Pemicu 2

Blok Sistem Hepatobilier

Dibuat oleh :
Vincent Vandestyo (405150156)
 Learning Objectives
1. Menjelaskan Hepatitis

2. Menjelaskan Sirosis hepar

3. Menjelaskan Hepatoma

4. Menjelaskan Gagal Hepar

 LO 1. Hepatitis
(a) Klasifikasi berdasarkan etiologi; (b) Menjelaskan Hepatitis A-E, G &
cara penularan; (c) Patofisiologi; (d) Tanda & gejala; (e) Pemeriksaan
penunjang;(f) Komplikasi; (g) Tatalaksana; (h)Pencegahan (vaksin)
 Klasifikasi Hepatitis
Hepatitis

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 ?

• Viral hepatitis is a systemic disease

with primary inflammation of the
liver by any one of a heterogenous
group of hepatotropic viruses
 HEPATITIS VIRUSES
• Hepatitis A (HAV) Picornaviridae (1973)

• Hepatitis B (HBV) Hepadnaviridae (1970)

• Hepatitis C (HCV) Flaviviridae (1988)

• Hepatitis D (HDV) ? (1977)

• Hepatitis E (HEV) (Caliciviridae) (1983), Hepeviridae

• Hepatitis F – Not separate entity – Mutant of B Virus.

• Hepatitis G (HGV) Flaviviridae (1995)

 Type of Hepatitis
A B C D E

Source of Feces Blood Blood Blood Feces

virus Blood derived Blood derived Blood derived
Body fluids Body fluids Body fluids

Route of Feco-oral Percutaneous Percutaneous Percutaneous Feco-oral

Transmission Permucosal Permucosal Permucosal
Chronic No Yes Yes Yes No
Infection
Prevention Pre Post Pre Post Blood donor Pre Post Ensure
Exposure Exposure screening Exposure Safe
Immunization Immunization Immunization Drinking
Blood donor water
screening
Hepatitis A
HAV
 Hepatitis A Virus
• Naked RNA virus
RNA

• Related to enteroviruses, formerly known as Enterovirus 72,

now put in its own family: heptoviridae

• One stable serotype only

• Difficult to grow in cell culture: primary marmoset cell
culture and also in vivo in chimpanzees and marmosets

• 4 genotypes exist, but in practice most of them are group 1

 RESISTANCE ( HAV)
• Resistant to inactivation by heat at 600 C for one
hour, ether & acid at pH 3.

• Inactivated by boiling for one minute, 1: 4,000

formaldehyde at 370 C for 72 hours & chlorine 1
ppm for 30 minutes.

• Not affected by anionic detergents.

• Survives prolonged storage at 40 C or below.

 Hepatitis A
• Common cause of acute hepatitis
• Single-stranded, positive-sense, linear RNA enterovirus
(Picornaviridae)
• Transmission fecal-oral route; Contaminated water and food
• The incubation period of hepatitis A virus is 2-7 weeks,
• AST & ALT levels usually return to reference ranges over 5-20 weeks.
• High risk  Travellers: vaccinations; passive immunoglobins given to
those exposed
• Mild self-limited disease and confers lifelong immunity to hepatitis A
virus. Chronic infection with hepatitis A virus does not occur.
• Treatment: supportive
Hepatitis A

• ALT↑
• Pada fase akut:
• Anti-HAV terdeteksi
 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, raw shellfish)

• Blood exposure (rare)

(e.g., injecting drug use, transfusion)
• Prodromal or Preicteric phase :
o (symptoms: fatigue, joint- and abdominal pain,
malaise,vomiting, lack of appetite,
hepatomegaly)
• Icteric phase:
o Icterus: jaundice (skin, sclera, mucous
membranes cause: elevated bilirubin level,
bilirubinuria: dark urine, pale stool)
 PATHOGENESIS - HAV
• Cause subacute disease in children & young adults.

• HAV invade into human body by fecal-oral route, multiplies in the

intestinal epithelium & reaches the liver by hematogenous spread.

• After one week, the HAV reach liver cells replicate within.Then enter
intestine with bile and appear in feces.

• Incubation Period : 2 to 6 weeks.

PATHOGENESIS – HAV contd--

– After HAV replicating and

discharging,liver cells damage begin

– Animal experiment proved that immune

complex may attend the pathogenesis of
HAV

– Complement level reduce the

pathogenesis maybe following:
– activated T cell secrete γ-INF that
promote the representation of HLA on
the liver cells,CTL may kill the target cell
infected with HAV
 LAB.DIAGNOSIS
1. Demonstration of Virus in feces:
By: Immunoelectron microscopy
2. Virus Isolation
3. Detection of Antibody :By ELISA
4. Biochemical tests:
i) Alanine aminotransferase (ALT)
ii) Bilirubin
iii) Protein
5. Molecular Diagnosis : RT PCR of feces
 Hepatitis A Infection
Typical Serological Course
Symptoms IgG anti-HAV

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.

 Sexual - sex workers and homosexuals are

particular at risk.

 Perinatal (Vertical) – mother (HBeAg+) →infant.

 4、Epidemiology
• 350,000,000 carriers worldwide
• 120,000,000 carriers in China
- the carrier rate can exceed 10%
-15 to 25% of chronically infected patients will die from chronic liver disease
• 500,000 deaths/year in China
• 982,297 liver disease in China 2005
• 50% of children born to mothers with chronic HBV in the US are Asian
American
 Concentration of Hepatitis B Virus
in Various Body Fluids
Low/Not
High Moderate Detectable
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
Breast milk
 High-risk groups for HBV infection
• People from endemic regions
• Babies of mothers with chronic HBV
• Intravenous drug abusers
• People with multiple sex partners
• Hemophiliacs and other patients requiting blood and blood
product treatments
• Health care personnel who have contact with blood
• Residents and staff members of institutions for the
mentally retarded
 Acute Hepatitis B Virus Infection with Recovery
Typical Serologic Course
Symptoms
HBe Ag anti- HBe

Total anti- HBc

Titr
e
HBs Ag IgM anti- HBc anti- HBs

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%

Acute case-fatality rate: 0.5%-1%

Chronic infection: < 5 yrs, 30%-90%
≥ 5 yrs, 2%-10%

More likely in asymptomatic infections

Premature mortality from
chronic liver disease: 15%-25%
Possible Outcomes of HBV Infection
Acute hepatitis B infection
3-5% of adult- 95% of infant-
acquired infections acquired infections
Chronic HBV infection

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

• Interferon alfa (Intron A)

– Response rate is 30 to 40%.
• Lamivudine (Epivir HBV)
(relapse ,drug resistance)
• Adefovir dipivoxil (Hepsera)
 Treatment
• Interferon - for HBeAg +ve carriers with chronic active hepatitis. Response
rate is 30 to 40%.
– alpha-interferon 2b (original)
– alpha-interferon 2a (newer, claims to be more efficacious and efficient)
• Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well
tolerated, most patients will respond favorably. However, tendency to
relapse on cessation of treatment. Another problem is the rapid
emergence of drug resistance.
• Adefovir – less likely to develop resistance than Lamivudine and may be
used to treat Lamivudine resistance HBV. However more expensive and
toxic
• Entecavir – most powerful antiviral known, similar to Adefovir
• Successful response to treatment will result in the disappearance of
HBsAg, HBV-DNA, and seroconversion to HBeAg.
 Prevention
• Vaccination
- highly effective recombinant vaccines
• Hepatitis B Immunoglobulin (HBIG)
-exposed within 48 hours of the incident/ neonates whose
mothers are HBsAg and HBeAg positive.
• Other measures
-screening of blood donors, blood and body fluid
precautions.
 Prevention
• Vaccination - highly effective recombinant vaccines are now
available. Vaccine can be given to those who are at increased
risk of HBV infection such as health care workers. It is also
given routinely to neonates as universal vaccination in many
countries.
• Hepatitis B Immunoglobulin - HBIG may be used to protect
persons who are exposed to hepatitis B. It is particular
efficacious within 48 hours of the incident. It may also be given
to neonates who are at increased risk of contracting hepatitis B
i.e. whose mothers are HBsAg and HBeAg positive.
• Other measures - screening of blood donors, blood and body
fluid precautions.
 Hepatitis B Vaccine
• Infants: several options that depend on status of
the mother
– If mother HBsAg negative: birth, 1-2m,6-18m
– If mother HBsAg positive: vaccine and Hep B immune
globulin within 12 hours of birth, 1-2m, <6m
• Adults
* 0,1, 6 months
• Vaccine recommended in
– All those aged 0-18
– Those at high risk
HEPATITIS C
HEPATITIS C VIRION: spherical, icosahedral,
NUCLEIC ACID: ss (+) RNA
 Hepatitis C Virus
capsid envelope protease/ helicase RNA- RNA polymerase
protein dependent
c22 33c c-100

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

 morphological structure remains unknown

 HCV has been classified into a total of six genotypes (type 1 to 6) on the basis of phylogenetic
analysis

 Genotype 1 and 4 has a poorer prognosis and response to interferon therapy

 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

(+) Translation & processing

(+)

(-)
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

 Transfusion or transplant from infected donor

 Injecting drug use
 Hemodialysis (yrs on treatment)
 Accidental injuries with needles/sharps
 Sexual/household exposure to anti-HCV-positive contact
 Multiple sex partners
 Birth to HCV-infected mother
 Laboratory Diagnosis
• HCV antibody - generally used to diagnose hepatitis C
infection. Not useful in the acute phase as it takes at least 4
weeks after infection before antibody appears.
• HCV-RNA - various techniques are available e.g. PCR and
branched DNA. May be used to diagnose HCV infection in
the acute phase. However, its main use is in monitoring the
response to antiviral therapy.
• HCV-antigen - an EIA for HCV antigen is available. It is
used in the same capacity as HCV-RNA tests but is much
easier to carry out.
 HCV RNA (PCR testing)

• Virus load

• Lower detection limit can be 10-615 IU/ml

• 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!

• Helps predict response rate to treatment (lower means a higher chance

of cure with therapy)

• Used to monitor response during treatment

 Prognostic Tests
• Genotyping – genotype 1 and 4 have a worse prognosis overall and
respond poorly to interferon therapy. A number of commercial and
in-house assays are available.
– Genotypic methods – DNA sequencing, PCR-hybridization e.g.
INNO-LIPA.
– Serotyping – particularly useful when the patient does not have
detectable RNA.

• 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

 Screening of blood, organ, tissue donors

 High-risk behavior modification

 Blood and body fluid precautions

 Hepatitis D (Delta) Virus
 antigen HBsAg

RNA
 Hepatitis Delta Virion

From Murray et. al., Medical

Microbiology 5th edition, 2005,
Chapter 66, published by Mosby
Figure 66-14 Philadelphia,,
 HEPATITIS D VIRUS
(HDV, DELTA AGENT)
• VIRION: spherical, 36-38 nm,
• HBV capsid, HDV
nucleoprotein
• NUCLEIC ACID: (-) ss RNA,
circular
• Satellite virus : replicates only
• in the presence of HBV
 Hepatitis D Virus
• The delta agent is a defective virus which
shows similarities with the viroids in plants.

• The agent consists of a particle 35 nm in diameter

consisting of the delta antigen surrounded by an
outer coat of HBsAg.

• The genome of the virus is very small and consists

of a single-stranded RNA
 The HDV genome

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

Time after Exposure

 HBV – HDV Superinfection
Typical Serologic Course
Jaundice
Symptoms

Total anti-HDV
ALT
Titre

HDV RNA
HBsAg

IgM anti-HDV

Time after Exposure

 Hepatitis D - Prevention
 HBV-HDV Coinfection
Pre or post exposure prophylaxis to prevent
HBV infection.
 HBV-HDV Superinfection
Education to reduce risk behaviors among
persons with chronic HBV infection.
Hepatitis E Virus
 Hepatitis E Virus
• Calicivirus-like viruses

• unenveloped RNA virus, 32-34nm in

diameter

• +ve stranded RNA genome, 7.6 kb in size.

• very labile and sensitive

 Hepatitis E - Clinical Features
 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 Virus Infection
Typical Serologic Course
Symptoms

ALT IgG anti-HEV

Titer IgM anti-HEV

Virus in stool

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Weeks after Exposure

 Hepatitis E -
Epidemiologic Features
 Most outbreaks associated with faecally contaminated drinking
water.

 Several other large epidemics have occurred since in the Indian

subcontinent and the USSR, China, Africa and Mexico.

 In the United States and other nonendemic areas, where

outbreaks of hepatitis E have not been documented to occur, a
low prevalence of anti-HEV (<2%) has been found in healthy
populations. The source of infection for these persons is
unknown.
 Prevention and Control Measures for
Travelers to HEV-Endemic Regions
 Avoid drinking water (and beverages with ice) of
unknown purity, uncooked shellfish, and uncooked
fruit/vegetables not peeled or prepared by traveler.
 IG prepared from donors in Western countries
does not prevent infection.
 Unknown efficacy of IG prepared from donors in
endemic areas.
 Vaccine?
 HEPATITIS G VÍRUS
FLAVIRUS: similar morphology and genome

◊ in risk groups: acute, chronic and fulminant hepatitis

◊ transmission: blood (mother- newborn babies)

◊ prevalence is higher in HCV infected people

Fulminant hepatic failure
 Definition
• Clinical syndrome resulting from
– massive necrosis of hepatocytes
– or from severe functional impairment of
hepatocytes
– in a patient who does not have pre-existing liver
disease
 Definition

• Evolves over a period of 8 weeks

• Synthetic, excretory and detoxyfying function of

the liver are usually affected

 Pathology
• Liver biopsy
– Patchy / confluent massive necrosis of hepatocytes
 Etiology

• CAUSES OF ACUTE HEPATITIS

 Clinical features
• FHF may complicate previously known acute liver disease
• or may be the presenting feature of liver disease in a
previously well child
• Fever, anorexia, vomiting, abd. pain
• Progressive jaundice
• Fetor hepaticus
• Rapidly decreasing liver size
• Ascites, hemorrhagic manifestations
 Complications of FHF
• Hepatic encephalopathy
• Cerebral edema
• Respiratory failure
• Hypotension, Hypothermia
• Infection
• Bleeding
• Renal failure
• Metabolic
 Diagnosis of FHF
• Consists of
– Evidence of acute onset of liver disease and no
evidence of CLD
– Duration – 8wks
– No physical evidence of CLD
– Biochemical evidence of hepatic dysfunction
– Hepatic Encephalopathy
Hepatic encephalopathy
 Hepatic encephalopathy
• Neuropsychiatric syndrome

• Occurs most often on pts. with cirrhosis

– Can also occur in FHF
 Hepatic encephalopathy
• Factors ppt. hepatic encephalopathy
– GI bleed
– Excess dietary protein
– Constipation
– Paracentasis
– Infections
– Trauma
– Uremia – spont / diuretic induced
– Electrolyte disturbances- hypokalemia
– Portosystmeic shunts
 Hepatic encephalopathy

• 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)

False NTM Endogenous BZD

 Lab investigations
• Etiology
– IgM anti HBs
– IgM anti HAV
– Anti HEV, CMV, HS, EBV
– Se.Ceruloplasmin , Copper
– Auto Ab – ANF, ANA, ASMA, LKM
– USG liver + Doppler of hepatic vein
– Toxicology screen of blood & urine
 Lab investigations
• LFT
– TB / DB
– AST / ALT/ALP
– TP/ALB
– PT/APTT
• RBS. Electrolytes, ABG
• Serum ammonia
 Lab investigations
• General tests
– CBC, platelets
– Creat, Ca, Mg

• 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

metobolic disorder of liver eg. Wilsons ICC,

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

• median age 5 - 20 years.

• Liver disease: acute hepatitis, chronic active
hepative hepatitis, cirrhosis and fulminant
hepatitis
• Recurrent episodes of liver disease may occur in a
variable interval (months to years) until
neurologic symptoms develop
• Hemolytic anemia
• Kayser-Fleischer ring denotes neurologic
impairment and consists of copper
deposition in the cornea. It presents as a
greenish or golden brown ring around the
cornea and is pathognomonic of Wilson's
disease
 Diagnosis
• (1) Kayser-Fleischer rings,
• (2) low serum ceruloplasmin (< 20 mg/dl)
• (3) increased amounts of amounts liver and
urinary copper.
 treatment
• Should start as soon as possible, either in
symptomatic or asymptomatics patient.
• Total symptomatic recovery can be
acheived if intervention is made early.
• Penicillamine is the drug of choice.
 LO 2. Sirosis
(a) Klasifikasi berdasarkan etiologi; (b) Patofisiologi; (c) Tanda &
gejala; (d) Pemeriksaan penunjang;(e) Komplikasi; (f)
Tatalaksana; (g)Pencegahan (vaksin)
 LO 3. Hepatoma
(a) Klasifikasi berdasarkan etiologi; (b) Patofisiologi; (c) Tanda &
gejala; (d) Pemeriksaan penunjang;(e) Komplikasi; (f)
Tatalaksana; (g)Pencegahan (vaksin) ; (h) Faktor risiko
 LIVER FUNCTION TESTS
• Total bilurubin ,congugated bilirubin
• Serum amino transferases :ALT,AST
• Serum albumin
• Alkaline phosphatase, 5’nucleotidase,gamma
glutamyl transpeptidase
• Prothrombin time
Typical AST or ALT Values in Disease
 imaging
• Plain x ray:calcifications ,gallstones,gas with
in abcess,biliary tract or portal circulation
• Ultrasonography :size,composition and
blood flow,spenic size ,ascites
• Doppler US :patency of portal vein and
collaterals
• Radionucleotide scan:Tc 99m imidodiacetic
acid agents
 LIVER BIOPSY
• Histological diagnosis
• Enzyme analysis
• Analysis of stored material
LO 4. Gagal hepar
(a) Klasifikasi berdasarkan etiologi; (b) Patofisiologi; (c) Tanda &
gejala; (d) Pemeriksaan penunjang;(e) Komplikasi; (f)
Tatalaksana; (g)Pencegahan (vaksin)