This document provides information about Hepatitis A virus and Hepatitis A disease. It discusses the virus structure and properties, pathogenesis, transmission routes, clinical presentation, diagnosis, treatment, prevention including vaccination, and complications. The key points are: - Hepatitis A virus causes an acute infectious liver disease transmitted primarily through the fecal-oral route. - It is a non-enveloped RNA virus that is heat and acid resistant. - After ingestion, it replicates in the liver causing inflammation and symptoms like jaundice. - Diagnosis is based on IgM antibody detection in serum. Treatment is supportive and prevention includes vaccination and hygiene measures.

1. Int. Dr. Amit Poudel

2. A“Infectious”
“Serum”
Viral hepatitis
Enterically
transmitted
Parenterally
transmitted
other
E
“NANB”
B D
C
VIRAL HEPATITIS

3. Hepatitis A

4. • is an acute infectious disease of the liver caused by the hepatitis A
virus (HAV)
• formerly known as infectious hepatitis

5. HEPATITIS A VIRUS
• nonenveloped 27-nm, RNA virus ,Hepatovirus genus
,picornavirus family
• heat, acid, and ether-resistant
• virion contains four capsid polypeptides, designated
VP1 to VP4,
• despite the recognition of four genotypes affecting
humans, all strains of this virus are immunologically
indistinguishable and belong to one serotype.

6. • Inactivation of viral activity can be achieved by
• boiling for 1 minute,
• by contact with formaldehyde and chlorine,
• by ultraviolet irradiation

7. • incubation period of 4 weeks. (15-45 days)
• replication is limited to the liver
• the virus is present in the liver, bile, stool and blood during the late
incubation period and acute preicteric phase of illness.
• Despite persistence of virus in the liver, viral shedding in feces,
viremia, and infectivity diminish rapidly once jaundice becomes
apparent.

8. PATHOGENESIS
• After ingestion, the HAV survives gastric acid, moves to the small
intestine and reaches the liver via the portal vein
• Replicates in hepatocyte cytoplasm
• Not a Cytopathic virus
• Immune mediated cell damage more likely
• Once mature the HAV travels through sinusoids and enters bile
canaliculi, released into the small intestine and systemic circulation,
excreted in feces

10. • has a worldwide distribution.
• The highest seropositivity is observed in adults in urban Africa, Asia,
and South America.
• Acquisition in early childhood is the norm in these nations and is
usually asymptomatic.
• transmitted almost exclusively by the fecal-oral route
• Factors predisposing humans to early acquisition include
• overcrowding,
• poor sanitation, and
• lack of a reliable clean water resource.

11. CONCENTRATION OF HEPATITIS A VIRUS IN VARIOUS
BODY FLUIDS
Source: Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
Feces
Serum
Saliva
Urine
100 102 104 106 108 1010
BodyFluids
Infectious Doses per mL

12. 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)
• Blood exposure (rare)
(e.g., injection drug use, rarely by transfusion)

13. RISK FACTORS ASSOCIATED WITH
REPORTED HEPATITIS A,
Sexual or Household
Contact
14%
International travel
5%
Homosexual activity
9%
Injection drug use
6%
Child/employee in day-
care
2%
Food- or waterborne
outbreak
4%
Contact of day-care
child/employee
5%
Other Contact
8%
Unknown
47%

14. SYMPTOMS
• Appears in two different phases
• Prodrome
• Patients may have mild flu like symptoms of anorexia, nausea and vomiting,
fatigue, malaise, low-grade fever (usually <39.5°C), myalgia, and mild
headache.
• Smokers often lose their taste for tobacco

15. • Icteric phase
• Dark urine appears first (bilirubinuria).
• Pale stool soon follows
• Jaundice -(70-85%) adults.
• Abdominal pain (40%).
• Itch (pruritus)
• Arthralgias and skin rash,

16. SIGNS
• Hepatomegaly is common.
• Jaundice or scleral icterus may occur.
• Patients may have a fever with
temperatures of up to 40°C.

17. LAB STUDIES
• Anti–hepatitis A virus immunoglobulin M
• The diagnosis of acute HAV infection is based on serologic testing for IgM
antibody to HAV.
• are positive at the time of onset of symptoms and usually accompany the first
rise in alanine aminotransferase (ALT) level.
• This test is sensitive and specific, and results remain positive for 3-6 months
after the primary infection and for as long as 12 months in 25% of patients.
• False-positive results are uncommon and should be considered in the event
that anti-HAV IgM persists.
• IgM persists in patients with relapsing hepatitis for the duration of this
pattern of disease.

18. Anti–hepatitis A virus immunoglobulin G
• Anti-HAV IgG appears soon after IgM and generally persists for many years.
• The presence of anti-HAV IgG in the absence of IgM indicates past infection or
vaccination rather than acute infection.
• IgG provides protective immunity

20. • Liver enzymes
• Rises of levels in ALT and aspartate aminotransferase (AST) assays are
sensitive for this disease.
• Levels may exceed values of 10,000 mIU/mL, with ALT levels generally greater
than AST levels.
• Levels usually return to reference ranges over 5-20 weeks.
• Rises in alkaline phosphatase accompany the acute disease and may progress
during the cholestatic phase of the illness following the rises in transaminase
levels.

21. • Hepatic synthetic function
• Bilirubin level rises soon after the onset of bilirubinuria and follows rises in
ALT and AST levels.
• Levels may be impressively high and can remain elevated for several months;
persistence beyond 3 months indicates cholestatic HAV infection.
• Older individuals have higher bilirubin levels.
• Both direct and indirect fractions increase because of hemolysis, which often
occurs in acute HAV infection.
• Modest falls in serum albumin level may accompany the illness.

22. • Prothrombin time
• Prothrombin time usually remains within or near the reference range.
Significant rises should raise concern and support closer monitoring.
• In the presence of encephalopathy, an elevated prothrombin time has
ominous implications (eg, fulminant hepatic failure).
• CBC count
• Mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia
may rarely accompany infection.
• Indices of low-grade hemolysis are not uncommon.

23. MEDICAL CARE
• For acute cases, therapy is generally supportive, with no specific
treatment for acute uncomplicated illness.
• Locating the primary source and preventing further outbreaks are
paramount.
• Initial therapy often consists of bed rest.
• Returning to work should probably be delayed for 10 days after the
onset of jaundice
• The patient should probably not work during the acute phase of the
illness.
• Diet:
• Encourage an adequate diet.
• Patients should avoid alcohol and medications that may accumulate in liver
disease. Otherwise, no specific dietary restrictions are necessary

24. CRITERIA FOR HOSPITAL ADMISSION
• Age > 45 years
• Fever > 38.5˚C since 72 hours accompanied with vomiting and clinical signs of
dehydration and renal insufficiency.
• Clinical signs of hepatic encephalopathy (flapping tremor, coma)
• Hemorrhagic manifestations
• Ascitis
• Consumption of more than 3g of paracetamol, aspirin during the past week.
• Anemia or leucopenia
• Obese or post-partum patient
• Cirrhosis and/or cardiopathy and/or chronic renal insufficiency
• Patient with HIV/AIDS

25. SURGICAL CARE
• Consider patients with fulminant hepatic failure for referral for liver
transplantation.
• Recurrent disease after transplantation has not been reported.
• Selection of patients who require transplantation may be difficult because
60% of them recover from fulminant failure without a need for
transplantation
• Late referral has ominous implications, with the accompanying
comorbidities (eg, renal failure, coagulopathy, cerebral edema) and
waiting times contributing to poor outcomes.

26. Complications:
• Death is rare, occurring in fewer than 0.2% of cases,frequent in
elderly patients and in those with underlying liver disease. .
• Prolonged cholestasis characterized by a protracted period of
jaundice (>3 mo) and resolves without intervention.
• Acute renal failure,
• interstitial nephritis,
• pancreatitis,
• red blood cell aplasia,
• agranulocytosis,

27. • bone marrow aplasia,
• transient heart block,
• Guillain-Barré syndrome,
• acute arthritis,
• Still disease,
• Lupus like syndrome,
• Sjögren syndrome
• Autoimmune hepatitis

28. Relapsing HAV infection
• occurs in 3-20% of patients with acute HAV infection and uncommonly takes the
form of multiple relapses.
• Following a typical acute course of HAV infection, a remission phase occurs, with
partial or complete resolution of clinical and biochemical manifestations. The
initial flare usually lasts 3-6 weeks; relapse occurs after a short period (usually <3
wk) and mimics the initially presentation, although it usually is clinically milder.
• A tendency to greater cholestasis.
• Vasculitic skin rashes and nephritis
• During relapses, shedding of virus can be detected. IgM antibody test +. .
• Liver transplantation has been performed in patients with this condition when
signs of significant decompensation have occurred.
• Corticosteroid treatment has been shown to improve the clinical course,
although the course is generally benign without treatment.

29. PREVENTING HEPATITIS A
• Hygiene (e.g., hand washing)
• Sanitation (e.g., clean water sources)
• Hepatitis A vaccine (pre-exposure)
• Immune globulin (pre- and post-exposure)

30. PREPARATION OF INACTIVATED HEPATITIS A
VACCINES
•Cell culture adapted virus grown in human fibroblasts
•Purified product inactivated with formalin
•Adsorbed to aluminum hydroxide adjuvant

31. •Highly immunogenic
•97%-100% of children, adolescents, and adults have protective levels of antibody
within 1 month of receiving first dose; essentially 100% have protective levels after
second dose
•Highly efficacious
•In published studies, 94%-100% of children protected against clinical hepatitis A
after equivalent of one dose
HEPATITIS A VACCINES

32. HEPATITIS A VACCINES
Age Volume 2-Dose Schedule
Vaccine (yrs) Dose (mL) (mos)
HAVRIX ® # 2-18 720 (EL.U.*) 0.5 0, 6-12
>18 1,440 1.0 0, 6-12
VAQTA ® ## 2-18 25 (U**) 0.5 0, 6-18
>18 50 1.0 0, 6-12
* EL.U. – Enzyme-linked immunosorbent assay (ELISA) units
** Units
# has 2-phenoxyethanol as a preservative
## has no preservative
Recommended Dosages of Hepatitis A Vaccines

33.  Most common side effects
 Soreness/tenderness at injection site - 50%
 Headache - 15%
 Malaise - 7%
 No severe adverse reactions attributed to vaccine
 Safety in pregnancy not determined – risk likely low
 Contraindications - severe adverse reaction to previous dose or allergy
to a vaccine component
 No special precautions for immunocompromised persons
SAFETY OF HEPATITIS A VACCINE

34. DURATION OF PROTECTION AFTER HEPATITIS A
VACCINATION
• Persistence of antibody
• At least 5-8 years among adults and children
• Efficacy
• No cases in vaccinated children at 5-6 years of follow-up
• Mathematical models of antibody decline suggest protective
antibody levels persist for at least 20 years
• Other mechanisms, such as cellular memory, may contribute

35.  Decreased antibody concentration:
 Concurrent administration of IG
 Presence of passively-transferred maternal antibody
 Age
 Chronic liver disease
 Decreased seroconversion rate:
 HIV infection
 May be related to degree of
immunosuppression
 Liver transplantation
FACTORS ASSOCIATED WITH DECREASED IMMUNOGENICITY
TO HEPATITIS A VACCINE

36. USE OF HEPATITIS A VACCINE FOR INFANTS
• Safe and immunogenic for infants without maternal antibody
• Presence of passively-acquired maternal antibody blunts immune response
• all respond, but with lower final antibody concentrations
• Age by which maternal antibody disappears is unclear
• still present in some infants at one year
• probably gone in vast majority by 15 months

37.  Approved by the FDA in United States for persons >18 years old
 Contains 720 EL.U. hepatitis A antigen and
20 μg. HBsAg
 Vaccination schedule: 0,1,6 months
 Immunogenicity similar to single-antigen vaccines given separately
 Can be used in persons > 18 years old who need vaccination against
both hepatitis A and B
 Formulation for children available in many other countries
COMBINED HEPATITIS A HEPATITIS B
VACCINE

38. • 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 A PREVENTION IMMUNE GLOBULIN

39. HepatitisE

40. • Hepatitis E is an acute disease caused by hepatitis E virus that usually
manifest as acute jaundice.
• Previously labeled epidemic or enterically transmitted non-A, non-B
hepatitis
• is an enterically transmitted self-limited infection.
• Hallmarks of the disease are high attack-rate in young adults and high
mortality in pregnant women
• spread by fecally contaminated water within endemic areas
• Outbreaks can be epidemic and individual.
• It has many similarities with hepatitis A.

41. HEPATITIS E VIRUS
• discovered during electron microscopy of feces contaminated with
enteric non-A, non-B hepatitis
• round, non-enveloped virus -30 nm.
• The genome of the virus is a single stranded, positive–sense RNA of
approximately 7.2 kb.
• consists of a short 5’ untranslated region (UTR) followed by three
partially overlapping open reading frames (ORFs: ORF1, ORF2, and
ORF3), and then a short 3’UTR terminated by a poly (A) tract

42. • ORF1 encodes viral non-structural
proteins,
• ORF2 encodes the capsid protein,
• ORF3 encodes a small
phosphorylated protein

43. • classified tentatively into four major genetic groups (genotype 1-4)
• Genotype 1 is further segregated into five subgroups, subtypes 1a to
1e.
• The predominant HEV genotype seen in Nepal is 1a.
• Genotype 1c was observed only during 1996 to 1998
• Study of 250 HEV isolates from Nepal over ten years period from 1986
to 2006 showed some genetic changes in hepatitis E virus of subtype
1a

44. NEPAL AND HEPATITIS E
• The first documented epidemic hepatitis in Nepal occurred in the
Kathmandu valley in 1973
• affected more than 10,000 people, mostly young adults in the age group
of 16 to 35 years age
• Another epidemic of hepatitis occurred in the valley in 1981 to 1982 was
identified as epidemic non-A, non-B hepatitis.
• reoccurred in the valley in 1987 - HEV was isolated from stool of a
patient.

45. • Between 1985 and 1986 five localized focal outbreaks of non-A, non-B
hepatitis occurred in different institutions like Central jail, police training
center, Military hospital and two localities in Kathmandu.
• These outbreaks were caused by local sewerage contamination of the
drinking water
• As the adult population of Nepal has solid immunity against HAV (99% has
anti-HAV IgG), the common occurrence of acute infectious jaundice mainly
affecting adults pointed to the presence of hepatitis E in the country at
least since early 20th century.

46. In April 2014 there was an outbreak in Nepal, Biratnagar Municipality
with over 6,000 locals infected and at least 9 dead
• Prevalence of Hepatitis E (in percentage) among patient with Acute
Hepatitis in Kathmandu valley from 1996 to 2005

49. INCUBATION PERIOD
• ranges from 15 days to 60 days

50. MORTALITY/MORBIDITY:
• The overall case fatality rate is 4%.
• The case fatality rate among pregnant women is 20%, which increases
during the second and third trimesters.
• Reported causes of death include encephalopathy and disseminated
intravascular coagulation.
• The rate of fulminant hepatic failure in infected pregnant women is
high.

51. AGE
• predominantly affects those aged 15-40 years.
• may affect younger age groups but generally is not recognized and
may be subclinical.
• No chronic cases have been described.

52. SYMPTOMS
• Appears in two different phases
• Prodromal-phase
• Myalgia
• Arthralgia
• Fever with mild temperature elevations (25-97%)
• Anorexia (66-100%)
• Nausea/vomiting (30-100%)
• Weight loss (typically 2-4 kg)
• Dehydration
• Right upper quadrant pain that increases with physical activity

53. • Icteric-phase symptoms include the following:
• Jaundice
• Dark urine
• Light-colored stools (20-40%)
• Pruritus (50%)
• Urticarial rash
• Diarrhea

54. SIGNS
• Right upper quadrant tenderness
• Possible enlarged liver (palpable edges)
• Possible splenomegaly
• Possible transient spider angiomata

55. LAB STUDIES
• Western blot and enzyme immunoassays detect anti-HEV antibodies
by using the antigenic domains from ORF-2 and ORF-3. Assays of ORF-
2 are more sensitive.
• Testing to detect anti-HEV immunoglobulin M (IgM) and immunoglobulin G
(IgG) differentiates acute and chronic infection.
• The IgM titer falls rapidly after infection, becoming virtually undetectable
within 6 months.
• Anti-HEV IgG persists for longer than 6 months, although its actual duration of
positivity is unknown.
• IgG anti-HEV appears to afford protection against reinfection.

56. Symptoms
ALT IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
TYPICAL SEROLOGIC COURSE
Titer
Weeks after Exposure

57. AMINOTRANSFERASE LEVELS (AST, ALT)
• are elevated several days before the onset of symptoms
• generally return to normal within 1-2 months after the peak severity
of the disease has passed.
• Elevations can be associated with underlying liver disease or exposure to
other hepatotoxins.
• Whether the magnitude of elevation correlates with the histological severity
is not clear

58. • Serum bilirubin elevations occur in both the total and direct fractions.
• Hemolysis is unusual.
• In most cases, bilirubin levels take longer to return to normal than
aminotransferase levels.
• Many patients develop a mild leukocytosis.
• If associated with fever, bacteremia should be suspected.
• More commonly, WBC counts are decreased.
• Differential counts may show atypical cells and lymphocytosis

59. IMAGING STUDIES
• Abdominal ultrasonography is recommended.
• It helps rule out biliary obstruction in cases with significant nausea, vomiting,
or fever.
• It can demonstrate the presence of an enlarged liver; echo texture is
heterogeneous and coarsened.
• It can demonstrate splenomegaly, if present.

60. HEPATITIS E IN PREGNANCY
• High incidence of death from acute hepatic failure in pregnant
women is recognized as a distinct characteristic feature of hepatitis E..
• Pregnant women are not found to be more prone to HE, but the
incidence of AHF is higher among pregnant women during the
epidemics
• It was more common in 3rd trimester (41%), compared to 1st
trimester (20%) or 2nd trimester (26%).
• Majority of patients with AHF are young (78% were aged below 25
years age) and prime-gravida (70%)

61. • The common complications noted among the patients with AHF
during 1973 epidemic were
• Coagulopathy with bleeding tendency (75.6%),
• Hypoglycemia (41%),
• hyperventilation (17%),
• cerebral edema and
• edema of legs.

63. • Mortality correlated with the period of gestation.
• There was no death in first trimester.
• The mortality in 2nd and 3rd trimesters was 16.6% 32.4%
• respectively.
• Highest incidence of death occurred in the immediate postpartum
period.
• Fetal loss among the infected pregnant women, which included
abortion, stillbirth and maternal death before delivery was seen.

64. MEDICAL CARE:
• predominantly preventive, relying on clean drinking water, good
sanitation, and proper personal hygiene.
• Travelers to endemic areas should avoid drinking water or other
beverages that may be contaminated and should avoid eating
uncooked shellfish.
• Care should be taken while preparing uncooked fruits or vegetables.
• Boiling water may prevent infection, but the effectiveness of
chlorination is unknown.

65. • No immunoprophylaxis is available.
• Immunoglobulin from infected patients is not effective in preventing
outbreaks or sporadic cases.
• Prototype vaccines are being developed using animal models.
• this is hindered by an inability to maintain the virus in cell cultures.
• Once infection occurs, therapy is limited to support.
• Provide patients with adequate hydration and electrolyte repletion.

66. • Hospitalization is indicated only for patients unable to maintain oral
intake.

67. DIET:
• The acute illness may result in anorexia, nausea, and vomiting,
predisposing patients to dehydration.
• These symptoms tend to be worse in the afternoon or evening.
Patients should attempt to ingest significant calories in the morning.
As they improve, frequent small meals may be better tolerated.
• Neither multivitamins nor specific dietary requirements are required

68. ACTIVITY:
• Patients should be allowed to function at whatever levels they can
tolerate.
• No evidence indicates that bedrest hastens recovery. It actually may
retard recovery.