Kuliah Patofisiologi dan Perjalanan

Klinis Hepatitis Akut, Kronis ,

Sirosis Hati dan Keganasan Hati
2018
Poernomo Boedi Setiawan
Divisi Gastro-Hepatologi Departemen Penyakit Dalam
FK UNAIR – RS Dr Soetomo
 Spectrum of Liver disease
From acute stage to chronic stage
From inflammation to fibrosis stage
From fibrosis to liver cirrhosis
From liver cirrhosis to malignancy
From self limiting disease to non self
limiting disease ( drugs specific )
 Terminology
Acute < 6 months , Chronic > 6 months
Inflammation vs fibrosis stage ( liver cell
???)
Fibrosis vs cirrhosis ( damage of liver
architecture )
Cirrhosis vs Malignancy ( change of liver
cell patterns )
Self limiting disease vs non self limiting
disease ( antiviral ?? Anti fibrosis ??)
 Viral
Infections
Autoimmune
Parasites
diseases
Alcohol
Liver
Hepatic fibrosis
Cryptogenic
Injury

Drugs and toxins

Cirrhosis

Venous outflow Metabolic Cholestatic

obstruction disorders disorders
 Acute Hepatitis
Definition :
Acute inflammation of the liver cell
Acute : time terminology , below than 6
month after exposure of the etiologies
In Indonesia : Viral Hepatitis is the main
etiology
 Classification of Acute Hepatitis
Hepatitis due to infection :
Virus
Liver specific ( A,B,C,D and E)
Non Liver specific ( EBV,CMV etc)
Non Virus: Malaria, Typhoid fever , DHF etc
Hepatitis due to other than infection
Drug Induced Liver Injury (DILI)
Auto Immune Hepatitis
etc
Long-Term Sequelae of Chronic Hepatitis

HBV
HCV
HDV

Hepatocellula
r carcinoma

Normal Chronic Cirrhosi

liver hepatitis s
 Acute Hepatitis A
• Picorna Viruse
• Particle 27 nm, non enveloped
• Genome 7.5kb, RNA , Linear,ss
• Antigen HAV Ag
• Anti bodi
IgM anti HAV (acute infection )
IgG anti HAV (recent )
• Humans are only natural host

• Stable at low pH
• Inactivated by high temperature, formalin, chlorine
Virus Hepatitis A
 Hepatitis A Pathogenesis
• Entry into mouth
• Viral replication in the liver
• Virus present in blood and feces 10-12 days
after infection
• Virus excretion may continue for up to 3
weeks after onset of symptoms
 Pathophysiology
• HAV is exclusively a virus of humans and primates
• Transmitted by the fecal-oral route
• Absorbed in the small intestine and replicates in
the liver
• HAV is secreted in the bile and shed in feces for 1-
2 weeks BEFORE clinical illness and approximately
1 week after the onset
• Incubation period is 15-50 days (on average 30
days)
• There is NO chronic carrier state
 Hepatitis A Clinical Features
• Incubation period 28 days (range 15-50
days)
• Illness not specific for hepatitis A
• Likelihood of symptomatic illness directly
related to age
• Children generally asymptomatic, adults
symptomatic
 Hepatitis B Virus Infection
• Acute Infection
• Chronic Infection
 Geographic Distribution of Hepatitis B Infection

HBsAg Prevalence
≥ 8% (high)
2% to 7% (intermediate)
< 2% (low)

.
Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20
Geographic Distribution of HBV Genotypes
Greenland:
A, B, D
Ae, Bj, C,
D, F
B, A/Bj A
e D
B,C,A,D G C
G
D A D Bj

FF&
1, H
H Ba B
H
E B3

F2
Aa BC D

Slide 6
 HBsAg Prevalence in Indonesia

Prevalention is variatif in every

island; generaly, in out of Jawa
more high (9.2%) betwen Jawa
(5%)

Mulyanto, et al. Arch Virol 2009; 154(7):1047-59

Schematic Representation of HBV

DNA polymerase HBV DNA

Outer lipoprotein
envelope containing
Inner protein HB surface antigen
core (HBcAg)

HBsAg

HBeAg
HBV : Life Cycle
Acute infection of HBV
Chronic Infection of HBV
Torbenson M, Thomas DL; Lancet Infect Dis 2002; 2:479-86
 Overview :
Clinical Outcomes of HBV Infection
10–70% Perinatal/childhood Adult 95%
Recovery acute infection acute infection Recovery

< 1%
30–90% < 5%
Fulminant
hepatitis
Chronic infection  1*

Inactive
Mild, moderate or severe chronic hepatitis
carrier state
 2–10*
5–50
years Cirrhosis
 0.1*
 4*  3* 2–8*

Decompensation Transplant HCC

or
Death
* per 100 patient-years

Adapted from EASL Consensus Statement. J. Hepatol. 2003; 39 (S1):S3–25

Natural history of HBV

Slide 7
The HBV Iceberg
2 million individuals in the US
have chronic HBV infection
50,000 receive
 Clinical populations are treatment
150,000 are
diagnosed in care
the tip of the iceberg 300,000 are diagnosed and meet treatment
in care
500,000 are potentiallyguidelines
eligible
 Individuals in treatment for treatment
600,000 are aware of their chronic HBV
are the tip of the tip infection
 Population-based studies
allow us to look at the 1.4 million are unaware of
their chronic HBV infection
whole iceberg
 Asia has been the place
for these

Cohen C, et al. J Viral Hepatitis. 2011;18:377-383.

 Progression of Hepatitis B Infection
Liver
Cancer
(HCC)

30% of chronically
infected
individuals2
Acute Chronic Liver
Cirrhosis Death
Infection Infection Transplantation

 > 90% of infected infants

progress to chronic disease1

 < 5% of infected
immunocompetent adults
Liver Failure
Chronic hepatitis B is
progress to chronic disease1 (Decompensation)
the 6th leading cause of
liver transplantation in
23% of patients decompensate within 5
the US4
yrs of developing cirrhosis3

1. CDC. HBV FAQs for health professionals. 2. Torresi J, et al. Gastroenterology. 2000;118(2 suppl 1):S83-S103. 3. Fattovich G, et al.
Hepatology. 1995;21:77-82. 4. Seaberg EC, et al. Clin Transpl. 1998:17-37.
 Factors Associated With Disease
Progression in Patients With CHB
Host Factors Virus Factors Environmental Factors
• >40 years of age • High serum HBV • Concurrent
• Male DNA concentrations infection (HCV,
• Immune status • Prolonged time to HDV, HIV)
HBeAg • Alcohol
seroconversion consumption
• Development of • Diabetes mellitus
HBeAg(-) chronic • Obesity
hepatitis
• Core promoter HBV
variant
• Genotype C

Yim HJ, Lok ASF. Hepatology. 2006;43:S173-S181.

 Chronic Hepatitis B Marker
 Serological Marker: HBsAg1,
1
Anti-HBs ,
Anti-HBc2,
HBeAg1,
1
Anti-Hbe
 Virological marker: HBV DNA1
 Biochemical marker: ALT/SGPT1
1
 Histological marker : biopsy

1. Keefe EM, et al. Clinical Gastroenterology and Hepatology 2006;4:936-962;

2. Keefe EM, et al. Clinical Gastroenterology and Hepatology 2008;6:1315-1341
 4 Phases of Chronic HBV Infection
Current Understanding of HBV Infection
HBeAg
Anti-HBe
ALT activity

HBV DNA

Phase Immune Immune Inactive Reactivation

Tolerant Clearance Carrier State
Minimal Mild hepatitis
Chronic active Active
Liver inflammation and minimal
inflammation inflammation
and fibrosis fibrosis

Optimal treatment times

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-
S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.
 5 Clinical profiles of CHB Infection
Immune Immune Inactive Reacvitation HBsAg
Tolerance Clearance HBsAg Carrier (HBeAg- CHB, negative
HBeAg+ CHB Precore phase
Mutant)

HBsAg + + + + -

HBeAg + + – – -

Anti-HBe – – + + +

ALT Normal  Normal  normal

> 20,000 > 20,000 Not
< 200 IU/mL > 2000 IU/mL
IU/mL IU/mL detectable
HBV DNA (< 103 (> 104
(> 105 (> 105 Or
copies/mL) copies/mL*)
copies/mL) copies/mL) Occult B I
Histology Normal/mild Active Normal Active Depend on
 Hepatitis C Virus Infection
• Acute infection
• Chronic Infection
 HCV INFECTION

 Estimated 170 million people to be infected

 Largely asymptomatic, subclinical
 70-85% cases fail to recovery spontaneous
 Leading cause of chronic liver disease
 Last 10 years : better understand of genotype, viral
load, viral kinetic and response rate
 Exposures Associated with
the Majority of HCV Infections

 Injecting drug use

 Transfusion, transplant from infectious
donor
 Contaminated therapeutic injections
 Occupational blood exposure (needle
sticks)
 Birth to an infected mother
 Sex with infected partners (multiple
 Hepatitis C is NOT
Spread By:
 Sneezing  Handshakes
 Coughing  Holding hands
 Food or water  Hugging
 Sharing drinking  Kissing on the cheek
glasses or eating  Playing with children
utensils
HCV Infection: Worldwide Prevalence

• Estimated global prevalence:

–  3% (170 million persons)
– 3-fold increase of morbidity and
mortality in 2015

• Risk of chronicity
– 75%–85%

• Risk of cirrhosis
– ~ 10% in 20 years
– ~ 20% in 30 years

• Cirrhosis-related mortality
– 1%–5%/year

• Incidence of HCC
– 1–4%/year in patients with cirrhosis
Hepatitis C Virus

• Virus first identified in 1989

• Major cause of NANB hepatitis
• First virus discovered by
molecular cloning
• RNA virus from the Flaviviridae
family

Zein NN, Clinical Microbiology Review, April 2000, p2223-235.

 Hepatitis C Virus

• Family Flaviviridae
• Enveloped
• RNA-Virus

IRES
(Internal Ribosomal Entry Site)

5’-UTR Open Reading Frame 3’’-UTR

• single-stranded RNA (9.6 kb)
• One Open Reading Frame
HVR1 HVR2

 3000-amino acid polyprotein

Host

Efficient Protein synthesis

 Variability from
Person to Person

Lauer & Walker, 2001,

N Engl J Med;345:41-52

Massard J et al. J. Hepatology (2006); 44:S19–S24

 HCV Replication
5. Translation and
1. Binding polyprotein processing

3. Membrane
fusion
4. Uncoating
2. Endocytosis
6. RNA replication
7. Virion assembly + strands
and maturation - strands

T½:  2.7 hours

8. Vesicle fusion and Daily production: 10 trillion (1012) virions
virion release

Davis GL et al. Semin Liver Dis. 1999;19(suppl 1):103-112.

 Specific Characteristics

1. HCV genome and its protein product:

– Simple structure
– Efficient Protein synthesis
– Efficient replication
2. Propensity to mutation
 Time course of HCV markers for acute
hepatitis C
HCV RNA
1 000
– + + + + + – – – – – – – –
800
Anti - HCV
ALT (U/L)

600

Symptoms
400

200

0
0 2 4 6 8 10 12 24 1 2 3 4 5 6
Weeks Years
TIME AFTER EXPOSURE
Marcelin, 1998
 Time course of HCV markers for chronic
hepatitis C
HCV RNA
1 000
– + + + + + – + + + + + + +
4
800

3
Anti - HCV
ALT (U/L)

600

2
Symptoms
400

1
200

0
0 2 4 6 8 10 12 24 1 2 3 4 5 6
Weeks Years
TIME AFTER EXPOSURE
Marcelin, 1998
 From Chronic Hepatitis to
Liver Cirrhosis or HCC (Hepatocelullar Carcinoma

• Fibrogenic Cascade
Cartoon illustrating the important aetiological
factors in the development of Liver Cirrhosis
HCC
HCV

Environmental
Factors
Metabolic and
INFLAMMATION Hormonal
HBV
REGENERATION
Growth Factor AND
Activation GROWTH

HYPERPLASIA
CIRRHOSIS

GENETIC
MUTATIONS
 Injury/Initiating Events Toxin / Infection /
(Including oxidative stress) Activation of effector cells

Cytokines, ECM
Perpetuating/Immunomodulatory
Recruitment, continued activation of
Events
Effector cells

ECM deposition
Pathologic Damage
Wound fibrosis/contraction

Clinical Disease Portal hypertension

Liver failure
Fibrogenic cascade. The chain of events occurring after
the injury are shown. The depicted pathway is oversim-
plified for clarify because multiple pathways intercross.
ECM = extracellular matrix.
(Rockey DC, 2000)
 (Normal) (Cirrhotic)

Injury

Quiescent Activated

Rich in retinoid Decreased retinoid content

Few smooth muscle proteins Multiple smooth muscle proteins
Little extracellular matrix Abundant extracellular matrix
Receptors Increased receptor density
Little proliferation Marked proliferation
Stellate cell activation. During injury, activation of stellate cells
represents a critical component of the wounding response. The
process is complex, both in terms of the events that induce
activation and the effects of activation
(Rockey DC, 2000)
 Risk to HCC and Cirrhosis of
Hep B Chronic Infection
Risk Of HCC Risk of Cirrhosis
Male sex 3+ +
Age > 40 3+ 3+
Family History of HCC 3+ +
Alcohol Consumption 3+ +
Smoking + +
Alfatoxin 3+ Unknown
Steatosis, Metabolic Syndrome and ?? No
Diabetes
Coffee Decreased Risk of HCC Slower progression
of liver fibrosis
 Viral Risk factors to HCC and Cirrhosis
of Hep B Chronic Infection
Increased Risk of HCC Increased Risk of Cirrhosis
HBV Genotype C 3+ 2+
HBV Genotype F 2+ No evidence to date
HBV DNA > 20.000 IU/ml 3+ 2+
in person > 40 years
BCP (basal core promoter) 3 + +
Co Infection :
HBV/HIV + 2+
HBV/HCV 3+ 2+
HBV/HDV + 3+
 Comparison Hepatitis B and C (1)
Hepatitis B Hepatitis C

Virus type DNA RNA

Genotype A, B,C,D,E,F,G 1a. b, 2a. b, 3a. b,
4 (more)

Carriers ww 200 million 170 million

Possibility to eliminate virus with treatment

impossible possible

Chronicity vertical 60~80% adult 60~80%

adult 5~10%

Vaccination available in development

 Hepatitis B Hepatitis C
Progress feature and Prognosis
1) Spontaneous remission
2) CH or LC hepatitis → cirrhosis →carcinoma
3) CH→HCC
4) CH→LC→HCC
Inflammatory activities
ALT elevated ALT persistent
Annual incidence of HCC from each phase
AS 0.1% F1 0.5%
CH 1% F2(CH) 2%
LC 3~10% F3(CH) 5%
F4 (LC) 8%
CH→LC→HCC (>80%)
Carcinogenesis Rate
5 year 6.2% 11.0%
10 year 7.7% 29.9%
15 year 34.3% 52.6%
Histologic Findings and Topo-morphology of cancer
more steatosis, fibrosis
single nodule multiple nodules
Fulminant hepatitis and liver failure
frequently rare