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3. Menjelaskan Hepatoma
Non-infeksi
Infeksi
Metabolic
Virus Bakteri Fungi Parasit Alkohol Drugs Autoimmune
diseases
Hep: Adenovirus,
A,B,C, CMV, EBV,
D,E HSV, YFV
Etiology
• Infections
o Viral hepatitis
• Hep A,B,C,D,E ( B+D )
• EBV, HSV, Adenovirus, enterovirus, CMV, varicella
o Non viral causes
o Bacteria: leptospira,salmonella,brucella
o Protozoa: toxoplasma
o Helminths:Echinococcus
Etiology
• Drugs
o Hepatotoxic drugs – acetaminophen ( overdose)
o Idiosyncratic damage – sod. Val, prophthiouracil, halothane, INH, tetracycline
Poisons
o Amanita Phalloids
o Carbon tetra chloride
• Metabolic disorders
o (Wilson’s, Galactosemia, hereditary tyrosinemia, NIS, organic acidemias,)
• Ischemia and hypoxia
o Circulatory shock, hepatic VOD, CCF, CHD
Clinical features
• Prodrome of malaise
• Anorexia
• Nausea,vomiting
• Fever
• Tender hepatomegaly
• Jaundice
• Pale stools
• Splenomegaly / lymphadenopathy
Diagnosis
• HBsAg: first serological marker
• HBeAg:acute phase,highly infectious
• IgManti HBcAg:acute HBV infection
• antiHBsAg & anti HBcAg:resolving infection
• antiHBsAg(only):immunized with Hep B vaccine
What is Viral Hepatitis ?
• ALT↑
• Pada fase akut:
• Anti-HAV terdeteksi
Hepatitis A Virus Transmission
• Close personal contact
(e.g., household contact, sex contact, child
day care centers)
• After one week, the HAV reach liver cells replicate within.Then enter
intestine with bile and appear in feces.
Titre ALT
Fecal
HAV
IgM anti-HAV
0 1 2 3 4 5 6 1 2
Months after exposure
2 4
Hepatitis A Vaccination Strategies
Epidemiologic Considerations
• Many cases occur in community-wide outbreaks
– no risk factor identified for most cases
– highest attack rates in 5-14 year olds
– children serve as reservoir of infection
• Persons at increased risk of infection
– travelers
– homosexual men
– injecting drug users
Hepatitis B Virus
Hepatitis B Virus
1、Properties of HBV
• a member of the hepadnavirus group
• Circular partially double-stranded DNA viruses
• Replication involves a reverse transcriptase.
• endemic in the human population and
hyperendemic in many parts of the world.
• a number of variants
• It has not yet been possible to propogate the
virus in cell culture
HBV : Structure
HBV : Structure
• Virion also referred to as Dane particle (ds-tranded DNA)
• 42nm enveloped virus
• Core antigens located in the center (nucleocapsid)
* Core antigen (HBcAg)
* e antigen (HBeAg)- an indicator of transmissibility
(minor component of the core- antigenically distinct from
HBcAg)
• 22nm spheres and filaments other forms- no DNA in these
forms so they are not infectious (composed of surface
antigen)- these forms outnumber the actual virions
HBV Structure & Antigens
Dane particle
HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)
HBcAg = inner core protein (a single serotype)
HBeAg = secreted protein; function unknown
decoy particles
• HBsAg-containing particles
are released into the serum
of infected people and
outnumber the actual
virions.
• Spherical or filamentous
• They are immunogenic and
were processed into the
first commercial vaccine
against HBV.
GENOME
Open Reading Frames
There are 4 open reading frames derived from the same strand (the
incomplete + strand)
• S - the 3 polypeptides of the surface antigen (preS1, preS2 and
S - produced from alternative translation start sites.
• C - the core protein
• P - the polymerase
• X - a transactivator of viral transcription (and cellular genes?).
HBx is conserved in all mammalian (but not avian)
hepadnaviruses. Though not essential in transfected cells, it is
required for infection in vivo.
HBx activates the Ras-Raf-MAPK cascade:
Influence on cell proliferation?
Unlike the magnitude of Ras activation by
growth factors, HBx stimulation is modest
but sustained
Downstream signaling: activate transcription
factors (eg. AP-1, NF-KB and c-myc)
Activation of the Ras-Raf-MAPK signaling
pathway is essential for HBx activation
of AP-1 and NF-KB
HBx-mediated activation of the
Ras-Raf-MAPK pathway has been linked
to accelerated entry of cells into S phase
2、HBV: Replication
• Reverse transcription: one of the mRNAs is replicated
with a reverse transcriptase making the DNA that will
eventually be the core of the progeny virion
• RNA intermediate: HBV replicates through an RNA
intermediate and produces and release antigenic decoy
particles.
• Integration: Some DNA integrates into host genome
causing carrier state
Replication of HBV
3、HBV: Modes of Transmission
Parenteral - IV drug abusers, health workers are
at increased risk.
0 4 8 12 16 20 24 28 32 36 52 100
Weeks after Exposure
5、Pathogenesis & Immunity
• Virus enters hepatocytes via blood
• Immune response (cytotoxic T cell) to viral
antigens expressed on hepatocyte cell surface
responsible for clinical syndrome
• 5 % become chronic carriers (HBsAg> 6 months)
• Higher rate of hepatocellular ca in chronic carriers,
especially those who are “e” antigen positive
• Hepatitis B surface antibody likely confers lifelong
immunity (IgG anti-HBs)
• Hepatitis B e Ab indicates low transmissibility
6、Clinical Features
Incubation period: Average 60-90 days
Range 45-180 days
Insidious onset of symptoms.
Tends to cause a more severe disease than Hepatitis A.
Clinical illness (jaundice): <5 yrs, <10%
≥ 5 yrs, 30%-50%
1/3 adults-no symptoms
Clinical Illness at presentation 10 - 15%
Chronic hepatitis
12-25% in 5 years
Cirrhosis
6-15% in 5 years 20-23% in 5 years
Hepatocellular Liver failure
carcinoma
Death Liver transplant Death
7、Laboratory Diagnosis
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.
、Current Treatment Options
5’ 3’
cor E1 E2 NS NS NS NS
e 2 3 4 5
hypervariable
region
Hepatitis C Virus
Genome resembled that of a flavivirus
positive stranded RNA genome of around 10,000 bases
1 single reading frame, structural genes at the 5' end, the non-structural genes at the 3' end.
enveloped virus, virion thought to 30-60nm in diameter
HCV has been classified into a total of six genotypes (type 1 to 6) on the basis of phylogenetic
analysis
In Hong Kong, genotype 1 accounts for around 67% of cases and genotype 6 around 25%.
HCV replicates exclusively in the cytoplasm
via an RNA intermediate
Viral entry & uncoating
(-)
HCV RNA
Virus particle replication Replicative
assembly intermediate
(+)
Nucleus
Hepatitis C - Clinical Features
• 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
Chronic Hepatitis C Infection
• The spectrum of chronic hepatitis C infection is
essentially the same as chronic hepatitis B
infection.
• All the manifestations of chronic hepatitis B
infection may be seen, albeit with a lower
frequency i.e. chronic persistent hepatitis, chronic
active hepatitis, cirrhosis, and hepatocellular
carcinoma.
Hepatitis C Virus Infection
Typical Serologic Course
anti-
Symptoms
HCV
Titre
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after Exposure
Risk Factors Associated with
Transmission of HCV
• Virus load
• NOT a predictor of disease severity: a high viral load does not mean the
liver disease is more severe, and a low viral load does not mean the
patient is ok and does not need therapy!
• Viral Load – patients with high viral load are thought to have a
poorer prognosis. Viral load is also used for monitoring response
to IFN therapy. A number of commercial and in-house tests are
available.
Treatment
• Interferon - may be considered for patients with
chronic active hepatitis. The response rate is
around 50% but 50% of responders will relapse
upon withdrawal of treatment.
• Ribavirin - there is less experience with ribavirin
than interferon. However, recent studies suggest
that a combination of interferon and ribavirin is
more effective than interferon alone.
OUTCOMES of HCV hepatitis
Prevention of Hepatitis C
RNA
Hepatitis Delta Virion
Figure 88-4 Structure of the HDV RNA Genome. The single-stranded circular RNA genome is indicated by the heavy
black continuous line. The genome has the ability to form an unbranched rod structure, in which approximately 70%
of the bases are engaged in Watson-Crick pairs with counterparts from the opposite side of the circular RNA. In this
unbranched rod structure, the region encoding HDAg (nt 1598-957) is on one side. The RNA editing site is at position
1012 in the antigenome. The region on the right-hand side contains the autocatalytic cleavage sites (ribozymes), one
in the genome (nt 686) and the other in the antigenome (nt 900). The genome binds HDAg and is transcribed by a
host DNA–dependent RNA polymerase.
Fields Virology 4th edition, 2002, Chapter 88, Lippincott, Williams and Wilkins, 2002 Fig. 88-4
Hepatitis D - Clinical Features
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.
Consequences of hepatitis B and delta virus
infection
Figure 66-15. Consequences of deltavirus infection. Deltavirus (d) requires the presence of
hepatitis B virus (HBV) infection. Superinfection of a person already infected with HBV
(carrier) causes more rapid, severe progression than co-infection (shorter arrow).
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia.
Hepatitis D Virus Modes of
Transmission
Percutaneous exposures
injecting drug use
Permucosal exposures
sex contact
HBV - HDV Coinfection
Typical Serologic Course
Symptoms
ALT Elevated
Titre
anti-HBs
IgM anti-HDV
HDV RNA
HBsAg
Total anti-HDV
Total anti-HDV
ALT
Titre
HDV RNA
HBsAg
IgM anti-HDV
Virus in stool
0 1 2 3 4 5 6 7 8 9 10 11 12 13
• Stages
– Stage 1
• Symptoms
– Lethargy, euphoria, reversal of day and night sleeping
• Signs
– Trouble drawing figures, performing mental tasks
• EEG
– Normal
Hepatic encephalopathy
• Stages
– Stage 2
• Symptoms
– Drowsiness, inapp. Behaviour, agitation, wide mood swings
• Signs
– Asterixis, fetor hepaticus, incontinence
• EEG
– Generalized slowing of waves
Hepatic encephalopathy
• Stages
– Stage 3
• Symptoms
– Stupor but arousable, confused, incoherent speech
• Signs
– Asterixis, hyperreflexia, extensor reflexes, rigidity
• EEG
– Markedly abnormal , triphasic waves
Hepatic encephalopathy
• Stages
– Stage 4
• Symptoms
– 4a ( respond to noxious stimuli), 4b ( no response)
• Signs
– Areflexia, no astereixs, flacidity
• EEG
– Markedly abnormal , b/l slowing of waves
Hepatic encephalopathy
• Clinical signs
– Fetor hepaticus
• fecal smell in breath
• Due to volatile substances normally found in stool by
bacteria
– Asterixis
• Impaired inflow of joint and afferent information to the
brainstem reticular system, resulting in lapses in posture
Hepatic encephalopathy
• Clinical signs
– Constructional apraxia
• Inability to reproduce simple designs
– Reitan test
Multifactorial mechanism of HE
Ammonia
Direct neural toxin
Encephalopathy
Ammonia Tryptophan
( glutamine) ( serotonin)
• Infection surveillance
– Cultures of blood and urine
– Chest radiographs
• Liver biopsy
Treatment
• PICU
• Cont. monitoring of vital signs/GRBS
• Mechanical vent if required
• IVF – glucose ( 10 % D) – 2/3 maint
• Vit K / FFP to correct coagulopathy
• Packed cells/platelets
• Prophylactic antacids
Treatment
• Measures to decrease ammonia
– (Enteral neomycin)
– Oral Ampiciliin )
– Lactulose Q6h ) NG tube
– Bowel wash
• Mannitol – to reduce cerebral edema
• Cover for infections
• Parentral suppl. Of Ca, Mg, Ph
• Flumazenil
Management of FHF
– Double volume exchange
– Plasmapherasis
– Extra corporeal blood cleansing
• MARS
– Activated charcoal
– Cultured hepatocytes
– Liver transplantation
Prognosis
• No reliable criteria in children
• Poor
– NANB Hepatitis – 10 % recovery
– Higher stage of HE
– Complications ( cerebral edema, renal failure)
– Shrinking liver mass
– PT > 50 secs
Prognosis
• No reliable criteria in children
• Good
– HAV
– Drug induced ( PCT)
Chronic liver disease
ETIOLOGY
Metabolic disorders
Wilsons disease, alpha 1 anti trypsin def,
tyrosinemia ,NP disease, GSD type IV, cystic fibrosis,
galactosemia
Chronic viral hepatitis:B,C,D
Autoimmune hepatitis
Drug induced hepatitis
Bile acid biosynthetic abnormalities
History taking
• Jaundice- onset, duration
• Urine colour
• Stool colour
• Itching
• Swelling – site
• Bleeding tendencies
• Encephalopathy symptoms
• History s/o cystic fibrosis
History taking
appetite,nausea,vomiting,wt loss
• Night blindness
• Renal symptoms
• Endocrine symptoms
• Involuntary movements
• Fever and abd pain
• Effect of disease in school and family
HISTORY
• H/o transfusions
• Recurrent LRI
• Malabsorption
Drug history
• ATT
• Sodium valporate
• Chemotherapy
• Family history :Similar history (inherited
GSD, galact.)
• COOKING UTENSILS
O/E examination
• Mental state
• Pallor,Icterus ,clubbing
• Signs of liver cell failure – ascites ,FTT
• Vit def
• xanthomata
• Asterixis
• Leuconychia
Examination
• Cataract
• KF ring
• Facies
• Veins
• Liver span
• Free fluid
• spleen
• Early and well-compensated cirrhosis
• anorexia and weight loss, weakness, fatigue, and
even osteoporosis as a result of vitamin D
malabsorption and subsequent calcium deficiency.
• Decompensated disease
• complications such as ascites, spontaneous
bacterial peritonitis, hepatic encephalopathy, and
variceal bleeding from portal hypertension
complications of cirrhosis
• ascites
• spontaneous bacterial peritonitis
• hepatic encephalopathy
• portal hypertension
• variceal bleeding
• hepatorenal syndrome
KF Ring
Palmar erythema
Diagnosis
• Chronic liver disease - etiology
• Cirrohsis
• Compensated vs decompensated
• Liver cell failure
• Portal hypertension
• SBP
• ENCEPALOPHATHY
Investigations
• GRBS , LFT
• HB TC DC PLAT BP MCV
• PT PTT RBS NA K HCO3 Creat BLOOD C/S
• VIRAL MARKERS
• CERULOPASMIN,24hr urine Cu
• Alpha 1 antitrypsin levels
• Sweat electrolytes
• OPTHAL
Investigations
• USG – liver size ,composition ,blood flow- patency
of portal vein/collateral circulation , stones in gb/
biliary tree, ascites
• LIVER BX
• Precise histological d”sis –neonatal
cholestasis,CAH,metabolic liver
disease,intrahepatic cholestasis,cong hepatic
fibrosis
• Enzyme analysis to detect IEM
• Stored material – cu,iron,specific metabolites
treatment
• Nutrition – low protien/MCT
• Fat soluble vitamins-A 10-15,000IU/day
• D2 5- 8000iu/day
• E 50– 400IU/day
• K 2.5-5mg/Alt day
• Micronutrient deficiency-Ca,Zn
• Water soluble vit – twice RDA
• Ascitis-salt restriction+spironolactone
• Pruritis- UDCA 15mg/kg/day
• Portal hypertension - OGD
Wilson's disease
• hepatolenticular degeneration
• autossomal recessive
• acumulation of copper in tissues all over the
body, mainly in the liver, brain, kidneys and
cornea.
Clinical Manifestations