Curriculum Vitae

Nama : I Gede Arinton

Lahir : Singaraja, 1 Januari 1950
Alamat : Jl. Pramuka 249 Purwokerto
Istri : 1
Anak/Mantu/Cucu : 5/3/7
Pendidikan : 1. dr. umum FK. UNUD 1977
2. dr. SpPD FK. UNDIP 1987
3. MKom STIBBi Jkt 1999
4. MMR UNSUD 2005
5. KGEH FK. UI 2007
6. Doktor Ilmu Kedokteran UNDIP 2008
Pekerjaan : Bag. Penyakit. Dalam RSUD. Margono
Soekarjo/FKIK Unsud Purwokerto
Pendidikan Tambahan : 1. Pelatihan Endoscopy di RSU dr.
Hasan Sadikin Bandung.
2. International Endoscopy Workshop
2007, Jakarta 5 7 April 2007.
3. Training Endoscopy Showa
University Yokohama 2009
Hepatitis

Dr.dr. I Gede Arinton,SpPD-KGEH

The Internal Medicine of FK Unoed

Purwokerto

2015
Vial 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
Stages of Acute
Hepatitis
Incubation entry
(preclinical) initial amplification
Preicteric liver
(prodromal) Little or no cytopathology
Icteric Liver damage (jaundice) due to immune
pathology

Convalescent Usually complete recovery

Initial laboratory
evaluation of jaundiced
patient
TEST PERFORMED MEASUREMENT

Urine bilirubin Conjugated bilirubin

Serum bilirubin Conjugated and unconjugated bilirubin

Alanine aminotransferase (ALT) Hepatocellular damage

Aspartate aminotransferase (AST) Heptocellular damage

Alkaline phosphatase Intrahepatic or extrahepatic obstruction

Prothrombin time, partial Clotting mechanism

thromboplastin time, platelet count,
bleeding
Blood count with blood smear exam Red blood cell morphology, parasites,
atypical lymphocytes
Hepatitis A Virus

HAV
HAV Factoids

Picornaviridae
Heparnavirus
Plus-stranded RNA
Naked capsid
Insensitive to environmental
factors
Easily transmitted in the
environment
ONE serotype
HAV Epidemiology

Man is a natural host

Virus spread: fecal-oral
Water: drinking, bathing;
washing food
Food: shellfish and other filter
feeders
Hands: personal hygiene;
contaminated water
HAV Epidemiology USA

Household (person-to-person)
or sexual (oral or anal)
contact: 24%
Daycare attendance or
employment: 15%
Food or waterborne: 5%
Unknown: 45%
HAV Pathogenesis
 HAV Pathogenesis

HAV replication: hepatocytes and

Kupffers cells
Liver damage
Virus does not induce cytopathic effects
Damage to liver is immune mediated
Histology is similar to other hepatitis viruses
infection
Virus released into bile-small
intestine-stool
Stages of HAV infection
Incubation (preclinical) ingestion
Range:15-50 days intestinal tract (initial HAV replication)
Average 28 days blood (transient viremia; 106 particles/ml)
HAV in feces
Preicteric (prodromal) HAV in liver
HAV in feces
Icteric Liver damage (jaundice)
Immunopathology
Convalescent Usually complete recovery
Diagnosis for HAV

History of patient
Biochemical assessment of
liver function
Serology: anti-HAV IgM by
ELISA
Treatment for HAV

Immune serum globulin

Given before or early in
incubation phase
Supportive
Complications for HAV
Fulminant Hepatitis
Extensive necrosis of the liver
1-3/1000 cases; 80% mortality
Relapsing hepatitis
4-15 weeks after initial
symptoms
Biochemical changes only in
some patients
Cholestatic hepatitis
Total blockage/suppression of
bile
High bilirubin levels
Prevention of HAV

Disrupt oral-fecal
spread
Killed vaccine
Formalin inactivated
HAV
HAVRIX; VAQTA
Travelers; sexually
active
Serum immune
HAV Summary
Hepatitis B

Electron
micrograph of
serum
containing
hepatitis B virus
after negative
staining.
Overview

Discussion Hepatitis B
Epidemiology
Serologies
Clinical course
Prevention
Treatment options
Herbs
 Hepatitis B
Hepadnaviridae family Diagrammatic
DNA virus representation of
the hepatitis B
virion and the
Double-shelled particles surface antigen
components
Outer lipoprotein
envelope (surface Ag)
Inner viral nucleocapsid
(core)
seven genotypes
four major subtypes. EM of Hepatitis
All HBV subtypes share one B viron
common antigenic
determinant - "a.
Thus, antibodies to the "a"
determinant confer protection
to all HBV subtypes
 Hep B epidemiology
1/3 of worlds
population has
been infected
350 million with
chronic disease
15-25% of these
die due to liver
related diseases
1 million
deaths
annually
United States
1.25 million
chronic
carriers
5000 deaths
annually Hep B surface Ag prevalence, 2002 Source: CDC website
 Hepatitis B transmission
Dominant mode of transmission related to
prevalence
Low prevalence (.1 to <2%) adults
unprotected sexual intercourse
intravenous drug use
Moderate (3-5%) - children
Horizontal transmission
High prevalence (>10-20%) - infants
Maternal infant
Percutaneous
Other
Occupational exposure
Blood transfusions
Increasingly rare
Hepatitis B primary
infection
Symptoms
Malaise, fatigue,
anorexia, nausea, low
grade fever after 45-
160 day incubation
Can be
asymptomatic
More common in
children
Usually self limited in adults
Viral clearance from blood and liver
Lasting immunity
Can result in fulminate hepatic failure
Hepatitis B primary
infection
HBsAg 4-10 wks
Anti-HBc
antibody follows
+/- HBeAg
Viral load very
high
109 to 1010
Highly
contagious at
this time
Hepatitis B primary
infection
Decrease in HBsAg
correlates with onset
of T-cell mediated
immune response
Also, when present,
correlates with onset
of elevated liver
enzymes
Traditionally,
conversion to anti-
HBs antibodies
signals cure
Viral DNA may persist
for years to lifetime
Significance unknown
 Hep B - Persistent
Infection
Definition:
Persistence of HBsAg for greater
than 6 months
 Hepatitis B persistent
infection
Persistent viral load
that declines over time
HBeAg declines
overtime, converting
eventually to anti-HBe
antibody
Seroconversion
correlates with rise in
LFTs and 5 order of
magnitude decline in
viral load.
Classically, to Anti-HBe
antibody = no viral DNA
circulating, which is
incorrect
0.5% clear HBsAg
annually
 Persistent Hepatitis B
Two clinical patterns
Chronic liver disease
Elevated LFTS
Abnormal hepatic histology
20% develop cirrhosis
Asymptomatic carrier
Normal LFTs
Asymptomatic
Near normal liver histology
Both risk development of
Hepatocellular Carcinoma
 Persistent Hepatitis B
HBV replication
extensive and
continuous in
chronic carriers
Replication is not
cytotoxic
Host immune
response to viral
antigens expressed
on infected
hepatocytes
Hepatocellular carcinoma
100 times the risk in persistently
infected patients
Risk is greater if HBeAg positive
Twice a year screening is
recommended in persistent
carriers
Alpha fetoprotein and/or hepatic U/S
When to start screening is unclear
Who gets chronic
disease?

Rule of thumb, the younger the

age, the more likely to become
chronic
Neonates 95% chronic, most
asymptomatic
Infant to 6 yo 30% chronic
Older children to adults 3-5%
chronic
 Hepatitis B - Serology
Surface Antigen (HBsAg)
Hep B surface antigen Outer
surface lipoprotein, appears early
Hallmark of infection
Surface antigen antibody (anti-
HBs) signifies cure

Hep B core antigen (HBcAg)

intracellular antigen
expressed in infected hepatocytes
not detectable in serum
Core antibody appear early in
infection (Anti-HBc)
Predominately IGM early in
infection
detection of IgM anti-HBc usually
regarded as an indication of acute
HBV infection
Traditionally, the sole marker of
HBV infection during the window
period between the disappearance
of HBsAg and the appearance of
Hep B e antigen
secretory protein that is processed from
the precore protein
Elevated early in infection and usually
coverts to antibody early on.
Traditionally used as a marker for viral
load as viral load was undetectable with
early assays when Ag was absent.
However, certain variants of the Hep B virus do
not create the HBeAg as it has no known
function.
When present, it does correlate with
elevated viral load and seroconversion the
antibody usually correlates with a
decrease in viral load by a magnitude of 4-
Hep B serology
interpretation
Acute infection
HBsAg positive and anti-
HBcAg IGM
Rarely, IgM anti-HBc only
marker
Usually seen in acute
fulminate Hep B
Chronic infection
HBsAg positive and anti-
HBcAg
Previous Infection
HBsAg negative
anti-HBs positive
IgG anti-HBc positive
Screening Who?
Who
Persons born in hyperendemic areas
Men who have sex with men
Injection drug users
Patients on dialysis
HIV infected patients
Pregnant women
Family and household contacts and
sexual contacts of HBV-infected
persons.
Testing should be performed by
obtaining an HBsAg and anti-HBs.
Hepatitis B Treatments
Prevention
Neonates
Vaccine
Prophylaxis
Possible exposure
Chronic infection
Prevention
In 1991, US started routine
vaccination
Since then incidence of acute HBV
infection has declined by 67%
However, incidence has continued
to increase in adults
Offer vaccine to high risk individuals
Prophylaxis
Hepatitis B immune globulin (HBIG)
and vaccine
Indications
Patients with no history of vaccine and
Percutaneous exposure (needle sticks)
Household contacts exposed to blood
Perinatal exposure prevents
transmission in 95% of mothers HBsAg
positive when given within 12 hours of
birth
Breast feeding ok if baby received
prophylaxis
 Treatment of persistent
infection-
Who to treat?
Treat: HBeAg
HBeAg positive with Pos Neg
persistent infection
Chronic Probably
treat
No treatment: dz treat

HBeAg negative and

carrier (nl LFTs, viral Probably
Carrier treat
load less than 105 and not treat
asymptomatic)

Probably treat:
HBeAg negative with
chronic infection (high
viral load, abnormal
LFTs)
Treatment options
FDA approved
Interferon Alfa
Lamivudine reverse transcriptase
inhibitor
Adefovir nucleotide analogue that
inhibits viral polymerase
Investigational
Tenofovir adenine nucleotide analogue
Approved for HIV
Entecavir guanosine analogue, highly
selective for the HBV polymerase
Interferon alfa
Had been mainstay for therapy
Subcutaneous injection three times
per week for 3 months or longer
30% of patients who could tolerated
regime had a successful response
Seroconverted to HBe antibodies
Normalization of LFTs
Multiple side effects
Fever, myalgia, thrombocytopenia,
depression
Interferon alfa
Contraindicated in very
advanced liver disease
Flairs or bump in LFTs occur at
time of seroconversion to anti-Hbe
due to increased immune response
may precipiate overt liver failure
Lamivudine
Oral medication
Usually given for year or longer
Found to inhibit HIV reverse
transcriptase.
Noted that patients with both HIV and
chronic Hep B had large declines in Hep
B viral load
This phenomenon was then noted in
patients with only chronic Hep B
By itself, results in a 3 to 4 log decrease
serum viral load
Increased rate of seroconversion to
Lamivudine
Those who respond best are those
with elevated LFTs
>5 times normal -> 65% response rate
2-5 times normal -> 26% response
<2 times normal -> 5% response
Remember, liver damage is caused
by immune response
So higher LFTs likely correlates to a
most robust host immune response
By inhibiting viral reproduction, the
immune system is able to clear the virus
more effectively.
Lamivudine
Use limited by resistance
At one year of treatment 15-20% of
patients develop resistance
40% at two years
67% at four years
However, the resistant virus is less
hearty than the native virus resulting
is lower replication rates than
pretreatment
Resistant variants also convert to
anti-HBe antibodies at higher rates.
Lamivudine
Resistance
No clear evidence regarding
continuation of treatment
Prior to new meds, many
continued.
Discontinuing medication is
associated with flairs
Overlapping with another
medication recommended
Adefovir
Initially, devoloped for HIV
Nucleotide analogue
Prodrug phosphorylated
intracellularly to yield active
drug
Inhibits viral polymerase
Has been evaluated for primary
monotherapy and in patients
with resistance to Lamivudine
Adefovir
Efficacy
Reduces viral load by 3 to 4 log
Enhances HBeAg seroconversion
Results in histological improvement of
liver
Improved LFTs
Effective even in Lamivudine resistant
patients
Much lower rate of resistance than
Lamivudine
Approach to treatment
Unfortunately, studies are lacking to
define what is the best approach
Presently, alpa interferon, Adefovir and
Lamivudine are all considered first line
therapy
Considerations
Adefovir less resistance, possibly
nephrotoxic
Lamivudine good side effect profile
Interferon difficult course
All provided about the same results
Unknown if benefit to using combination
therapy.
Hepatitis B/C Alternative Therapy:
What your patient might read about on
the internet
MTH-68/B. vaccine strain of Both studies
Newcastle disease, virus
investigated
the use in
that causes a bird infection both Hepatitis
Controlled study - conventional
B and C.

txment vs vaccine in acute

phase n=42, showed more
progressed to chronic infection
with conventional txmt.
Case reports of benefit to pts
given this vaccines after
progressing to decompensated
liver failure.
 Hepatitis B and Herbs
Cochrane review
Asymptomatic carries
Very few quality studies
Three randomised clinical trials of carriers (307 patients)
three months or more of follow identified.
The methodological quality was poor overall, only one
significant trial
'Jianpi Wenshen recipe'
significant effects on viral markers compared to interferon
serum:
HBsAg,HBeAg, and seroconversion of HBeAg to anti-HBe.
Poor long term f/u

Chronic carriers
Fuzheng Jiedu Tang (compound of herbs)
positive effects on clearance of serum HBsAg, HBeAg, and HBV
DNA
Polyporus umbellatus polysaccharide vs interferon
Positive effects on serum HBeAg and HBV DNA
Phyllanthus amarus vs interferon
 Hepatitis B Alternative Therapies
One small retrospective study showed patients in
fulminent hepatic failure who took dietary or herbal
supplements often did worse than those who did
not. Arch Surg. 2003 Aug;138(8):852-8.
Thought to be due to heptotoxic effects of componds
in these supplements.

Basically
No firm evidence supporting medicinal herbs
follow-up randomized trials seem justified for some
Would not recommend due to potential hepatotoxic effects
References

Images:
http://www.cdc.gov/ncidod/diseases/hepatitis/
http://gsbs.utmb.edu/microbook/ch070.htm
http://web.uct.ac.za/depts/mmi/jmoodie/dihep.html
http://www.aids-hepatitisc.org/healthinsurance/maps-graphs/figure7-infectious-hepatitis.gif

Am J Gastroenterol. 2003 Mar;98(3):538-44

Arch Surg. 2003 Aug;138(8):852-8
N Engl J Med Mar 11,2004;
Pediatrics in Review, Vol 24, No.12 Dec 2003
Hepatitis C Virus
HCV
HCV Factoids

Flaviviridae
Positive-sense RNA
virus
Genotypes
6 major genotypes
30 subtypes
Quasispecies:
many serotypes?
HCV Epidemiology
Worldwide distribution
Humans and
chimpanzees
Parenteral
Intravenous drug users
(70%)
Transfusion and organ
recipients (screening)
Hemophiliacs receiving
factors VIII or IX
Sexual (5%-8%)
Vertical (6%-10%)
HCV Pathogenesis

Hepatocytes
Cell associated infection
persistent infection
15% of cases are self-limiting
85% become chronic infections
Liver damage due to immune
pathology
HCV Diagnosis

Clinical
similar to acute HAV and
HBV
Although milder
Laboratory
ELISA to recognize antibody
to capsid
Reverse-transcriptase-
polymerase chain reaction
HCV Complications

Chronic infection
Fulminant hepatitis
Cirrhosis
Hepatocellular
carcinoma
Extrahepatic:
Variety of autoimmune
diseases