Viral Hepatitis (Part I)

Viral
Hepatitis(Part I)
Viral hepatitis is caused by 5 distinct viruses. Each of these viruses has worldwide
distribution. Indices of infection: general, localized in developed countries.

A B C D E
Source of Feces Blood/bodily Blood/bodily Blood/bodily Feces
virus fluids fluids fluids
Route of Fecal-‐oral Childbirth, Childbirth, Childbirth, Fecal-‐oral
transmission needles, sex, needles, sex, needles, sex,
transfusion transfusion transfusion
(requires
HBV
co-‐infection)
Chronic No Yes Yes Yes No
infection
Prevention Vaccine, Vaccine, Blood donor HBV vaccine Ensure safe
Immune Immune screening, drinking
globulin globulin Risk water
management,
education

Viral Hepatitis A
-‐ acute viral hepatitis A is common
-‐ affects children without producing symptoms
-‐ often with jaundice(when >50% liver affected)
-‐ in child, regeneration process is active, therefore symptoms sometimes not seen
-‐ doesn’t result in acute liver failure and chronic liver disease
-‐ no persistent viremia/intestinal carrier state

Virology
Family : Piconarviridae
Genus : Hepatovirus
Serotype : One human
Genotype : 4
Nucleic acid : Linear, single-‐stranded RNA
Genome size : 7.5kb
Open reading frame : Single, 6.7kb
Size : 27-‐28nm iscosahedral particle
Envelope : None
Replication : Hepatocyte cytoplasm
Capsomeric structural proteins : 4, VP1-‐4
Non-‐structural protein : 7

-‐ HAV – small, non-‐enveloped with cubic symmetry
-‐ chemically stable and acid-‐resistant
-‐ some time after its identification, it was classified as “Enterovirus”. In 1991 it was sub-‐
classified into its own genus “Hepatovirus”
-‐ infection titer of HAV in feces is as high as 10! infectious dose/g

Epidemiology
-‐ HAV transmission: fecal-‐oral route
-‐ person-‐to-‐person spread is the most common route
-‐ it can also be spread through contaminated food/water
-‐ during incubation period and early acute phase of HA, there is viremia
-‐ incubation period is from 15-‐30 days(~1 month)
-‐ HAV is excreted in feces about 1-‐2 weeks before the onset of illness(correlates with
incubation period, no clinical signs) and at least 1 week after
-‐ [HAV] decreases rapidly after development of first symptoms but HAV can be detected in
blood during incubation period
*acute phase: 18-‐30 days after onset of disease -‐> early recovery period*
-‐ highly influenced by personal and public hygiene
-‐ HAV has diminished in importance in developed and industrialized countries: Europe,
North America
-‐ HAV is non-‐existent in Scandinavian countries but is present
-‐ HAV is highly endemic in Africa, Central and South East Asia, and Latin America where
seroprevalance rates of antibodies to HAV IgG approximates 100%
-‐ HAV affects children and young people; most frequently diagnosed in underdeveloped
countries > developed countries
-‐ risk depends on local hygiene and sanitary standards
-‐ family, poor education, inadequate waste disposal often lead to HAV outbreaks
-‐ oral-‐anal practice(especially in homosexual individuals), digital-‐rectal intercourse
increase the risk of transmission
*these individuals may repeatedly get HA due to HIV infection(immunocompromised)*

Pathogenesis
-‐ after oral inoculation, HAV enters intestinal epithelium and then blood, where it is taken
up by hepatocytes. Here, specific receptors are involved and glycoprotein serves as a
cellular receptor for HAV in 1 cell line
-‐ liver is the only target organ of injury
-‐ HAV genome replication in cytoplasm of infected hepatocytes by the mechanism of RNA-‐
dependent RNA polymerase
-‐ from liver, HAV travels through biliary tree to the intestine. Its resistance to inactivation
by bile and intestinal proteolytic enzymes owes it to be eliminated in feces and facilitate
fecal-‐oral transmission
-‐ HAV does not affect a direct cytopathic action
-‐ antigen(Ag) attracts cytotoxic lymphocyte(CD8+; T-‐cell immunity) and natural killer
cells(NK cells) to hepatocytes, causing cytolysis and develops antibodies(B lymphocytes;
humoral response). Antibodies(Ab) attach to antigens, forming immune complexes.
-‐ cell mediated immune mechanism leads to necro-‐inflammation of hepatocytes
-‐ hepatocyte death by apoptosis
-‐ in acute phase: presence of dominant IgM and IgG against capsid polypeptide
-‐ non-‐secretory IgG Ab to HAV is present in serum after infection. Life-‐long immunity is
maintained

Clinical Picture
-‐ HAV: mild to moderate severity with mortality rate of 0.2% or less. Disease is never
chronic(due to adequate immune response)
-‐ virus excretion precedes symptoms

-‐ HAV RNA: incubation period(no jaundice)
*jaundice: present in acute phase with increasing intoxication signs, IgM and total IgG
levels at the end of incubation period and peak during jaundice period). IgM levels drop
after 3 months.*

-‐ Symptomatic HAV with mild preicteric illness occurs 1-‐7 days prior to onset of dark
urine

The Prodromal Periods of Acute Viral Hepatitis
1) Flu-‐like syndrome : fever, headache, stuffed in throat, hacking cough/dry cough,
coryza
2) Dyspeptic syndrome : anorexia, nausea, vomiting
3) Asthenic syndrome : malaise, general weakness, sleepiness, muscular pains, dizziness

*maybe combination of several syndromes*

-‐ increased bilirubin levels lead to jaundice
-‐ nausea is severe enough to be triggered by sight of food but vomiting rarely severe
-‐ loss of taste for tobacco and find cigarette smoking offensive(due to decreased
detoxification function of liver)
-‐ atypical symptoms occasionally occur: diarrhea, arthralgia
-‐ 1st objective sign: onset of dark urine
-‐ bilirubinemia is followed by pale/clay colored feces and yellow discoloration over sclera,
skin and visible mucus membrane(soft palate, hard palate, frenulum, tongue)
-‐ return of color of stool after 2/3 weeks after onset of illness means good sign of
resolution of disease
-‐ itching: cholestasis in <5% of symptomatic patients; maybe sub-‐febrile fever
-‐ hepatosplenomegaly(hepatomegaly found in older patients; splenomegaly found in few
cases)
-‐ in elderly patients, during the preicteric period of disease and the whole icteric period,
there is an elevation of serum ALT and AST. They are the signs of cytolytic process in
liver(serum aminotransferases level may reach up to 500-‐5000IU/L)
-‐ after 3-‐4 weeks, patient feels better, liver and spleen sizes return to normal,
normalization of serum aminotransferases and bilirubin levels(cytolytic process stops)
-‐ prolonged jaundice/relapsing pattern is present but ultimate resolution is universal(for
adults)

Complications
-‐ prolonged jaundice leads to fever and pruritus(indication of cholestatic hepatitis)
-‐ peak serum bilirubin levels may reach a high figure and jaundice up to 4-‐5 months(18
weeks)
-‐ peak AST and ALT levels are <500IU/L(moderate) during icteric phase but alkaline
phosphatase(AP) increase(sign of cholestasis)
-‐ prognosis of HAV complicated with cholestasis is universally favorable
-‐ fulminant HAV: rare complication characterized by marked severity of jaundice,
deterioration of liver function, coagulation disorder and encephalopathy
-‐ mortality rate of 0.01-‐2% in various areas
-‐ fulminant post hepatitis A is common in elderly and recovery from severe disease is less
common in patients >50 years old

Serological Diagnosis
-‐ acute HAV is not distinguishable from others in clinical course
-‐ liver function test: ALT, AST levels in serum and sensitive measures of liver damage is
non-‐specific for hepatitis A
-‐ biochemical tests are specific for HBV, HCV, HDV
-‐ elevation of ALT > AST may be found in preicteric/prodromal period
AST > ALT indicates toxic hepatitis
-‐ high aminotransferases levels indicate severe hepatitis
-‐ AP usually mildly increase in HAV except when complicated with cholestasis
-‐ biochemical abnormalities may persist for 2-‐3 weeks but <4 weeks(acute phase of
disease)
-‐ HA: differentiate from others by serological test(clinical and biochemical pictures are the
same)
-‐ find IgM to HAV during acute phase of disease
-‐ IgM Ab persists for 3-‐6 months afterwards
-‐ Patients with asymptomatic HA: detection of IgM anti-‐HAV for shorter period compared
to symptomatic patients
-‐ IgG anti-‐HAV: present early in infection, accompanied by IgM anti-‐HAV at onset of
disease
-‐ IgG anti-‐HAV alone indicates past infection(s)
-‐ ALT peak(jaundice and intoxication symptom) correlates with serum IgM anti-‐HAV

Prevention
2 types of prophylaxis: passive immunization with human Ig and vaccine

Passive immunization:
-‐ IgG anti-‐HAV(main way before appearance of vaccines)
-‐ good record
-‐ its use decrease due to appearance of vaccines
-‐ individuals with contact with HAV persons should get Ig ASAP after recognition
-‐ Ig not effective if >2 weeks after exposure
-‐ duration of protection is dose-‐dependent and short
-‐ large doses provides 4-‐6 months of protection
-‐ effective in control of HAV in hyperendemic areas/common outbreaks

Vaccine:
-‐ 2 types: live-‐attenuated and inactivated
-‐ currently inactivated vaccine more widely used
-‐ HAV vaccine: stable, can be stored up to 2 years at 4°C without adverse effect of
immunogenicity
-‐ after injecting inactivated vaccine, serum concentration of anti-‐HAV may be 15 times
more than active doses of Ig
-‐ anti-‐HAV is present in serum as early as 15th day after vaccination(single dose)
-‐ all healthy people will be seroconverted by 1 month
-‐ peak of anti-‐HAV titers may decrease a little after simultaneous administration of HAV Ig
rather than vaccine alone

Viral Hepatitis B
-‐ almost ½ of the world’s population live in areas with high HBV prevalence
-‐ HBV prevalence can cause cancer/cirrhosis(25-‐40% die)
-‐ according to WHO there are 2 billion people with HBV, in which 5% suffer from chronic
HBV(300-‐400 million)

Epidemiology
-‐ transmissibility is 100 times greater than HIV
-‐ vertical: infected mother to infant during first year of life
-‐ horizontal: household exposure, multiple sexual partners, IV drug use, contaminated
blood transfusion, contaminated needle
-‐ earlier age at exposure increases the risk of developing chronic HBV infection
90% in child <1 year old
30% in child 1-‐5 years old
5% in child > 5 years old and adults
% decreases due to increase of immunity
-‐ infection dose: 10! /ml
-‐ virus is present in saliva and serum
-‐ ¾ patients with chronic HBV are Chinese and South Africans
-‐ prevalence in this region is 10-‐20%(during neonatal/whole childhood(early))
-‐ prevalence of 0.2-‐0.5% in North America, Northern and Southern Europe, and Australia
where transmission is through sexual contact and IV drug abuse

Clinical Outcome

-‐ immune response differs: if younger, outcome is bad; if older, outcome is better
Virology of Hepadnaviruses
-‐ characteristics: -‐ hepatotropic
-‐ partially as DNA genome
-‐ virion-‐associated polymerase activity
-‐ common occurrence of persistent infection and development of HCC
-‐ animal models: -‐ duck hepatitis B virus(DHBV)
-‐ Woodchuck hepatitis virus(WHV)
-‐ widely accepted as models for predicting viral efficacy in man

-‐ genotype: A – pandemic
B & C – Asia
D – in Southern Europe
E – Africa
F – USA
G – in USA and France
A, B & C – Russia

-‐ HBV consists of nucleus and covering
-‐ 4 Ag’s in virion: Hbs Ag
Hbc Ag
Hbx Ag
Hbe Ag
-‐ Hbs Ag + Hbc Ag = primary Ag

Structure of HBV
-‐ core, Hbc Ag
-‐ surface, Hbs Ag(SHbs, LHbs, MHbs)
-‐ partially double-‐stranded DNA
-‐ size is 42nm(smallest known DNA virus)
-‐ Hbs Ag(basic): hepatocyte receptor which means it promotes HBV penetration into
hepatocyte
-‐ Hbc Ag: exist only in hepatocyte nucleus and cannot be found in blood
-‐ Hbe Ag: scrap of Hbc Ag, exists not only in nucleus but circulates in peripheral blood
which shows active virus replication(individual must be hospitalized)
-‐ Hbx Ag: not studied completely, considered to trigger process of hepatocytes’
malignization

Pathogenesis
-‐ HBV replication cycle is observed in cell cultures but don’t appear to be directly cytotoxic
to cells
-‐ viral replication itself doesn’t cause injury to cell. Therefore, carriers are asymptomatic
with decreased liver injury despite hepatocytes’ death(infection)
-‐ immune response affects 2 aspects of HBV liver disease as the prime determinant of
hepatocyte injury influence both viral clearance, whether primary infection is reserved
or becomes resistant
-‐ individuals with immune defects presents with acute liver injury but cause the increase
in number of carriers(eg: neonates has immature cell-‐mediated immunity with
decreased rate of viral clearance)
-‐ severe acute fulminant HB is often associated with hyperactive immune response over
virus. Patients who don’t die of liver failure has decreased rates of viral persistence
compared to people with conventional HB
-‐ outcome with chronic HB
outcome with recovery
-‐ 1/3 part of virus DNA
2/3 part of defective patient DNA
-‐ 2/3 part of virus DNA
1/3 part of defective patient DNA

-‐ in acute self-‐limited HB, strong T-‐cell responses to viral Ag’s readily in peripheral blood.
Response includes histocompatible complex(class I restricted(CD8+)) which invade
population comprising of class II restricted(CD4+) cytotoxic lymphocytes(polyclonal and
multispecific directed against multiple proteins)
(against multiple epitopes of Hbc polymerase, strong T-‐helper cells to proteins in acute
infection)
-‐ T-‐helper against proteins -‐> related to large HbAg load
-‐ Carriers(CD4+ and CD8+ greatly attenuated) do not have Ab to Hbs because there are
Hbs circulating Ag. T-‐cells(cytotoxic cells, anti-‐Hbc and anti-‐Hbe play role in viral
clearance). T-‐helper response to core proteins help by contributing to stimulating
cytotoxic T-‐lymphocytes and enhance production of Ab by augmenting underdeveloped
B-‐cell production
-‐ Interferon γ, TNF-‐α, IL-‐2: additional antiviral effects are independent of their
contribution to cytotoxicity
Clinical Picture
-‐ incubation period: 75 days(1-‐6 months)
-‐ moderate to severe, more likely to become chronic
-‐ symptomatic HB -‐> prodromal period(7-‐14 days) prior to appearance of dark urine
-‐ icteric period(cyclic course): presence of dyspeptic syndrome, asthenia syndrome,
arthral syndrome(arthralgia in large joints, myalgia, malaise). 10-‐12% of patients has
urticarial rash on their skin. There may be combination of several syndromes
-‐ severe form of HB: dizziness, headache, increase in body temperature, hemorrhagic
syndrome(prothrombin index decrease -‐> gum and nose bleeds; normal prothrombin
index > 75%)
-‐ 95% of patiens with icteric forms of HB recover; 5% progresses to chronic infection
-‐ patients with chronic HBV seldom have extrahepatic manisfestations until appearance of
cirrhosis and hepatocellular carcinoma(HCC)
-‐ acute exacerbation symptoms
-‐ 3 phases of chronic HB: -‐ long immune tolerance in children and adults
-‐ increased concentration of HB DNA and HB Ag positivity
-‐ immune clearance phase of seroconversion form by active
inflammation and fibrosis with increased ALT
-‐ residual phase: low HB DNA and decreased ALT
-‐ for adulthood, in wide population there is no immune
tolerance phase
-‐ complicated with precore mutations as a result of immunosuppression on Hbe Ag
producing HBV and response for viral replication
-‐ Hbe Ag seroconversion: leads to cirrhosis and HCC
HAV: jaundice -‐> intoxication signs decrease, if severe then intoxication signs increase
HBV: after jaundice -‐> intoxication signs increase in icteric period

Complications
-‐ acute encephalopathy

Diagnosis
-‐ routine blood test(lymphocytosis and normal leukocyte count in moderate cases; anemia
and leukopenia in severe cases)
-‐ urine(bile pigments)
-‐ blood serum(increased contents of general bilin(direct)) -‐> icteric
-‐ preicteric, icteric and early convalescence period(increased ALT and AST) -‐> cytolysis
-‐ Hbs Ag presence in blood at the end of incubation period -‐> maximum
concentration(when symptoms present)
-‐ Hbe Ag(product disintegration of Hbc Ag; complication of HBV(seroconversion);
eliminated from blood earlier than Hbc Ag)
-‐ anti-‐Hbc IgM and Hbe Ag -‐> in blood during intoxication; during preicteric -‐> peak when
jaundice is in full swing
-‐ Hbs Ag: during incubation period only
-‐ during virus elimination, anti-‐Hbe takes place of Hbe Ag
-‐ anti-‐Hbc IgM: in acute period and remains >6 months after illness
-‐ anti-‐Hbc IgG and anti-‐Hbc IgM appear simultaneously
-‐ only anti-‐Hbc IgG remains whole life(post-‐infection immunity)
-‐ in case of complete virus elimination, anti-‐Hbs Ag present in blood 5-‐6 months after
illness and remains lifelong
-‐ anti-‐Hbs Ag: development of immunity against reinfection(post-‐infection immunity)

Biochemical Markers of Liver Function
-‐ bilirubin: -‐ by-‐product of RBC breakdown excreted into bile
-‐ measured as “total”/”unconjugated”
-‐ elevated bilirubin can occur when excretion is limited because of liver/bile
duct damage
-‐ albumin: -‐ secreted by hepatocytes
-‐ in chronic HBV, albumin levels gradually fall with progression to cirrhosis

Biochemical Markers of Liver Damage
-‐ elevated levels of liver enzymes in blood can indicate liver cell damage
ALT: more indicative of liver damage; used to monitor HBV disease progression
AST: commonly associated with non-‐specific liver damage
AP
γ-‐GT
-‐ raised liver enzyme levels should be interpreted alongside other clinical information
-‐ liver enzymes are also found in other tissues(eg: heart, kidney, intestine, muscle) and
can indicate damage to these organs
-‐ liver enzyme levels can vary with age, sex, BMI, smoking, alcohol use and pregnancy

Markers of HBV Infection
-‐ ALT(elevated levels in blood indicative of liver damage; used to monitor disease
progression)
-‐ HBV DNA(quantitative marker of viral replication; used to assess and monitor treatment
of patients with chronic HBV infection)
-‐ persistent viremia indicates ongoing biral replication and potential liver damage
-‐ reduction of HBV DNA is associated with normalization of ALT, improvement in liver
histology, and Hbe Ag loss and seroconversion

Serologic Markers of HBV Exposure: HBV Core Antigen
-‐ HBV core Ag(Hbc Ag)
-‐ not detected in serum
-‐ cytotoxic lymphocytes epitopes expressed on hepatocyte surface in association with
HLA-‐A2 molecules
-‐ Hbc Ab(anti-‐Hbc)
-‐ presence of high titers of anti-‐Hbc IgM indicates early acute infection
-‐ anti-‐Hbc IgG can be detected in both acute and chronic HBV infection(remains for
lifetime)

Serologic Markers of HBV Exposure: HBV Early Antigen
-‐ HBV early Ag(Hbe Ag)
-‐ “early” appearance during acute HBV infection
-‐ marker of high degree of HBV infectivity
-‐ correlates with high level of HBV replication
-‐ Hbe Ab(anti-‐Hbe)
-‐ often associated with decreasing levels of HBV DNA and liver enzymes in blood marking
the end of replication phase of disease
-‐ may lead to selection of variants unable to produce Hbe Ag which can lead to increased
levels of HBV DNA and progress to Hbe Ag – negative chronic hepatitis

Serologic Markers of HBV Exposure: HBV Surface Antigen
-‐ HBV surface Ag(Hbs Ag)
-‐ marker of infectivity
-‐ presence in serum for at least 6 months indicates chronic infection
-‐ Hbs Ab(anti-‐Hbs)
-‐ plays artificial role in viral clearance by preventing infection of susceptible cells by free
virus
-‐ indicates immune response to HBV infection(vaccination, or presence of passively
acquired Ab(HBIg)

Prevention of HBV Infection
-‐ vaccine against HBV: anti-‐Hbs Ag -‐> present in serum 5-‐6 months after vaccination
-‐ 3 doses: first dose at birth; second dose 1-‐2 month after; third dose 6-‐18 months after
-‐ screening of blood/organ/tissue donors
-‐ HB vaccine(95% effective)
-‐ available since 1981
-‐ vaccination programs adopted in more than 150 countries worldwide
-‐ inactivated/recombinant Hbs Ag
-‐ routine vaccination of infants and previously unvaccinated children(by age 1)
-‐ catch-‐up vaccination of high-‐risk group of all ages
-‐ screening pregnant women and rapid vaccination of infants born to infected mother
(HBIg and vaccination)

Viral Hepatitis (Part I)

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