ACUTE VIRAL HEPATITIS DIAGNOSIS & MANAGEMENT

I DEWA NYOMAN WIBAWA DIV.GASTROENTERO-HEPATOLOGY DEPT. 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

A “Infectious”

“Serum”

Viral hepatitis

Enterically

transmitted

Parenteraly

transmitted

F, G, TTV

? other

E

NANB

B D C

Viral Hepatitis - Historical Perspectives

Source of

virus

feces blood/

blood-derived

body fluids

blood/

blood-derived

body fluids

blood/

blood-derived

body fluids

feces

Route of

transmission

fecal-oral percutaneous

permucosal

percutaneous

permucosal

percutaneous

permucosal

fecal-oral

Chronic

infection

no yes yes yes no

Prevention pre/post-

exposure

immunization

pre/post-

exposure

immunization

blood donor

screening;

risk behavior

modification

pre/post-

exposure

immunization;

risk behavior

modification

ensure safe

drinking

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

Fecal HAV

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 contacts

Selected 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

Transplant or

Death

Perinatal/childhood acute 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-HBs HBsAg

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 Infection

Typical 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 wks

Range 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 Infection Typical Serologic Course

Titre

Months Years

Time after Exposure

Acute HCV

Liver Transplant

Candidates

Chronic HCV

60%-85%

Cirrhosis

20%-50%

Hepatic

Failure ~ 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 of Hepatitis 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 highly effective

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

Outcome of Acute HCV Infection

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

24 cleared (52%),

all within 16 wks

46 symptomatic

None cleared

9 asymptomatic

54 cases observed for 3 months without treatment

First 12 Weeks Are Important

• If symptoms develop, 50% chance of spontaneous viral clearance by 12 weeks

• If no symptoms in first 12 weeks, little chance of spontaneous clearance

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

• Transition from acute to chronic infection probably occurs between 12 and 16 weeks

• Nearly 100% cure rate if antiviral treatment started 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 Studies

N Time to Rx (wk) Treatment

SVR (%)

1. 20 20

12 12

PEG (180 or 1.5/kg) PEG + Ribavirin

80 85

2. 15 15

8 52

IFN 6MU/d x 4 wks 6MU TIW x 20 wks

100 53

3. 26 12-24 IFN or PEG x 24-52 wks 80

4. 44 4-16 IFN 5MU TIW 98

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 Summary

ALT normal, anti-HCV negative

PCR weekly x 2

Negative Positive

(Get viral load)

Repeat at 12 weeks

Flu sx/Jaundice

PCR at 12 weeks

Asymptomatic

PCR at 6 weeks

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

Done PEG-IFN x 24 weeks

(-) (+)

Done

sx, 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: Summary

1. Symptomatic patients may clear HCV 2. Spontaneous clearance usually

occurs by 6 weeks, almost always by 12 weeks

3. Start treatment for asymptomatic infections at 6 weeks

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

5. Standard dose of PEG-IFN weekly x 24 weeks 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 exposures

sex contact

Hepatitis D Virus Modes of Transmission

anti-HBs

Symptoms

ALT Elevated

Total anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV Coinfection

Typical Serologic Course

Time after Exposure

Titre

Jaundice

Symptoms

ALT Total anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV Superinfection Typical Serologic Course

Time after Exposure

Titre

Hepatitis E

Infection

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 Infection

Typical 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