Viral Hepatitis

from “A” to “E”

Khaled Jadallah, MD
 Educational Objectives
 Outline the epidemiology of viral hepatitis
 List causative agents for viral hepatitis
 Recognize the clinical features of acute and
chronic viral hepatitis and their complications
 Interpret serologic tests to accurately diagnose
the specific cause of viral hepatitis
 Outline the treatment of acute and chronic
hepatitis
 Identify appropriate candidates for vaccination
against HAV and HBV
 Viral Hepatitis - Historical Perspectives

“Infectious” A Enterically
E
transmitted

Viral NANB
hepatitis

Parenterally
“Serum” B D C transmitted

G,?
other
 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 fecal-oral percutaneous percutaneous percutaneous fecal-oral

transmission permucosal permucosal permucosal

Chronic no yes yes yes no

infection

Prevention pre/post- pre/post- blood donor pre/post- ensure safe

exposure exposure screening; exposure drinking
immunization immunization risk behavior immunization; water
modification risk behavior
modification
 Clinical Manifestations of
Acute Hepatitis
 Acute HAV mostly symptomatic, especially in adults
 Acute HEV is most symptomatic and severe in
pregnant women
 Acute HCV is least symptomatic
 Acute HBV can present with a serum sickness-like
picture (fever, arthritis, urticaria, angioedema)
 Generally, symptoms improve after jaundice appears
 Symptoms are non specific-the viral syndrome
(fever, malaise, anorexia, RUQ pain, diarrhea, pruritis)
 Acute Hepatitis-LAB
 Markedly elevated levels of AST/ALT (more
than 500 U/L) typically occurs in acute
hepatocellular injury (viral, drug-induced,
ischemic)
 Modest elevations (less than 300 U/L) may be
seen in a variety of conditions (acute or chronic
hepatocellualr injury, infiltrative diseases,
biliary obstruction, acute alcoholic hepatitis)
 Bilirubin and AP may or may not be elevated
 WBC count may show leucopenia
Stigmata of Chronic Liver
Disease
 Spider Agiomatas
 Palmar erythema
 Clubbing of fingers
 Dupuytren contractures
 Gynecomasita (male) or breast
atrophy (female)
 Testicular atrophy
 Hepatitis A
Clinical Features
 Incubation period: Average 25 days
Range 15-50 days
 Jaundice by <6 yrs, <10%
age group: 6-14 yrs, 40%-50%
>14 yrs, 70%-80%
 Complications: Fulminant hepatitis (0.1 %)
Prolonged Cholestasis
? Autoimmune hepatitis
 Chronic sequelae: None
 Hepatitis A Infection
Typical Serological Course
Sympto TotalTotal
anti-
ms anti-HAV
HAV

Titre ALT

Fecal
HAV
IgM anti-HAV

IgM anti-HAV

0 1 2 3 4 5 6 1 2
2 4
Months after exposure
 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)
 Serologic Diagnosis

 Acute infection is diagnosed by the

detection of anti-HAV IgM in serum
 Past Infection i.e. immunity is
determined by the detection of
HAV-IgG (HBsAb and HBcAb)
 Vaccination is characterized by the
presence of HAV-IgG (HBsAb)
 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 A Prevention -
Immune Globulins
 Pre-exposure
 travelers to intermediate and high
HAV-endemic regions
 Post-exposure (within 14 days)
Routine
 household and other intimate contacts

Selected situations
 institutions (e.g., day care centers)
 common source exposure (e.g., food
prepared by infected food handler)
 Hepatitis B
Clinical Features

 Incubation period: Average 60-90 days

Range 45-180 days
 Clinical illness (jaundice): <5 yrs: <10%
> 5 yrs: 30%-50%
 Acute case-fatality rate: 0.5%-1%
 Chronic infection: <5 yrs: 30%-90%
5 yrs: 2%-10%
 Premature mortality from
chronic liver disease: 15%-25%
 Global Burden of HBV
 2 billion current or past infections
 380-400 million with chronic HBV disease
 40 million in the Eastern Mediterranean region
 25%-40% of persons with chronic HBV disease die from
cirrhosis or HCC
 Over 300,000 cases/year of HBV-related HCC
 HBV is second most important carcinogen behind tobacco
 HBV is 100 times more contagious than HIV

World Health Organization. Fact sheet. Available at: http://www.who.int

Center for Disease Control. Fact sheet. Available at: http://www.cdc.gov
Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.
 10 Leading Causes of
Infectious Disease
Deaths Worldwide
Disease
(2000)
Deaths per Year
Lower respiratory tract infections ~ 3.5 million
HIV/AIDS ~ 3.0 million
Diarrheal diseases ~ 2.2 million
Tuberculosis ~ 2.0 million
Malaria ~ 1-3 million
Measles ~ 888,000
Hepatitis B ~ 500,000-750,000
Pertussis ~ 355,000
Neonatal tetanus ~ 300,000
Hepatitis C ~ 250,000

WHO. Hepatitis B. 2002. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New
York: Alan R. Liss, Inc. 1988. CDC. Epidemiology & prevention of vaccine-preventable
diseases. The Pink Book. 8th ed. CDC. MMWR. 2001;50:RR-11.
Clinical Consequences of
HBV Acquisition
 Acute Infection
 Major risk of death related to development
of fulminant liver failure (rare)
 Chronic Infection
 Progressive liver disease
 Risk of cirrhosis, liver failure, hepatocellular
carcinoma (HCC)
 Extrahepatic manifestations
 Possible Outcomes of
Chronic HBV Infection
Patient Populations in Chronic Hepatitis B
Marker Immune HBeAg+ Inactive HBeAg– CHB
Tolerant CHB HBsAg (Precore
Carrier Mutant)
HBsAg + + + +
HBeAg + + – –
Anti-HBe – – + +
ALT Normal  Normal 
HBV DNA > 105 > 105 < 103 > 104
(copies/mL)

Histology Normal/Mild Active Normal Active

Lok AS, et al. Gastroenterology. 2007;120:1828-1853

 Extrahepatic Manifestations of
Hepatitis B

 Acute infection
 Arthralgias
 Papular acrodrmatitis (Gianotti-Crosti
syndrome)
 Chronic infection
 Glomerulonephritis
 Arthrlalgias
 Polyarteritis nodosa (PAN)
Papular acrodermatitis
PAN
 Acute Hepatitis B Virus Infection with
Recovery-Typical Serologic
Course
Symptoms
HBeAg anti-HBe

Total anti-HBc
Titre

HBsAg IgM anti-HBc anti-HBs

0 4 8 12 16 20 24 28 32 36 52 100

Weeks after
Progression to Chronic Hepatitis B Virus
Infection Typical Serologic
Course
Acute Chronic
(6 months) (Years)
HBeAg anti-HBe
HBsAg
HBsAg
Total anti-HBc
Titr Total anti-HBc
e

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after Exposure
 Outcome of Hepatitis B Virus
100 Infection 100
by Age at Infection
80
80

Symptomatic Infection (%)

60 60
Chronic Infection

40 Chronic Infection (%) 40

( noi t cef nI ci nor h C

20 20

Symptomatic Infection
0 0
) %

Birth 1-6 months 7-12 months 1-4 years Older Children

and Adults
Age at Infection
 Clinical-Epidemiologic
HBV
Correlations
Location Age of Mode of Chronicit HCC
Endemicity Infection Transmission y Risk

High 10- Asia Birth Perinatal Likely High

15% Sub-Sahara Toddler Horizontal
Africa
Low < 2% N. America Early Percutaneo Rare Low
W. Europe Adulthoo us
Scandinavia d Sexual
Centers for Disease Control. Hepatitis B fact sheet
 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
breastmilk
 Hepatitis B Virus
Modes of Transmission

 Sexual – promiscous heterosexuals and

homosexuals are particular at risk
 Parenteral - IVDA, Health Workers are at
increased risk
 Perinatal - Mothers who are HBeAg positive are
much more likely to transmit to their offspring
than those who are not. Perinatal transmission is
the main means of transmission in high
prevalence populations
 Initial Evaluation of
HBsAg+ Patient
 History and PE  Investigations
 Liver disease activity
 Assess risk factors  Serologic and
(coinfection) virologic markers
 Alcohol use  Screening for HCC
(AFP and ultrasound)
 Family history of  Test for HCV and HIV
HBV and HCC infection
 Physical findings of
cirrhosis
 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-HBc IgG - 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
 Hepatitis B Serological
Scenarios
HBsAG HBcAb HBsAb Interpretation
(IgG)
+ - - Acute infection (+ HBc IgM Ab)
+ + - 3 possibilities:
1. Acute infection
2. Chronic infection (high ALT)
3. Carrier (normal ALT)
- - + 2 possibilities:
1. Remote infection
2. Immunized
- + - 2 possibilities:
1. Window disease
2. Remote infection
+ + + Acute on chronic infection
 Treatment

 Interferon - for HBeAg +ve carriers with chronic

active hepatitis. Response rate is 30 to 40%
 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
 Successful response to treatment will result in the
disappearance of HBsAg, HBV-DNA, and
seroconversion to HBeAb
 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. 3 doses are given (at 0,1,and 6 months)
 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 C
Virus
6 different genotypes

capsid envelop protease/helica RNA- RNA

e se dependent polymerase
protein
c2 33 c-
2 c 100
5’ 3’

core E1 E2 NS2 NS3 NS4 NS5

hypervariable
region
 Hepatitis C
Clinical Features

Incubation period: Average 6-7 wks

Range 2-26 wks
Clinical illness (jaundice): 20-30%
Chronic hepatitis: 75-85%
Persistent infection: 85-100%
Immunity: No protective
antibody
response identified
 Extrahepatic
Manifestations of
Hepatitis C
 Mixed cryoglobulinemia (Vasculitis, non-
deforming arthritis, membranous GN)
 Porphyria cutanea tarda(hyperpigmentation
and photosensitivity with blistering skin
lesions)
 Sjogren-like syndrome
Porphyria cutanea tarda
 Hepatitis C Virus Infection
Typical Serologic Course
anti-
HCV
Symptom
s

Titr
e

ALT

Norma
l
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.
 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 -Combination of interferon and
ribavirin is more effective than interferon
alone
 Prevention of Hepatitis
C

 Screening of blood, organ, tissue donors

 High-risk behavior modification

 Blood and body fluid precautions

 Hepatitis D (Delta)
δ Virus HBsAg
antigen

RNA
 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
 Hepatitis D
Virus
Modes of Transmission
 Percutanous exposures
 Injecting drug use
 Permucosal exposures
 Sexual contact (rare)
 HBV – HDV
Coinfection
Typical Serologic Course
Symptoms

ALT
Elevated

Titre
anti-
IgM anti- HBs
HDV

HDV RNA

HBsAg
Total anti-
HDV

Time after
 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 postexposure prophylaxis to prevent
HBV infection.
 HBV-HDV Superinfection
Education to reduce risk behaviors among
persons with chronic HBV infection.
 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 Symptom
s

ALT IgG anti-HEV

Titer IgM anti-HEV

Virus in stool

0 1 2 3 4 5 6 7 8 9 1 1 1 1
0 1 2 3
Weeks after
 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
 Minimal person-to-person transmission
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
Clinical Features
 HGV is an RNA virus
 HGV is blood borne
 Mode of transmission is not well defined
but believed to be similar to HCV
 Evidence of infection in 1.5 % of blood
donors
 It causes less than 0.5 % of community-
acquired hepatitis
 There is no evidence that HGV causes
chronic liver diasease
 Viral Hepatitis Serological
Diagnosis
Organism Acute Chronic Recovered/late Vaccinated
nt
HAV •Anti-HAV IgM •NA •Anti-HAV IgG •Anti-HAV
IgG
HBV •Anti-HBc IgM •Anti-HBc IgG •Anti-HBc IgG •Anti-HBs

•HBeAG •HBsAg •Anti-HBs

•HBV DNA •HBeAg or

HBeAb

HCV •Alltests possibly •Anti-HCV Ab •Anti-HCV Ab •NA

negative •HCV RNA
•Anti-HCV Ab

•HCV RNA

HDV •Anti-HDV IgM •Anti-HDV •Anti-HDV •NA

•HD Ag •HDV Ag
•HBsAg
 Summary
 All hepatotropic viruses are RNA viruses, except for
HBV
 Only HBV, HDV and HCV can cause chronic liver disease
 Always consider alternative diagnosis of chronic liver
disease….recall the mnemonic “ABCDE”
 A: Autoimmune
 B: HBV
 C: HCV
 D: Drugs
 E: Etcetera….alcohol, alfa1-AT deficiency, Wilson’s,
Hemochromatosis, NAFLD or NASH
 Summary (cont’d)
 Accurate diagnosis of viral hepatitis depends on proper
interpretation of specific serologic tests
 Initial management of acute hepatitis is supportive,
with monitoring for signs of liver failure
 Antiviral therapy is effective in selected patients with
chronic HCV or HBV
 Immune globulins and vaccine are given to selected
contacts of the patient with acute hepatitis A or B
“Knowing is not enough;
we must apply.
Willing is not enough; we
must do.”
(Goethe)
AUTOIMMUNE HEPATITIS
Educational Objectives
 Define autoimmune hepatitis (AIH)
 Classify AIH
 Describe different presentations of
AIH
 Outline the management of AIH
 Know the prognosis of AIH
 AIH
 Definition: AIH is a necroinflammatory disease of
the liver characterized by the presence of specific
autoantibodies and, in general, a favorable
response to immunosuppressive treatment
 Epidemiology: 170/milion individuals
 Etiology: largely unknown. Sometimes it can
follow HAV or HCV infection
 Pathophysiology:
 Only partially understood
 Antibody-dependent cytotoxicity
 Strong association with HLA B8, DR3 and DR4
 AIH
 Autoantibodies:
 Antinuclear antibody (ANA)
 Anti-smooth muscle antibody (ASMA)
 Anti-liver/kidney microsomal antigen antibody
(A-LKM)
 Anti-soluble liver antigen antibody (A-SLA)
 Classification
 Type 1: positive ANA and ASMA
 Type 2: positive A-LKM
 Type 3: positive A-SLA
 Clinical Features of AIH
 Manifestations: usaually insidious and non
specific (e.g. fatigue, malaise, arthralgias,
RUQ pain and fluctuating jaundice)
 Young females most commonly affected
 Often associated with other autoimmune
disorders (e.g. thyroiditis, vasculitis, UC,
autoimmune hemolysis, ….)
 LAB: hypergammaglobulinemia
 Diagnosis of AIH
 Clinical features
 Serology for autoantibodies
 Negative viral hepatitis panel. AIH is
essentially a diagnosis of exclusion
 Liver biopsy is confirmatory but not
pathognomonic(portal infiltrate with
interface hepatitis, with plasma cells,
lymphocytes and eosinophils)
 Management and
Prognosis of AIH
 The mainstay of treatment is
glucocorticoids, with azathioprine or
mercaptopurine as steroid-sparing agents
 Type 1 is more responsive to steroids than
type 2 or 3
 A significant proportion of patients will
ultimately progress to cirrhosis despite
treatment
 Liver transplantation is an option for
selected patients
Hepatitis Case Scenarios
 A 28-year-old woman has had fatigue for 8 months and dark
urine , which she first noticed 6 weeks ago. Physical exam
revealed scleral icterus, spider nevi and hepatosplenomegaly.
AST elevated at 420 U/L, ALT 530, bilirubin 15 mg/dl, AP 130,
albumin 2.8 gm/dl, globulins 8.2 gm/dl INR 2.3.
 Q: What is going on with this patient?
 A: Chronic hepatitis
 Q: What kind of chronic hepatitis you think is this?
 A: Autoimmune
 Q:What further tests should be done to confirm the diagnosis?
 A: autoantibodies (ANA, ASMAS, Anti-LKM). Do not forget to R/O viral and
metabolic hepatitis. Consider liver biopsy
 Case 2
 A 30-y-old man is referred to you for further investigation of
abnormal liver chemistries. The patient’s AST was 90 U/L
and his ALT was 100. An anti-HCV was positive. Tests for
other viruses were negative. The patient admits to casual IV
drug use 20 yrs ago. Physical exam was WNL.
 Q: What further test is indicated to confirm his infection?
 A: None. The patient is high risk and thus high pre-test
probability
 Q: What if the patient was low risk?
 A: Anti-HCV RIBA (Recombinant Immuno Blot Assay) should be
done to confirm the diagnosis)
 Q: When's HCV RNA testing indicated?
 A: When treatment is contemplated or when acute infection is
suspected but Anti-HCV Ab test is negative
Thank You !