New Outlook of Hepatitis A Management;

Scientific and Clinical View

Nu’man AS Daud
 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
Hepatitis A Virus
HAV global distribution
Hepatitis A and Molecular Epidemiology (1)

• Naked RNA virus

• Related to enteroviruses, formerly known

as enterovirus 72, now put in its own
family: heptovirus
 Hepatitis A and Molecular Epidemiology (2)

• Six HAV genotypes have been identified, of which genotypes I and III are
the most common types infecting humans.

• Genotype IA is spreading world-wide, whereas IB is dominating in the

Middle East.

• Genotype IIIA is mainly found in Asia.

• Genotypes IV, V and VI are infecting monkeys (who, in turn, can infect
humans).
 PATHOGENESIS (1)
• After HAV is ingested and survives gastric acid, it traverses the
small intestinal mucosa and reaches the liver via the portal vein.

• The precise mechanism of hepatic uptake in humans is unknown.

• Once the virus enters the hepatocyte, it starts replicating in the

cytoplasm, subsequently distributed throughout the liver.

• Virus appears to replicate exclusively in hepatocytes.

 PATHOGENESIS (2)
• When the virus is mature, it reaches the systemic circulation via the hepatic sinusoids
and is released into the biliary tree through bile canaliculi, passed into the small
intestine, and eventually excreted in the feces.

• The pathogenesis of HAV-associated hepatocyte injury is not completely defined

• HAV is not cytopathic and immunologically mediated cell damage is more likely

• The emergence of anti-HAV could result in hepatic necrosis during immunologically

mediated elimination of HAV
The life cycle of the hepatitis A virus
HAVcr-1, HAV cellular receptor 1; IRES, internal ribosomal entry-site; UTR, untranslated
region. Kanda T. et al Journal of Clinical and Translational Hepatology 2015 vol. 3 | 205–210
Hepatitis A - Clinical Features
 Incubation period: Average 30 days
Range 15-50 days

 Jaundice by age group: <6 yrs, <10%

6-14 yrs, 40%-50%
>14 yrs, 70%-80%

 Complications: Fulminant hepatitis

Cholestatic hepatitis
Relapsing hepatitis
 Chronic sequelae: None

World Health Organization 2010, Hollinger FB, Hepatitis A virus. In: Fields Virology. 3rd ed. 1996. p. 735-782
 Hepatitis A - Clinical Features (1)
• Acute hepatitis A is clinically indistinguishable from other forms
of viral hepatitis.

• Infection with HAV does not result in chronic infection, only in an

acute self-limited episode of hepatitis.

• Rarely, acute hepatitis A can have a prolonged or a relapsing

course, and occasionally profound cholestasis can occur
 Hepatitis A - Clinical Features (2)
• Patients with HAV infection usually present with one of the
following five clinical patterns

 Asymptomatic without jaundice,

 Symptomatic with jaundice, self limited after ± 8 weeks
 Cholestatic , with jaundice lasting 10 weeks or more,
 Relapsing , with two or more bouts of acute HAV infection
occurring over a 6- to 10-week period
 Fulminant Hepatic Failure
 Hepatitis A - Clinical Features (3)
• The case-fatality rate in people older than 49 years with acute hepatitis A is
reported to be 1.8%

• Hepatic failure becomes manifest in the first week of illness in about 55% of
affected patients and during the first 4 weeks in 90%

• ALF reported to be greater in populations classified as hyperendemic

• Elderly, persons with CLD and HIV infection have increased morbidity and a
high risk of ALF
 Hepatitis A - Clinical Features (4)

• The patients had experienced sustained nausea or vomiting, and prolonged

PT (>3 seconds), serious complications ( hepatobiliary and extrahepatic
complications ), and died

• Morbidity and mortality correlated with age

 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., injecting drug use, transfusion)

 Groups at High Risk of HAV Infection
• Healthy persons who travel to endemic areas, work in occupations for which
the likelihood of exposure is high, are family members of infected patients, or
adopt infants or children from endemic areas

• Men who have sex with men

• Persons who have tested positive for HIV

• Persons with chronic liver disease

• Persons with clotting factor disorders
• Users of injection and noninjection illicit drugs
 Global Patterns of HAV Transmission

Disease Peak Age

Endemicity Rate of Infection Transmission Patterns

High Low to Early Person to person;

High childhood outbreaks uncommon
Moderate High Late Person to person;
childhood/ food and waterborne
young adults outbreaks
Low Low Young adults Person to person;
food and waterborne
outbreaks
Very low Very low Adults Travelers; outbreaks
uncommon
 Laboratory Diagnosis (1)
Detection of HAV-Specific Antibodies

• The humoral immune response plays the pivotal role in the diagnosis of
HAV infection and the differentiation from other types of viral hepatitis

• Detection of IgM and total anti-HAV , and IgG anti-HAV are usually
present at the onset of symptoms

• Since hepatitis due to HAV infection is clinically indistinguishable from

disease caused by other hepatitis viruses, serologic testing is required to
make the diagnosis
 Laboratory Diagnosis (2)
• The diagnosis is based on the detection of specific antibodies
against HAV in serum, acute (IgM anti-HAV), by EIA

• IgM anti-HAV usually remains (+) for approximately 4 months,

even more than a year after the initial infection (low level)

• IgG anti- HAV is also detectable, remains present usually for

life, and, after clinical recovery, as a marker of previous HAV
infection ( + total anti-HAV, - IgM anti-HAV)
 Laboratory Diagnosis (3)
• Past Infection i.e. immunity is determined by the detection of
HAV-IgG by EIA.
• Testing for HAV RNA is limited to research laboratories

• HAV RNA has been detected in serum, stool, and liver tissue (PCR).
• HAV genotype did not seem to play a role in the severity of clinical
manifestations
 Typical Serological Course
Jaundice (Typical course of a case of acute hepatitis A)
symptoms
Symptoms Total anti-HAV

Titre ALT

HAV
in
Feces IgM anti-HAV

0 1 2 3 4 5 6 12 24

Months after exposure

 Prevention and Treatment (1)
• No specific medications are available to treat acute hepatitis A;
symptomatic treatment is the rule.

• Attention to sanitation and administration of serum IG have

been the mainstays of preventing HAV infection

• June 2007, the HAV vaccine was approved for use in

postexposure prophylaxis of immunocompetent persons, ages
12 months to 40 years, without chronic liver disease.
 Prevention and Treatment (2)
• Postexposure prophylaxis with IG can be administered at the
same time as initiation of active immunization with the vaccine

• A combined formulation of hepatitis A and B vaccines

(TWINRIX) is available and has an excellent record of efficacy
and safety ( ≥ 18 years of age )

• After vaccination with (HAVRIX), anti-HAV is estimated to

remain detectable in serum for approximately 20 years;
immunity may last longer
 Immunization Against Hepatitis A Virus In
Patients With Chronic Illnesses

• Persons with CLD are at increased risk of HAV-related morbidity and mortality
if they acquire the infection.

• Recommended for patients with CLD who are susceptible to HAV.

• Patients awaiting liver transplantation as well as those who have already

undergone liver transplantation

• Patients infected with the HIV should be vaccinated against HAV, response to
vaccination, however, may be reduced because of a blunted immune system
 Hepatitis A Vaccination Strategies
Epidemiologic Considerations
• Persons at increased risk of infection
 Travelers ( at least 2 weeks before travel)
 Homosexual men
 injecting drug users

• The availability of vaccines to provide long-term immunity against HAV

infection has the potential to significantly reduce disease incidence and
possibly eliminate infection transmission
ELU, enzyme-linked immunoassay (ELISA) units; HBV, hepatitis B virus; U, units.
*Vaccines are injected intramuscularly into the deltoid muscle.
†Timing of booster dose (necessary for long-term protection): VAQTA, 6 mos; HAVRIX, 6-12 mos; TWINRIX, 12 mos.
††Not approved by the U.S. Food and Drug Administration.
 Summary
• Acute hepatitis A is clinically indistinguishable from other forms of viral
hepatitis

• Infection with HAV does not result in chronic infection, only in an acute
self-limited episode of hepatitis

• The diagnosis is based on the detection of specific antibodies IgM anti-HAV

in serum

• No specific medications are available to treat acute hepatitis A

• Attention to sanitation and administration vaccine have been the
mainstays of preventing HAV infection
 REFERENCES
• Bell, B. P., and S. M. Feinstone. 2004. Hepatitis A vaccine, p. 269–297. In S. A. Plotkin, W. A. Orenstein, and P. A.
Offit (ed.), Vaccine, 4th ed. Saunders, Philadelphia, Pa.

• Centers for Disease Control and Prevention. 1999. Prevention of hepatitis A through active or passive
immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb. Mortal.
Wkly. Rep. 48(RR-12):1–3

• Hollinger, F. B., and S. U. Emerson. 2001. Hepatitis A virus, p. 799–840. In D. M. Knipe and P. M. Howley (ed.),
Fields virology, 4th ed. Lippincott Williams & Wilkins, New York, N.Y.

• Margolis, H. S. 2000. Viral hepatitis, p. 174–188. In R. B. Wallace and B. N. Doebbeling (ed.), Maxcy-Rosenau-Last
Public Health and Preventive Medicine, 14th ed. Appleton & Lange, Stamford, Conn

• Maria H. 2000. Hepatitis A, p. 1279-1284. In Sleisenger And Fordtran’s Gastrointestinal And Liver Disease:
Pathophysiology/ Diagnosis/Management. 2010. Saunders, an imprint of Elsevier Inc

• Nainan OV. 2006. Diagnosis of Hepatitis A Virus Infection: a Molecular Approach. Clinical Microbiology Reviews,
Jan. 2006, p. 63–79
• Present research of current scientific view of Hepatitis A

• Develop skill in managing and evaluating Hepatitis A

• Developing skill in diagnosis ant treating Hepatitis A

• Developing skill in educate the general practitioner in decreasing the

rate of Hepatitis A

• Present the current guideline and recommendation of Hepatitis A