Hepatitis

dr Putra Hendra SpPD

UNIBA
 Liver

Pathology

Infectious Autoimmune
Diseases Hepatitis

Alcoholic Liver
Drugs & Toxins Disease

Metabolic Liver Intra Hepatic

Disease Biliary Diseases

Circulatory Hepatic disease-

Disorders Pregnancy

BM
Transplantation – Tumors
Hepatic Disease
 HEPATITIS - causes
 ACUTE:  CHRONIC:
 Viral hepatitis  Viral hepatitis
 Non-viral infection  Alcohol
 Alcohol  Drugs
 Toxins  Non-alcoholic
 Drugs steatohepatitis
 Ischemic hepatits  Autoimmune
 Autoimmune  Heredity
 Metabolic diseases
 What Is Hepatitis?
 Hepatitis means inflammation of the liver
 Hepat (liver) + itis (inflammation)= Hepatitis
 Viral hepatitis means there is a specific virus that is
causing your liver to inflame (swell or become larger
than normal)
WHAT IS VIRAL HEPATITIS ?
a serious disease caused by virus that attacks
the liver . There are various strains of viral
hepatitis which can cause:
 lifelong infection,

 cirrhosis ( scarring) of the liver

 liver cancer

 liver failure

 death
 Etiology
 Major agents:
 HAV
 HGV
 HBV

 HCV
 HFV

 HDV

 HEV
 Etiology
 Minor agents:
 EBV,CMV

 HSV,VZV

 Rubella,Measles

 Coxsackie B

 Adenovirus
Epidemiologi
Faktor resiko
 Risk Factors for Hepatitis B
Unknown
16%
Other
5%
Hetero-
sexual,
IDU multiple
16% partners
39%

MSM
24%

MMWR 2006;55(RR-16):6-7
 HEPATITIS B VIRUS:
HB E Ag

Anti HBE Anti HBc

HBV DNA

HB SAg
IgM Anti
HAV
Anti HBS
Anti
HCV

HCV RNA
 HOW THE VIRUS REPRODUCES ??
First the virus attached to a liver cell membrane.
The virus is then transported into the liver cell
The core particle then releases it’s contents of DNA
and DNA polymerase into the liver cell nucleus.
 Once within the cell
nucleus the hepatitis B
DNA causes the liver
cell to produce, via
messenger RNA ; HBs
protein , HBc protein ,
DNA polymerase, the
HBe protein , and
other undetected
protein and enzymes.
 DNA polymerase
causes the liver cell to
make copies of
hepatitis B DNA from
messenger RNA.
The cell then assembles ’live’ copies of virus.
However because of the excess numbers of surface proteins
produced many of these stick together to form small
spheres and chains. These can give a characteristic “
ground glass” appearance to blood samples seen under a
microscope.
 The copies of the virus and excess surface antigen are
released from the liver cell membrane into blood stream
and from there can infect other liver cells .
 HEPATITIS - symptoms
 ACUTE:  CHRONIC:
 Malaise  Malaise, tiredness,
 Muscle and join ache weakness
 Fever  Weight loss
 Nausea or vomiting  Peripheral oedema
 Loss of apetite  Ascites
 Abdominal pain
 Dark urine
 Jaundice
Penularan
 Transmission
HAV HBV HCV HDV HEV

Fecal-oral
+ - - - +
Percutan.
+ + + + -
Perinatal
- + + + -
Sexual
+ + + + -
 Routes of Transmission
Injecting drug use 60% Sexual 15%
Transfusion 10%
(before screening)

Occupational 4%

Other 1%*

Unknown 10%

* Nosocomial; iatrogenic; perinatal

Source: Centers for Disease Control and Prevention

 How do you get hepatitis B?

It is passed by contact with the blood or other body fluids of someone who
has the virus.
Inkubasi
 Incubation Period
 HAV:15-45 days(30)
 HBV: 30-180 days(60-90)

 HCV: 15-160 days(50)

 HDV: 30180 days(60-90)

 HEV: 14-60 days(40)

Hepatitis A
 Clinical Stages
 Incubation period
 Prodromal (preicteric) phase

 Icteric phase

 convalescence
 Hepatitis A - Clinical Features

 Incubation period: Average 30 days

Range 15-50 days
 Jaundice by <6 yrs, <10%
age group: 6-14 yrs, 40%-50%
>14 yrs, 70%-80%
 Complications: Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
 Chronic sequelae: None
 Preicteric Phase
 Systemic &nonspecific symptoms
 Flue like &Dyspepsia:

 Fever,sore throat,cough,headache

 Fever,anorexia,malaise,nausea

Vomiting,abdominal pain
Duration : 1-2 weeks
 Icteric Phase
 Clinical jaundice
 Dark urine:1-5 days before jaundice

 Patient may feel better

 Resolution of fever

 pruritus
 Hyperbilirubinemia
Hyperbilirubinemia (Jaundice)

Hepatic Posthepatic
Prehepatic
Genetic defects, Bile Duct Obstruction
(Hemolysis)
primary liver disease Pancreatic Head CA

Unconjugated Mixed Conjugated Bilirubin

Bilirubin
 Icteric Phase
 Liveris enlarged,tender
 Cervical adenopathy(10-20%)

 Splenomegaly(10-20%)

 Fever is absent

 Encephalopathy :Irritability

Letargy,confusion
Jaundice
 Laboratory Findings
 Serum bilirubin:5-20 mg/dl
 Direct bil =indirect bil

 SGOT,SGPT=400-4000 iu

 Alk.phosphatase :mild elevation

 PT is usually normal:in severe

hepatitis,PT is prolonged
 Hypoglycemia
 Diagnosis

 Acute infection is diagnosed by the detection of HAV-IgM

in serum by EIA.
 Past Infection i.e. immunity is determined by the detection
of HAV-IgG by EIA.
 Cell culture – difficult and take up to 4 weeks, not
routinely performed
 Direct Detection – EM, RT-PCR of faeces. Can
detect illness earlier than serology but rarely
performed.
Serologi
 Serologic Diagnosis
 A: Ig M anti-HAV
 B: HBs Ag and Ig M anti-HBc

 C: HCV Ab,HCV RNA PCR

 D: anti-HDV

 E: anti-HEV
 Hepatitis A Infection
Typical Serological Course
Symptoms Total anti-
HAV

Titre ALT

Fecal
HAV
IgM anti-HAV

0 1 2 3 4 5 6 1 2
2 4
Months after exposure
 Management
 Indicationof admission:
- Bilirubin>20 mg/dl
- Hypoglycemia
- Abnormal PT
- Hypoalbuminemia
 Management
 Indicationof admission :
- Poor oral intake
- Mental change,letargy
- Low compliance
- Other chronic disease
 Management
 Bedrest isnot mandatory
 Restriction activity

 No special diet &Therapy(HCV ? )

 Drug &Alcohol avoidance

 Isolation isnot necessary

except special cases

 Convalescence
 Resolution of symptoms
 Liver is enlarged

 Pruritus

 Complete recovery:

1-2 months A,E

3-4 months B,C
 Complications
 Hepatitis A:Relapsing hepatitis
 Cholestatic hepatitis

 Hepatitis B:serum sickness

 Chronicity: HBV,HCV,HDV

 fulminancy: HAV,HBV,HDV,

HEV
 prevention
 HAV:
 Pre-exposure prophylaxis:
Vaccine ,SIG:0.02 cc/kg
 Post-exposure prophylaxis:
SIG:0.02 cc/kg ;For day care
centers,family members
Vaccine ?
 Hepatitis A Vaccine
Recommendations

 International travelers
 Men who have sex with men
 Injection and noninjection drug users
 Persons with occupational risk (limited to
certain laboratory personnel and animal
handlers)
 Persons with chronic liver disease

MMWR 2006;55(RR-7)
 Twinrix
 Hepatitis B (adult dose) and hepatitis A
(pediatric dose)
 3-dose series at 0, 1, 6 to12 months
 4-dose series at 0, 7, 21 to 30 days, booster at 12
months
 Approved only for adults 18 years of age and
older
Hepatitis B
 Hepatitis B
SIGNS AND SYMPTOMS

•Loss of appetite,
•dyspepsia,
•abdominal pain
•Gen. aching malaise and weakness
•Jaundice
•Ligh-colored stools and dark urine
•Hepatomegaly and splenomegaly
•Enlarged posterior cervical lymph nodes
Pathogenesis

Thorgeirsson, S.S. and J.W. Grisham, Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet,
The Effect of The Liver Nodule
 HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER

Normal Cirrhosis

Nodules surrounded
by fibrous tissue
 Pathology
 Infiltrationof mononuclear cells
 Hepatic cells necrosis

 Kupfer cells hyperplasia

 Variable degrees of cholestasis

 In more severe cases;

Bridging necrosis
 Patterns of Liver Damage
 Hepatocellular damage
 Damage to hepatocytes themselves
 Inflammation, infection, ischemia, toxin, etc
 Cholestatic/Obstructive
 Blockage of bile ducts or impairment bile formation
 Determination of Liver Function
 Indicators of residual hepatocyte function and usually
indicative of chronic or fulminant liver damage
 Markers of Hepatocellular Injury
 Hepatocytes are damaged so they leak – so these
enzymes are HIGH
 Aspartate aminotransferase (AST)
 Alanine aminotransferase (ALT)

 Lactate dehydrogenase (LDH)

Markers of Cholestasis/Obstruction
 Cholestasis
 Alkaline phosphatase (AP)
 Gamma-glutamyltransferase (GGT)
 Bilirubin
HEPATITIS B MARKERS:
 HBsAg: Present in acute or chronic infection.
 HBsAb: Present in recovery or immunization.
 Anti -HB Core: May be “Total” (IgG&IgM)
or IgM. Lifelong marker of past and active
infection in either acute or chronic.
 HBeAg: Acute infection, and extremely
infectious.
 Anti-Hbe: Usually prognostic for resolution.
 Progression of Acute to
chronic Hepatitis
 Gejala tidak berkurang
(fatigue,anorexia,hepatomegaly)
 Kelainan Bil. ,LFT, lebih dari 6 bulan

 Persistence HBs Ag lebih dari 6 bulan

 HBe Ag lebih dari 3 bulan

 Adanya bridging necrosis

The phases of chronic hepatitis B

Immune Immune Immune Immune

tolerance clearance control escape

HBeAg+ve HBeAg–ve
< >< >
HBV-DNA

ALT

HBeAg +ve Inactive (carrier) HBeAg –ve active

chronic hepatitis state* chronic hepatitis

HBsAg (+)
*Previously considered to be ‘healthy carriers’ Slide 8
 Hepatitis B:

ACUTE CHRONIC- 5-10%

(infection >6months)

 Every year 1 to 2 million people die due to an infection by

this virus

complications of chronic hepatitis

 Diagnosis: HBsAg - 1-6 months after exposure
HBeAg - 1-3 months after acute
illness, high infectivity
anti-HBc - past infection
anti-HBs - implies vaccination

HBsAg-positive for at least 6 months - hepatitis B carriers (may

have chronic hepatitis B)
Hepatitis B Complications
 Fulminant hepatitis
 Hospitalization
 Cirrhosis
 Hepatocellular carcinoma
 Death
 Spectrum of Chronic Hepatitis B
Diseases

1 Chronic Persistent Hepatitis -

asymptomatic
2. Chronic Active Hepatitis -
symptomatic exacerbations of hepatitis
3. Cirrhosis of Liver
4. Hepatocellular Carcinoma
HBV Control
• Inflammatory: normalize serum ALT, biopsy
• Virologic: decrease HBV DNA
• Immune: seroconversion
o HBeAg to HBeAb
o HBsAg to HBsAb
• HBV never “cured” but controlled

Slide 9
 Therapeutic endpoints over time
Improved Improved
histology Anti-HBs+ survival

Anti-HBe+ Loss of
HBsAg
Loss of
HBeAg
Loss of
HBV DNA

TIME

Slide 10
Approved HBV treatments 2009
• Interferon alfa-2b – 1991
• Lamivudine – 1998
• Adefovir – 2002
• Entecavir – 2005
• Peginterferon alfa-2a – 2005
• Telbivudine – 2006
• Tenofovir – 2008

Slide 13
 HBV: The importance of monitoring

HBV is a dynamic disease!!!

Require treatment
40%
60%

Require monitoring…
• Inactive disease may not remain inactive
• Liver damage may occur if HBV
reactivates
HBV can be controlled but not cured
Slide 36
 Prevention
 HBV:
 Pre-exposure prophylaxis:
Vaccine :months 0,1,6
Booster isnot recommended
 Post-exposure prophylaxis:

HBIG:0.06 cc/kg and complete

course of vaccine
 Prevention
 Ab response unknown:
 Check anti-HBs;
If adequate:no treatment
If inadequate:HBIG(1) +
vaccine(1)
 Hepatitis B can be prevented!

If you have never had hepatitis B,

you can get 3 shots . . .

1 2 3

. . . and get long lasting protection.

 Baby Shots
for Hepatitis B
if the mother has Hepatitis B

Birth 1 - 2 months old

Hepatitis B
Vaccine + H-BIG
Hepatitis B
Vaccine

6 months old

Hepatitis B
Vaccine
Hepatitis c
 HCV/HIV Co-infection:
General Issues
 U.S. Prevalence 40% to 60%
 Varies geographically
 Varies by HIV risk behavior
 Major transmission routes are transfusion and IDU
 Sexual and vertical transmission are rare
 Coinfection may enhance
 Sexual transmission of HIV
 Vertical transmission of HCV
 Hepatitis C

ACUTE CHRONIC 50-80%

first 6 months after infection more than 6 months
60-70% asymptomatic often asymptomatic
most patients develop chronic 1/3 progress to cirrhosis in 20y
HCV

 Infects 3-4 million people per year

 Hepatitis C
SIGNS AND SYMPTOMS

•Asymptomatic or experience mild

symptoms
•Fatigue
•Abdominal pain and poor
appetite
•Jaundice
•Headaches
•joint aches
•muscle aches
•nausea
 Natural History of Hep C
20%
Only 20% will Clear the
show symptoms Virus
Initially !

Healthy Acute Chronic

Liver Infection Infection

80% Virus
Continues
to Damage
Liver
Adapted from Lauer and Walker, NEJM 2001
 Natural History Con’t

Chronic Cirrhosis Liver

Hepatitis 20-30% Cancer
1-4%/year

Most symptoms begin to show only when liver is more severely damaged
 Natural History of HCV Liver Disease

Liver
failure
(2 – 5% / yr)

~55-85%

25-30 yrs

2 - 4% / yr
 Factors That May Influence the
Progression of HCV Infection

Virus Host
Viral load? Sex
HCV genotype? Age
Race
Genetics
Immune response
Environment Duration of infection
Alcohol or drugs
HBV co-infection
HIV co-infection
Steatosis
Iron
NASH

Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.

 1.00 Progression to
cirrhosis
4682
0.83
patients
HIV-HCV
0.67
Alcohol
HBV
0.50 Haemochromatosis
rd function HCV
Steatosis BMI>25
0.33 2PBC

0.17

0.00
0 20 40 60 80
Age in years
Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265
 DIAGNOSIS
 Positive Hepatitis C antibody-exposure (Anti
HCV)
 Positive Hepatitis C RNA (PCR)
 RIBA
 Generally asymptomatic
 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
 Hepatitis C Virus Infection
Typical Serologic Course
anti-HCV

Symptoms

Titre

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after
Exposure
Serologic Pattern of Acute HCV Infection with
Progression to Chronic Infection
anti-HCV
Symptoms +/-

HCV RNA
Titer

ALT

Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after Exposure
 STANDARD ANTIVIRAL
THERAPY
 Pegylated interferon therapy (PegIFN)
 Pegasys
 PegIntron
 Injections one time per week, duration based on
genotype and response
 Must be kept cool (in the fridge!)
 Can be taken alone, although sustained viral response is
diminished.
 Ribavirin
 Tablets taken every day, dose based on genotype
 Not used as monotherapy
 HCV Treatment Options
 Interferon monotherapy
 Sustained response rates similar to HCV-
infected alone
 8% - 44%

 Minimal correlation with CD4 counts

 Interferon-ribavirin combination therapy

 Trials ongoing

 Preliminary findings encouraging

 >50% cure of chronic
Hepatitis C
80%

PEG IFN &

60% Ribavirin
IFN &
Ribavirin
tained virological
40% response PEG- IFN 48 weeks
48 weeks

12 kDa PEG- IFN alfa - 2b

IFN 48 weeks
20% 40 kDa PEG-- IFN alfa-2a
IFN 24 weeks

0%
1988 1990 1992 1994 1996 1998 2001
 Prevention
 Hand washing,hygiene
 Universal percaution
 No sharing of personal items
(razor,toothbrush,nail clipper)
 Sexual barrier
 Staging of fibrosis in chronic viral
hepatitis
Definition No Fibrosis Fibrous Few Bridges or Septa Numerous Bridges or Cirrhosis
Portal Expansion Septa

IASL No Fibrosis Mild Moderate Severe Fibrosis Cirrhosis

Fibrosis Fibrosis
Metavir F0 F1 F2 F3 F4

Goodman Z et al. J Hepatol 2007;47:598-607

Fibrosure
Fibroscan
 Hepatitis D
 Subviral satellite because it can propagate only in the presence of
hepatitis B

coinfection superinfection

 Transmission: parenteral (intravenous drug use mostly)

 > 60% develop cirrhosis

 Alcoholic hepatitis
 Major cause of liver cirrhosis in the Western world

hepatocellular necrosis and ballooning

degeneration