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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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04/19/23 57
MATUR SUKSMA