment for fulminant hepatitis and

cases with encephalopathy hepatic.

SUMMARY• DIAGNOSIS OF ACUTE HEPATITIS BASED ON CLINICAL

APPEARANCE, LIVER FUNCTION TEST ABNORMALITIES, AND SEROLOGIC DIAGNOSIS FOR ACUTE VIRAL HEPATITIS.

• MANAGEMENT IN GENERAL CONSIST OF SUPPORTIVE AND SYMPTOMATIC TREATMENTS, HEPATOTROPHIC DRUGS, EXCEPT FOR ACUTE HEPATITIS C EARLY INTERFERON TREATMENT IS IMPORTANT FOR PREVENTION OF CHRONICITY .

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MATUR SUKSMA