HEPATITIS

Dr. Leonardo B Dairi SpPD KGEH

Divisi Gastroenterologi Bag IPD
FKUSU/RS HAM Medan.
 Many causes of hepatitis
Leptospirosis
Infectious Bacterial Syphillis
Tuberculosis
Toxoplasmosis
Parasitic Amebiasis
Epstein Barr
Herpes Simplex
Viral Varicella Zoster
Coxsackievirus
Rubella
Yellow Fever
Alcohol
Noninfectious Drugs
 Viral agents that primarily or
exclusively infect the liver
Hepatitis A virus Infectious hepatitis
Hepatitis B virus Serum hepatitis
Hepatitis C virus Parenterally transmitted
Hepatitis E virus Enterically transmitted
Hepatitis D virus Coinfection with HBV
Hepatitis G virus Parenterally transmitted
 Viral Hepatitis - Historical
Perspective
Infectious A Enterically
E
transmitted

Viral NANB
hepatitis

Parenterally
Serum B D C transmitted
F, G,
? other
 Viral Hepatitis - Overview
Type of Hepatitis

A B C D E
Source of feces blood/ blood/ blood/ feces
virus blood-derivedblood-derived blood-derived
body fluids body fluids body fluids
Route of fecal-oral percutaneouspercutaneous percutaneous fecal-oral
transmission permucosal permucosal permucosal

Chronic no yes yes yes no

infection

Prevention pre/post- pre/post- blood donor pre/post- ensure safe

exposure exposure screening; exposure drinking
immunization immunization risk behavior immunization; water
modification risk behavior
modification
 Initial laboratory evaluation of jaundiced
patient
TEST PERFORMED
Urine bilirubin
Serum bilirubin
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase
Prothrombin time, partial
thromboplastin time, platelet
count, bleeding
Blood count with blood smear
exam
MEASUREMENT
Conjugated bilirubin
Conjugated and unconjugated
bilirubin
Hepatocellular damage
Hepatocellular damage
Intrahepatic or extrahepatic
obstruction
Clotting mechanism
Red blood cell morphology,
parasites, atypical lymphocytes
 HEPATITIS A VIRUS

RNA Picornavirus
Single serotype worldwide
Acute disease and asymptomatic infection
No chronic infection
Protective antibodies develop in response to
infection - confers lifelong immunity
 ACUTE HEPATITIS A CASE
DEFINITION FOR SURVEILLANCE
Clinical criteria

An acute :
discrete onset of symptoms (e.g. fatigue, abdominal
pain, loss of appetite, nausea, vomiting), and
jaundice or elevated serum aminotransferase levels

Laboratory criteria
IgM antibody to hepatitis A virus (anti-HAV) positive

Case Classification
Confirmed. Clinical case definition and is laboratory confirmed or a
clinical case and occurs in epidemiologic link with a person who
has laboratory- hepatitis A (i.e., household or sexual contact
during the 15-50 days before).
 HEPATITIS A - CLINICAL
FEATURES
Jaundice by <6 yrs <10%
age group: 6-14 yrs 40%-50%
>14 yrs 70%-80%
Rare complications: Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
Incubation period: Average 30 days
Range 15-50 days
Chronic sequelae: None
EVENTS IN HEPATITIS A VIRUS INFECTION
Clinical illness

Infection ALT

IgM IgG
Response

Viremia

HAV in stool

0 1 2 3 4 5 6 7 8 9 10 11 12 13
Week
 CONCENTRATION OF HEPATITIS A VIRUS
IN VARIOUS BODY FLUIDS
Feces
Body Fluids

Serum

Saliva

Urine

100 102 104 106 108 1010

Infectious Doses per mL
Source: Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
 GLOBAL PATTERNS OF
HEPATITIS A VIRUS TRANSMISSION
Rate Peak Age Transmission
Endemiciy
Diseas of Patterns
es Infection
Hi Low to high Early childhood Person to person;
outbreaks uncommon
Moderate High Late childhood/ Person to person;
young adults food and waterborne
outbreaks
Low Low Young adults Person to person;
food and waterborne
outbreaks
Very low Very low Adult Travelers; outbreaks
uncommon
GEOGRAPHIC DISTRIBUTION OF
HEPATITIS A VIRUS INFECTION
HEPATITIS A VIRUS TRANSMISSION

Close personal contact

(e.g., household contact, sex
contact, child day-care centers)

Contaminated food, water

(e.g., infected food handlers)

Blood exposure (rare)

(e.g., injection drug use, rarely by
transfusion)
 PREVENTING HEPATITIS A

Hygiene (e.g., hand washing)

Sanitation (e.g., clean water sources)
Hepatitis A vaccine (pre-exposure)
Immune globulin (pre- and post-exposure)
 HEPATITIS A VACCINES
Highly immunogenic
97%-100% of children, adolescents, and adults
have protective levels of antibody within 1
month of receiving first dose; essentially
100% have protective levels after second dose

Highly efficacious
In published studies, 94%-100% of children
protected against clinical hepatitis A after
equivalent of one dose
HEPATITIS A VACCINE EFFICACY STUDIES
Site/ Vaccine Efficacy
Age Group (95 % Cl)
Vaccine N

HAVRIX Thailand 38,157 94%

(GSK) 1-16 yrs (79%-99%)
2 doses
360 EL.U.

VAQTA New York 1,037 100%

(Merck) 2-16 yrs (85%-100%)
1 dose
25 units

JAMA 1994;271:1363-4; N Engl J Med 1992;327:453-7

 DURATION OF PROTECTION AFTER
HEPATITIS A VACCINATION

Persistence of antibody
At least 5-8 years among adults and children
Efficacy
No cases in vaccinated children at 5-6 years
of follow-up
Mathematical models of antibody
decline suggest protective antibody
levels persist for at least 20 years
Other mechanisms, such as cellular
memory, may contribute
 COMBINED HEPATITIS A
HEPATITIS B VACCINE
Approved by the FDA in United States for persons
>18 years old Contains 720 EL.U. hepatitis A antigen
and
20 g. HBsAg
Vaccination schedule: 0,1,6 months
Immunogenicity similar to single-antigen vaccines
given separately
Can be used in persons > 18 years old who need
vaccination against both hepatitis A and B
Formulation for children available in many other
countries
 HEPATITIS A PREVENTION
IMMUNE GLOBULIN
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)

 SAFETY OF HEPATITIS A VACCINE
Most common side effects
Soreness/tenderness at injection site - 50%
Headache - 15%
Malaise - 7%
No severe adverse reactions attributed to
vaccine
Safety in pregnancy not determined risk likely
low
Contraindications - severe adverse reaction to
previous dose or allergy to a vaccine component
No special precautions for
immunocompromised persons
Hepatitis B Virus
HBV
 HBV nomenclature

HBV: hepatitis B virus

HBsAg: hepatitis B virus surface
antigen
HBcAg: hepatitis B virus core
antigen
Hepatitis B Virus Infection
Global Facts
2 billion people infected.
>400 million chronic carrier of the virus.
75% of the chronic carriers are Chinese.
Annual incidence of liver cancer in the
world:
530,000 cases of which
316,000 cases (59.4%) due to hep. B
Lai CL, et al, Lancet, 2003
 HBV Epidemiology
Horizontal transmission
Person-to-person spread
Parenteral
Sexual
Vertical transmission
Chronically infected mother to child
At birth or via breast milk
 HBV Pathology
Portal of entry
Percutaneous is most efficient
Sexual or perinatal is less efficient but
major source
Into bloodstream and to liver
Hepatocytes
Little cytopathology
Immune pathology
 HBV Clinical Syndromes
ACUTE INFECTION
Incubation phase: long (6weeks-6month)
Prodromal phase: insidious
Flu-like: malaise, fatigue, anorexia, nausea, abdominal
discomfort, chills
Icteric phase: liver damage: jaundice, dark urine,
pale stools
Recovery: decline in fever; renewed appetite
 HBV Diagnosis
Clinical
Symptoms
Looks like HAV
 HBV Diagnosis
Laboratory
Liver enzymes
Serology
HBeAg, HBcAg, virus: active infection
Anti-HBc IgM: acute active infection
Anti-HBe IgG: acute infection
 HBV Complications
Fulminate hepatitis
Chronic hepatitis
5%-10% of HBV infections
10% of these progress to cirrhosis/liver
failure
At higher risk for fulminant hepatitis
Healthy Liver Hepatic Fibrosis

Cirrhosis Liver Cancer

Healthy Liver Hepatic Fibrosis

Cirrhosis Liver Cancer

 HBV Complications
Postviral; asymptomatic carrier
Chronic HBsAg antigenemia
state; HBsAg only
Postviral; elevated
Chronic persistent hepatitis
transaminase; no progression to
(CPH)
liver disease
Postviral; progresses to liver
Chronic active hepatitis (CAH)
disease
Postviral; no progression to
Chronic lobular hepatitis (CLH) liver disease; elevated
transaminase levels

Liver cirrhosis

20-30 years of persistent HBV

Hepatocellular carcinoma
infection leading to liver injury
 Treatment of Chronic Hepatitis B
C. When
Chronic HBV inf & Cirrhotic & HBV DNA 10 4 copies/ ml

D. How
5 Drugs for Chronic HBV inf
1. Interferon Alfa 2b ( 1992)
2. Peginterferon Alfa 2a ( 5/2005 )
3. Lamivudin ( 1998 )
4. Adifovir dipivoxil ( 2002 )
5. Entecavir ( 3/ 2005 )
6. Telbivudine ( 2/2007)
Treatment Strategy of CHB
Decompensated Cirrhosis or End-Stage Liver Disease (HBeAg+ or HBeAg -)

Decompensated Cirrhosis or End Stage Liver Disease (HBeAg+ or HBeAg -)

HBV DNA < 2000IU/ml HBV DNA 2000IU/ml

Or < 10000 copies/ml Or 10000 copies/ml

Observe/monitor closely Treatment indicated

Consider / refer to transplant
center for evaluation for OLT
ACT HBV Asia-Pasific
Steering Committee
Members, Chronic
hepatitis B; treatment
alert. Liver Int. 2006
Consider/refer to transplant center for
evaluation for OLT
Entecavir, adefovir, lamivudine or
combination are first-line options
Entecavir and adefovir preferred over lamivudine
due to its high rate of drug resistance, especially
In decompensated cirrhosis
Response No Response

Closely monitor hepatic function and DNA;

May delay OLT OLT
 HBV Prevention
Screen blood products
Sterilization of needles, etc.
Avoiding intimate contact, e.g.,
household or sexual contacts
Vaccination
Subunit vaccines
HBsAg
 Fulminant Hepatitis:
Hepatic failure with in 2-3 weeks.
Reactivation of chronic or acute hepatitis
Massive necrosis, shrinkage, wrinkled
Collapsed reticulin network
Only portal tracts visible
Little or massive inflammation time
More than a week regenerative activity
Complete recovery or - cirrhosis.
KLINIS
IKTERUS PROGRESIF

BILIRUBIN > 20MG%

GANGGUAN KESADARAN PROGRESIF,

MUAL DAN MUNTAH, HATI MENGECIL, MASA
PROTROMBIN MEMANJANG,
TRANSAMINASE NAIK CEPAT DAN SANGAT
MENINGGI SERTA ALBUMIN MENURUN.
IMUNOPATOGENESE DARI FULMINAN HEPATITIS
 ETIOLOGI
VIRAL HEMORAGIC FEVER VIRUS
HEPATITIS VIRUS SITOMEGALOVIRUS
HEPATITIS A HERPES SIMPLEX VIRUS
HEPATITIS B EPSTEIN BARR VIRUS
HEPATITIS C PARAMIXOVIRUS
HEPATITS E ADENOVIRUS
HEPATITIS G

DRUG/ TOXIN NEOPLASTIK

DOSE RELATED LIMFOMA
ACETAMINOFEN METASTASE HATI,
CCI 4 MELANOMA , PARU
AMANITA POISONING
YELLOW PHOSPORUS
BACILLUS CEREUS EMETIC TOXIN

PREGNANCY RELATED
ACUTE FATTY LIVER OF PREGNANCY
HELLP SINDROME
IDIOSINKRINASI METABOLIC
HALOTHANE INBORN METABOLISM ERROR
ISONIAZID GALACTOSEMIA
RIFAMPISIN FRUCTOSE INTOLERANCE
VALPROIC ACID TYROSINEMIA
DISULFIRAM NEONATAL IRON STORAGE
NSAID DISEASE
NORTRIPTYLINE WILSON DISEASE
REYE SYNDROME ALFA 1 ANTITRIPSIN DEFF.
HERBAL MEDICINE
MISC
BUDD CHIARI SYNDROME
VENO OCCLUSIVE DISEASE
AUTOIMUNE HEPATITIS
ISCHEMIC SHOCK LIVER
PRIMARY GRAFT NON FUNCTIONIN LIVER
TRANSPLANTED PATIENT
HEAT STROKE
ADULT ONSET STILLS DISEASE
TATALAKSANA
N-ASETIL SISTEIN
PENDEKATAN
FARMAKOLOGI PROSTAGLANDIN

HAEMOPERFUSI ARANG
KOLOUMN HEPATOSIT
PENDEKATAN REGULASI SITOKIN
MOLEKULER
REGULASI KASKADE KOAGULASI

INHIBISI APOPTOSIS
HEPATOSIT GROWTH FACTOR

HEPATOSIT TRANSPLANT
TRANSPLANTASI
LIVER TRANSPLANT
HEPATITIS C
VIRUS
 Features of Hepatitis C Virus
Infection

Incubation period Average 6-7 weeks

Range 2-26 weeks
Acute illness (jaundice) Mild (<20%)
Chronic infection 60%-85%
Factors Promoting Progression or
Severity
Increased alcohol intake
Age > 40 years at time of infection
HIV co-infection
Other
Male gender
Chronic HBV co-infection
Serologic Pattern of Acute HCV Infection
with Recovery
anti-
HCV
Symptoms +/-

HCV RNA
Titer

ALT

Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after exposure
 Exposures Known to Be Associated With
HCV Infection in the United States

Injecting drug use

Transfusion, transplant from infected donor
Occupational exposure to blood
Mostly needle sticks
Iatrogenic (unsafe injections)
Birth to HCV-infected mother
Sex with infected partner
Multiple sex partners
 HCV Prevention and Control

Reduce or Eliminate Risks for

Acquiring HCV Infection
Screen and test donors
Virus inactivation of plasma-derived products
Risk-reduction counseling and services
Obtain history of high-risk drug & sex behaviors
Provide information on minimizing risky behavior,
including referral to other services
Vaccinate against hepatitis A and/or hepatitis B
Safe injection and infection control practices
 HCV Counseling

Preventing HCV Transmission to Others

Avoid Direct Exposure to Blood
Do not donate blood, body organs, other
tissue or semen
Do not share items that might have blood on
them
personal care (e.g., razor, toothbrush)
home therapy (e.g., needles)
Cover cuts and sores on the skin
 HCV Counseling

Other Transmission Issues

HCV not spread by kissing, hugging, sneezing,
coughing, food or water, sharing eating utensils
or drinking glasses, or casual contact
Do not exclude from work, school, play, child-
care or other settings based on HCV infection
status
Diagnostik :
Ditemuinya anti HCV. (minggu 5-6 setelah terpapar)
Peninggian transaminase pada minggu ke-2 s/d 26,
puncaknya minggu ke-5 s/d 12.
Kadar ALT biasanya meninggi pada pasien lebih dari
15 kali dari batas atas normal.
RNA HCV (+) menetap pada yang terinfeksi.

Gejala :
Banyak kasus asimtomatik
Flu-like sindrome, anoreksia, BB menurun, nyeri
abdominal, mialgia, atralgia dan fatigue.
Simptom yang jarang : demam dan rash.
Jaundice < 1/3 pasien.
Suggested management of chronic HCV
Infection
 HEPATITIS - D
Terdeteksi bersamaan dengan virus Hepatitis B.
HDV (+) diseluruh dunia berhubungan dengan
prevalensi infeksi HBV (+).
Lebih dominan didaerah tropikal dan subtropikal.
Infeksi HDV di negara berkembang lebih besar dari
pada di negara maju (Barat).
Manifestasi klinis dari coinfeksi atau super infeksi
bervariasi dari asimptomatis sampai yang berat
80% kasus kronik hepatitis D menjadi sirosis dalam
5-10 tahun.
Gold standard diagnosis : HDV RNA (+) atau HDAg (+)
liver.
Transmisisi :
Melalui parenteral, seksual, transfusi, jarum suntik,
haemodialisis.
Infeksi HDV dapat berupa koinfeksi atau superinfeksi
dengan HBV.

Prevalensi Geografis :
+ 5% carier HbsAg terinfeksi dengan HDV

Diagnosa :
HDV (+) di serum dan liver, HDV RNA dan HDAg (+)
Diagnosa dini dengan IgM anti HD
Gambaran Klinis :
Biasanya berat dan ikterus
Amino transferase meningkat

Pencegahan :
Dengan cara vaksinasi HBV

Therapi :
Tidak banyak bermanfaat dengan pemberian
antivirus dan immunodulator
 HEPATITIS AKUT E
Tidak berkapsul, sporadis , bersifat akut.
Terdistribusi di Asia, Timur Tengah, sebagian Afrika, dan
Meksiko.
Transmisi fecal oral route.
Paling sering pada dewasa muda.
Masa inkubasi 2 - 10 minggu.
Mortalitas : 25 %.
Bersifat asimptomatis dan anikterik

Diagnosa :
HEV (+) , anti HEV (+) dan HEV RNA (+)
Tidak ada yang spesifik untuk terapi hepatitis E
 HEPATITIS AKUT G
Termasuk Flava virus.
Terdistribusi secara luas.
Ditularkan melalui parenteral, seksual
dan perinatal.
HGV RNA dideteksi dengan PCR.
HGV tidak mempengaruhi respon untuk
terapi antiviral.
 Drug-induced hepatitis

Many drugs including herbal products can cause acute

hepatotoxicity will induce chronic hepatitis with prolonged
administration.
These include gold, isoniazid, ketoconazole,
methyldopa, nitrofuratoin, phenylbutazone and
silfonamides.
Oxyphenisatin the first agent known to be associated
with chronic hepatitis.
Older females are affected more frequently.
 Wilsons disease

It is important to exclude wilsons disease as a cause of

chronic hepatitis when it apprears in patients younger than
35 years.
Liver disease often precedes symptoms attributed to central
nervous system involvement and the appearance of
Kayser-Fleischer rings and may be the initial presentation
in 50 % of cases.
Elevated urinary and hepatic copper levels are diagnostic.
Improvement may be achieved by early treatment with D-
penicillamine.
 Autoimmune hepatitis

Characteristic laboratory findings :

1. Polyclonal hypergammaglobulinemia
2. Presence of non-liver spesific autoantibodies :
a. Antinuclear factor c. Rheumatoid factor
b. Smooth muscle antibody d. LE cells
Liver biopsy confirm the diagnosis, to ascertain the
degree of activity and the extent of fibrosis
It ussually shows a very florid picture with marked activity
and accompanying cirrhosis is not unusual even at
presentation.
 Autoimmune hepatitis

Most patients do not survive years if left untreated and

succumb to hepatic failure and gastrointestinal bleeding.
Corticosteroids have been shown to improve the general
well-being of patients and to reduce the morbidity and
mortality.
Recent studies have shown that at pre-cirrhotic stage
autoimmune hepatitis will not progress to fibrosis if
inflammatory activity is maintained below a threshold with
corticosteroid therapy.
Azathioprine may be added for patients who need high
doses of steroids to maintain remission but should never be
given alone.
 Autoimmune hepatitis

Cyclosporin can be used in patients who do

not respond to corticosteroids.
Ursodeoxycholic acid has been shown to
have cytoprotective and immuno-
modulating properties and can be
considered for this condition.
Liver transplantation should be considered
when complication become troublesome
and before the patient becomes moribund.