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Hepatitis A
Richard K Gilroy… Updated: Jan 28, 2016
http://emedicine.medscape.com/article/177484-overview

Background
One of the more common causes of acute hepatitis is hepatitis A virus (HAV), which was
isolated by Purcell in 1973. Humans appear to be the only reservoir for this virus. Since the
application of accurate serologic tests in the 1980s, the epidemiology, clinical manifestations,
and natural history of hepatitis A have become apparent.
The relative frequency of HAV as a cause of acute hepatitis has declined in Western
societies, while in contrast, notification of individual cases has increased, primarily as a result
of improved reporting and diagnostic techniques. The nadir of reported cases was in 1987.
Improvements in hygiene, public health policies, and sanitation have had the greatest impact
on hepatitis A. Vaccination and passive immunization have also successfully led to some
reduction in illness in high-risk groups.
Reduced encounters with HAV at a young age have resulted in both a decline in herd
immunity and a change in the epidemiology of the illness, with increases in the mean age of
occurrence of illness attributed to acute HAV infection in Western societies. Although this
phenomenon may lay a framework for potential epidemics in the future, public health policies
and newly implemented immunization practices are likely to reduce this potential.
See the following for more information:
 Alcoholic Hepatitis
 Autoimmune Hepatitis
 Cutaneous Manifestations of Hepatitis C
 Hepatitis B
 Hepatitis C
 Hepatitis D
 Hepatitis E
 Hepatitis in Pregnancy
 Pediatric Hepatitis A
 Pediatric Hepatitis B
 Pediatric Hepatitis C
 Viral Hepatitis

Pathophysiology
HAV is a single-stranded, positive-sense, linear RNA enterovirus of the Picornaviridae
family. In humans, viral replication depends on hepatocyte uptake and synthesis, and
assembly occurs exclusively in the liver cells. Virus acquisition results almost exclusively
from ingestion (eg, fecal-oral transmission), although isolated cases of parenteral
transmission have been reported.
HAV is an icosahedral nonenveloped virus, measuring approximately 28 nm in diameter (see
the image below). Its resilience is demonstrated by its resistance to denaturation by ether,
acid (pH 3.0), drying, and temperatures as high as 56°C and as low as -20°C. The hepatitis A
virus can remain viable for many years. Boiling water is an effective means of destroying it.
Chlorine and iodine are similarly effective.
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Hepatitis A virus as viewed through electron microscopy.

Various genotypes of HAV exist; however, there appears to be only 1 serotype. Virion
proteins 1 and 3 are the primary sites of antibody recognition and subsequent neutralization.
No antibody cross-reactivity has been identified with other viruses causing acute hepatitis.
Evidence in recent years appears to show the exosomes play a dual role in the transmission of
HAV and HCV, allowing these viruses to evade antibody-mediated immune responses but,
paradoxically, can also be detected by plasmacytoid dendritic cells (pDCs) leading to innate
immune activation and type I interferon production.[1]
Liu et al performed phylogenetic and recombination analyses on 31 complete HAV genomes
from infected humans and simians. They identified 3 intra-genotypic recombination events (I-
III), which they believe demonstrate that humans can be co-infected with different HAV
subgenotypes.[2]
The first recombination event (I) occurred between the lineage represented by the Japanese
isolate AH2 (AB020565, subgenotype IA), and the second event (II) occurred between the
lineage represented by the North African isolate MBB (M20273, subgenotype IB).[2] These 2
recombination events resulted in the recombinant Uruguayan isolate HAV5 (EU131373).
The third recombination event (III) occurred between the North African lineage (isolate
MBB; M20273, subgenotype IB) and the German lineage (isolate GBM; X75215,
subgenotype IA), leading to the Italian isolate FG (X83302).[2]
Hepatocyte uptake involves a receptor, identified by Kaplan et al, on the plasma membrane of
the cell, and viral replication is believed to occur exclusively in hepatocytes.[3] The
demonstration of HAV in saliva has raised questions about this exclusivity. After entry into
the cell, viral RNA is uncoated, and the host ribosomes bind to form polysomes. Viral
proteins are synthesized, and the viral genome is copied by a viral RNA polymerase (see the
image below). Assembled virus particles are shed into the biliary tree and excreted in the
feces.

Hepatitis A.
Minimal cellular morphologic changes result from hepatocyte infection. The development of
an immunologic response to infection is accompanied by a predominantly portal and
periportal lymphocytic infiltrate and a varying degree of necrosis.
Many authorities believe that hepatocyte injury is secondary to the host’s immunologic
response. This hypothesis is supported by the lack of cytotoxic activity in tissue culture and
correlations between immunologic response and manifestations of hepatocyte injury.
Person-to-person contact is the most common means of transmission and is generally limited
to close contacts. Transmission through blood products has been described. The period of
greatest shedding of HAV is during the anicteric prodrome (14-21 d) of infection and
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corresponds to the time when transmission is highest (see the image below). Recognizing that
the active virus is shed after the development of jaundice is important, although amounts fall
rapidly.

Hepatitis A. Time course of infection.

Outbreaks of acute hepatitis A have received international attention. The most notable report
of transmission appeared in the New England Journal of Medicine.[4] This report describes a
point source epidemic of HAV infection at a Pennsylvania restaurant where the vehicle for
transmission was green onions used to make a mild salsa. The contamination of the onions
occurred before the vegetable arrived in the United States.
The incubation period usually lasts 2-6 weeks, and the time to onset of symptoms may be
dose related. The presence of disease manifestations and the severity of symptoms after HAV
infection directly correlate with patient age. In developing nations, the age of acquisition is
before age 2 years. In Western societies, acquisition is most frequent in persons aged 5-17
years. Within this age range, the illness is more often mild or subclinical; however, severe
disease, including fulminant hepatic failure, does occur.

Etiology
Most patients have no defined risk factors for hepatitis A. Risk factors for the acquisition of
hepatitis A include the following:
 Personal contacts
 Institutionalization
 Occupation (eg, daycare)
 Foreign travel
 Male homosexuality
 Illicit parenteral drug use

Epidemiology
United States statistics
Over the last century, improved sanitation and hygiene measures have resulted in a shift in
the age group that carries the burden of hepatitis A. This, in turn, may result in more
clinically apparent and severe disease.
Until comparatively recently, US Centers for Disease Control and Prevention (CDC) data
supported cycles of disease occurring every 5-10 years. Some of these outbreaks correlated
with the wars of the 20th century, in which people returned from areas of high endemicity. In
recent years, this pattern has disappeared and has been associated with a decline in the overall
incidence of new infection.
The United States is an area of low endemicity. In contrast, the nearest southern neighbor,
Mexico, has a high prevalence of anti-HAV antibody, indicating previous infection. The
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frequency of acute hepatitis appears to be higher in those US states that are adjacent to
Mexico.
In 1988, the number of reported cases of hepatitis A in the United States was 27,000; in 1995,
approximately 32,000 infections were reported. The CDC estimated the actual number of
infections in 1995 to be approximately 150,000. Subsequent data from the CDC showed the
number of reported acute clinical cases of hepatitis A in 2003 to be 7653, with the number of
actual clinical cases estimated to be 33,000. The estimated number of new infections in the
United States for that same year was 61,000.
Between 1995 and 2006, the reported hepatitis A incidence declined by 90% to the lowest
rate ever recorded, 1.2 cases per 100,000 population.[5] (This was paralleled by a similar
decline observed in Italy.) The greatest reductions were seen in children and in those states
where routine vaccination of children was commenced in 1999. In accordance with these
findings, in 2006, the CDC recommended an expansion of routine hepatitis A vaccination to
include all children in the United States aged 12-23 months.
Persons aged 5-14 years are most likely to acquire acute HAV infection before vaccination
programs. Over the past 40 years, the average age of infected persons has steadily increased.
Evidence of past infection is more prevalent in adults (approximately 40%) than in children
(approximately 10%), which supports acquisition during school-aged years.
Individuals in high-risk populations currently account for many sporadic cases of HAV
infection. These groups include contacts of recently infected individuals, foreign travelers
(particularly those to developing nations), male homosexuals, childcare workers,
institutionalized individuals, and those living in poverty. Health measures implemented for
these high-risk groups will likely modify the evolving epidemiology.
US military personnel who served recently in Asia or, more remotely, during World War II
often returned with evidence of infection acquired abroad. As many as 200,000 service
personnel experienced symptomatic HAV infection in World War II.
Food handlers, at the point of food preparation, are an infrequent source of outbreaks in the
United States, although cases have been documented. Virtually any food can be contaminated
with HAV.

International statistics
HAV has a worldwide distribution,[6, 7] particularly in resource-poor regions.[8, 9] The highest
seropositivity (ie, the highest prevalence of antibody to HAV) is observed in adults in urban
Africa, Asia, and South America, where evidence of past infection is nearly universal.[10, 11, 12,
13, 14]

Acquisition in early childhood is the norm in these nations and is usually asymptomatic.
Factors predisposing humans to early acquisition include overcrowding, poor sanitation,
certain social practices, and lack of a reliable clean water resource. Within the socioeconomic
framework (ie, class structure) of some developing nations are differing frequencies of HAV
antibody in the older population; accordingly, sporadic cases may be observed in some
individuals.
In Shanghai in 1988, a large shellfish-related epidemic occurred. This provided a unique
opportunity to study the incubation and natural history of acute HAV infection in a large
population.[15]
Immigrants from countries of high endemicity to countries of low endemicity may be
responsible for some of the periodicity observed with outbreaks of infection. In this setting,
affected individuals tend to be infants born since the last outbreak or susceptible adults who
moved to the area.
Age-related demographics
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With increasing age of acquisition, both symptomatic disease and adverse sequelae increase.
In the Shanghai outbreak (see above), most of those admitted to the hospital were aged 20-40
years. Mortality from fulminant hepatic failure increased with increasing age despite the
decreasing prevalence of disease as age increased. The lower incidence of infection in the
older population was related to a greater likelihood of immunity rather than to a decrease in
exposure.
Sex-related demographics
Except for persons in high-risk populations (eg, sewage workers, childcare workers, aid
workers, male homosexuals), no sexual predilection is apparent.

Prognosis
In general, the prognosis is excellent. Long-term immunity accompanies HAV infection.
Recurrence and chronic hepatitis do not usually occur. Typically, there are no lasting
sequelae.
Death is rare, though it is more frequent in elderly patients and in those with underlying liver
disease. Annually, an estimated 100 people die in the United States as a result of acute liver
failure due to HAV infection. Although the case-fatalities from fulminant HAV infection
have been reported in all age groups, where overall the mortality is estimated at
approximately 0.3%, the rate is 1.8% among adults older than 50 years and is also higher in
persons with chronic liver diseases.
In children, liver transplantation has been performed for fulminant hepatic failure (FHF). In
France, 10% of cases of FHF in children are caused by HAV infection. The outcomes from
liver transplantation are the same as for others with fulminant disease. Recurrent disease does
not occur following liver transplantation despite immunosuppression.
In the United States, most cases are symptomatic, with the frequency of icteric cases
approaching 80%. Globally, HAV infection is often asymptomatic and subclinical.
Approximately 75% of adults are symptomatic with infection, many with jaundice. In stark
contrast, 90% of those infected before age 2 years are asymptomatic.
The single most important determinant of illness severity is age; increasing age is directly
correlated with an increasing likelihood of adverse events (ie, morbidity and mortality). Most
deaths from acute HAV infection occur in persons older than 50 years, even though such
infections are uncommon in this age group. Case fatality rates approach 2%, and a vast
majority of persons who acquire infection when older than 50 years exhibit signs and
symptoms of the disease.
Other populations with increased likelihood of adverse sequelae caused by acute HAV
infection are those with significant comorbidities or concurrent chronic liver disease, as
highlighted by the high incidence of hepatitis B surface antigen in persons who died in the
Shanghai outbreak,[15] along with case reports of deaths from acute HAV infection in persons
with hepatitis C.
Infection in early life occurs commonly in developing countries. Therefore, symptomatic
disease is uncommon in natives of these countries and is most often observed in visitors.
Seropositivity for anti-HAV protects individuals against reinfection.
Some evidence suggests that reinfection may occur late in life in individuals in whom levels
of detectable antibody have disappeared. Although this phenomenon is reported to occur,
reinfection is not associated with clinical disease. A rapid rise in immunoglobulin G (IgG)
antibody to HAV in the absence of immunoglobulin M (IgM) is the hallmark of this event
(anamnestic response).

Complications
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Prolonged cholestasis may follow an acute infection. The frequency at which this occurs
increases with age. Prolonged cholestasis is characterized by a protracted period of jaundice
(>3 mo) and resolves without intervention. Corticosteroids and ursodeoxycholic acid may
shorten the period of cholestasis.
The usual features of cholestatic viral hepatitis A are pruritus, fever, diarrhea, and weight
loss, with serum bilirubin levels higher than 10 mg/dL. Some investigators believe that the
use of corticosteroids may predispose patients to developing relapsing hepatitis A. Good data
to support this hypothesis are lacking.
Acute renal failure, interstitial nephritis, pancreatitis, red blood cell aplasia, agranulocytosis,
bone marrow aplasia, transient heart block, Guillain-Barré syndrome, acute arthritis, Still
disease, lupus-like syndrome, and Sjögren syndrome have been reported in association with
HAV. These complications are all rare.
Autoimmune hepatitis after HAV infection has received substantial discussion in the
literature. A postulated mechanism involves molecular mimicry and genetic susceptibility.
With this condition, as with traditional autoimmune hepatitis, steroid therapy has been
associated with good clinical response and improvement in biochemical and clinical
parameters. However, these findings are confined to isolated case reports, and the results of
larger clinical trials are not available.
Relapsing HAV infection occurs in 3-20% of patients with acute HAV infection and
uncommonly takes the form of multiple relapses. After 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 initial presentation, although it usually is
clinically milder.
A tendency to greater cholestasis exists in these patients. Vasculitic skin rashes and nephritis
may be additional clinical clues to this syndrome. During relapses, shedding of the virus can
be detected. IgM antibody test findings are positive. The clinical course is toward resolution,
with lengthening periods between flares. The total duration is 3-9 months.
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.

Patient Education
Travelers should be educated about good hygiene and clean, safe water supplies. Advice
should be provided regarding the benefits of immunization, particularly in high-risk
individuals. Travelers should avoid uncontrolled water sources, raw shellfish, and uncooked
food. Boiling water or adding iodine inactivates the virus. All fruit should be washed and
peeled.
People with HAV infection who are treated at home and those around them should follow
strict enteric precautions.
For patient education resources, see the Infections Center, the Digestive Disorders Center,
and the Healthy Living Center, as well as Hepatitis A and Foreign Travel.

Hepatitis A Clinical Presentation

History
Along with outlining the presenting complaint and its severity and sequelae, the history
should also initiate a search for the source of exposure (eg, overseas travel, lack of
immunization, intravenous [IV] drug use) and attempt to exclude other possible causes of
acute hepatitis (eg, accidental acetaminophen overdose). The incubation period is 2-6 weeks
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(mean, 4 wk). Shorter incubation periods may result from higher total dose of the viral
inoculum.
Discussion focusing on excluding other potential causes should be undertaken early in order
to guide further investigation. Not every patient with fever, hepatomegaly, and jaundice has
hepatitis A virus (HAV) infection. Some of the important differential diagnoses for acute
hepatitis warrant early and specific management.

Prodrome
In the prodrome, patients may have mild flulike 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, like persons presenting with appendicitis.

Icteric phase
In the icteric phase, dark urine appears first (bilirubinuria). Pale stool soon follows, although
this is not universal. Jaundice occurs in most (70-85%) adults with acute HAV infection; it is
less likely in children and is uncommon in infants. The degree of icterus also increases with
age. Abdominal pain occurs in approximately 40% of patients. Itching (pruritus), although
less common than jaundice, is generally accompanied by jaundice.
Arthralgias and skin rash, although also associated with acute HAV infection, are less
frequent than the above symptoms. Rash more often occurs on the lower limbs and may have
a vasculitic appearance.

Relapsing hepatitis A
Relapsing hepatitis A is an uncommon sequela of acute infection, is more common in elderly
persons, and is characterized by a protracted course of symptoms of the disease and a relapse
of symptoms and signs following apparent resolution (see Complications).

Physical Examination
The physical examination focuses on detecting features that support a diagnosis of acute
hepatitis and should include an assessment of features of chronic liver disease and, similarly,
assessment of any evidence of decompensation.
Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever
with temperatures of up to 40°C.

Hepatitis A Differential Diagnoses

Diagnostic Considerations
The main condition to be considered in the differential diagnosis for acute hepatitis A virus
(HAV) infection is acute hepatitis E virus (HEV) infection. The 2 viruses have a similar
clinical presentation and the same mode of transmission, and both are common in developing
countries. Dual infection is believed to occur. Data on this implication (ie, prognosis, disease
course) are not available.
See the following for more information:
 Alcoholic Hepatitis
 Autoimmune Hepatitis
 Cutaneous Manifestations of Hepatitis C
 Hepatitis B
 Hepatitis C
 Hepatitis D
 Hepatitis E
 Hepatitis in Pregnancy
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 Pediatric Hepatitis A
 Pediatric Hepatitis B
 Pediatric Hepatitis C
 Viral Hepatitis
Other problems to be considered include the following:
 Acute drug-induced liver injury (eg, acetaminophen, Ecstasy)
 Acute HIV infection[16]
 Drug-induced hypersensitivity reactions (eg, sulfasalazine hypersensitivity)

Differential Diagnoses
 Budd-Chiari Syndrome
 Cytomegalovirus
 Viral Hepatitis

Hepatitis A Workup
Approach Considerations
Nucleic acid testing (NAT) is the gold standard for diagnosis of viremic stages of hepatitis
infection.[17]
Central to the prevention of any legal problem is establishing the correct diagnosis, which
comes from a combination of careful history and subsequent examination. Appearances may
be deceiving; therefore, always exclude drugs, particularly acetaminophen, as a cause of
acute liver injury. One of the most common reasons for the misdiagnosis of hepatitis A
infection is misinterpretation of the serology tests.
Liver biopsy has a minimal role in acute HAV infection. It may play a part in chronic
relapsing HAV infection or in situations where the diagnosis is uncertain. Other
investigations (eg, serum acetaminophen) may be necessary, depending on findings from the
history and clinical examination. Molecular diagnostic techniques performed on blood and
feces for HAV RNA are purely research tools at present.
Kodani et al have developed an NAT-based assay that may be able to detect five viral
genomes of hepatitis simultaneously: HAV RNA, HBV DNA, HCV RNA, HDV RNA, and
HEV RNA,[17] Independent validation would have potential clinical implications for wider
patient surveillance, donor specimens screening, and use in the setting of outbreaks.[17]
After establishing a diagnosis of hepatitis A virus (HAV) infection, tracing contacts and
notifying local public health authorities are important steps for preventing further cases.
Omitting these measures may place the practitioner in a vulnerable situation.
Complete Blood Count and Coagulation Study
Complete blood count
Mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely
accompany infection. Indices of low-grade hemolysis are not uncommon.

Prothrombin time
The prothrombin time (PT) usually remains within or near the reference range. Significant
rises should raise concern and support closer monitoring. In the presence of encephalopathy,
an elevated PT has ominous implications (eg, fulminant hepatic failure [FHF]).

Liver Function Tests

Liver enzymes
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Rises in the levels of ALT and aspartate aminotransferase (AST) are sensitive for hepatitis A.
Levels may exceed 10,000 mIU/mL, with ALT levels generally greater than AST levels.
These 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.
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.
Serologic Tests
Anti-hepatitis A virus immunoglobulin M
The diagnosis of acute HAV infection is based on serologic testing for immunoglobulin M
(IgM) antibody to HAV. Test results for anti-HAV IgM are positive at the time of onset of
symptoms and usually accompany the first rise in the alanine aminotransferase (ALT) level.
This test is sensitive and specific, and the results remain positive for 3-6 months after the
primary infection and for as long as 12 months in 25% of patients. In patients with relapsing
hepatitis, IgM persists for the duration of this pattern of disease. False-positive results are
uncommon and should be considered in the event that anti-HAV IgM persists.
Anti-hepatitis A virus immunoglobulin G
Anti-HAV immunoglobulin G (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.

Ultrasonography
Imaging studies are usually not indicated in HAV infection. However, ultrasonography may
be required when alternative diagnoses must be excluded. The goals should be to assess
vessel patency and to evaluate any evidence supporting the presence of unsuspected
underlying chronic liver disease. Ultrasound scanning is essential in patients with FHF.

Histologic Findings
Histopathology reveals pronounced portal inflammation early in the illness, which is
consistent with viral hepatitis. Focal necrosis and acidophilic bodies are less pronounced than
infections with hepatitis B virus (HBV) and hepatitis C virus (HCV).
In FHF, biopsy findings may show extensive cell loss with ballooning in many of the
remaining hepatocytes. Immunofluorescent stains for HAV antigen yield positive results.

Hepatitis A Treatment & Management

Approach Considerations
Treatment generally involves supportive care, with specific complications treated as
appropriate. Liver transplantation, in selected cases, is an option if the patient has fulminant
hepatic failure (FHF).
Patients at risk of developing acute hepatitis A virus (HAV) infection should undergo
immunization for the virus. In addition, immunization of those at greater risk for morbidity
from acute HAV infection is important.
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A German study of immunization rates in patients with autoimmune liver disease identified
that seroconversion rates in this population were lower; however, more importantly, the study
identified that vaccination was not offered to a large proportion of this population.[18] It is not
difficult to identify a low risk-benefit ratio in patients with chronic liver disease, and the
author recommends vaccination for HAV in all who have no contraindication.
The advent of new antiviral agents, such as direct-acting antivirals (DAAs) and host-targeting
agents (HTAs), has expanded the potential therapeutic options available against HAV.[19]
Kanda et al noted that amantadine and interferon-lambda 1 (IL-29) inhibit HAV internal
ribosomal entry site (IRES)-mediated translation and HAV replication, whereas Janus kinase
(JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication.[19]
See the following for more information:

 Alcoholic Hepatitis
 Autoimmune Hepatitis
 Cutaneous Manifestations of Hepatitis C
 Hepatitis A
 Hepatitis B
 Hepatitis C
 Hepatitis D
 Hepatitis E
 Hepatitis in Pregnancy
 Pediatric Hepatitis A
 Pediatric Hepatitis B
 Pediatric Hepatitis C
 Viral Hepatitis

Supportive Care
For acute cases of HAV infection, therapy is generally supportive, with no specific treatment
of acute uncomplicated illness. Locating the primary source and preventing further outbreaks
are paramount. Initial therapy often consists of bed rest. The patient should probably not
work during the acute phase of the illness.
Nausea and vomiting are treated with antiemetics. Dehydration may be managed with
hospital admission and intravenous (IV) fluids. In most instances, hospitalization is
unnecessary. The majority of children have minimal symptoms; adults are more likely to
require more intensive care, including hospitalization.
About 3-8% of cases of fulminant hepatic failure (FHF) are caused by HAV; however, only
1-2% of HAV infections in adults lead to FHF. Refer patients with FHF to facilities with
expertise in liver transplantation.
Acetaminophen may be cautiously administered but is strictly limited to a maximum dose of
3-4 g/day in adults. Other treatments are directed by specific complications.

Liver Transplantation
Patients with fulminant hepatic failure (FHF) are considered for liver transplantation.
Recurrent disease after liver transplantation has not been reported. Patient selection for liver
transplantation may be difficult, in that 60% of patients recover from FHF without needing
the transplant (much as with acetaminophen toxicity), and predicting who needs this life-
saving procedure is difficult.
Late referral has ominous implications, with the accompanying comorbidities (eg, renal
failure, coagulopathy, cerebral edema) and waiting times contributing to poor outcomes.
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Liver transplantation for chronic relapsing HAV infection has occurred in the context of
decompensation with good results; however, there is a report of clinical recurrence after liver
transplantation.

Postexposure Prophylaxis
Passive immunization with Gammagard reduces infection when administered within 14 days
of exposure (ie, postexposure prophylaxis). Recommendations for providing postexposure
prophylaxis are developed on the basis of risk.
Postexposure prophylaxis is recommended for nonimmunized close contacts of those recently
diagnosed with acute HAV infection. The appropriate public health authority should be
notified after a diagnosis of HAV infection, and the process of contact tracing should be
initiated. In the United States, as many as 10% of cases of acute HAV infection are seen in
commercial food handlers. In any suspected food handler transmission, it is imperative that
health department officials be notified immediately.
In many instances, preexposure prophylaxis has been somewhat replaced by immunization
(see Immunization). For travelers, cost-benefit analysis suggests that vaccination is preferred
over gamma globulin when an extended stay in the area of risk (ie, high endemicity) is longer
than 3 months or when repeat travel to the area (ie, >2 visits outside a 3-mo period) is likely.

Immunization
Vaccination is highly effective at preventing HAV disease. The efficacy of the hepatitis A
vaccine ranges from 80% to 100% after 1-2 doses compared to placebo. Current dosing
recommendations are available (see Medication).
Immunization is indicated for individuals traveling to areas of high endemicity who have less
than 2 weeks before departure. Both the vaccination and intramuscular (IM) immunoglobulin
should be administered to provide long-term immunity, particularly in persons who intend to
travel to these areas repeatedly.
People with chronic liver disease of any cause should consider hepatitis A vaccination.
Response rates in patients with advanced liver disease and in those on immunosuppressive
therapies are likely to be lower. The potentially disastrous outcome of acute HAV infection in
this group cannot be overemphasized.
Hepatitis A vaccination in some low-risk groups who are potential sources of larger
outbreaks of infection (eg, food handlers) has been implemented by some employers,
although cost-benefit analysis for the employer does not seem to support such measures.
Epidemiologic studies of current and historical information related to hepatitis A infection
patterns and risk factors show strong associations between socioeconomic improvement,
increased water and sanitation, and decreasing HAV infection rates.[20, 21]
Areas in which a transition of epidemic hepatitis A (childhood acquisition very high) to
endemic hepatitis A is occurring will likely lead to an increase in adult-acquired infections
and the morbidity associated with this in the absence of vaccination programs.
An excellent illustration of why this is likely is that the most prevalent risk factor for HAV
acquisition in the United States is international travel.[22] This study also lends further support
to the importance of vaccination for international travelers. Hepatitis A is the most frequent
vaccine-preventable disease in travelers, and it has the highest mortality and morbidity rates
for any vaccine-preventable infection in travelers.[23, 24, 25]
The global burden of acute cases of hepatitis A is changing and certainly is decreasing in
Western societies.[20] In the United States, vaccination programs targeting children during
urban outbreaks have demonstrated significant benefits.[26, 27] Immunization programs applied
to high-risk groups show morbidity and cost benefits. Approximately 20% of individuals with
acute HAV infection may require hospitalization.
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A 2012 Cochrane review of 9 studies including 732,380 participants reaffirmed the benefit of
pre-exposure vaccination. Data from the review show that both the inactivated and live
attenuated vaccines were effective for pre-exposure prophylaxis and that either vaccine
provided approximately a 10-fold reduction in acute infections when compared to placebo.
An interesting subgroup analysis of quality studies showed that if infections were to occur
they occurred in the first year. In addition, pre-exposure prophylaxis was cost-effective and
shared comparable risk of non-serious local and systemic adverse events in those receiving
the inactive vaccine compared to those receiving the placebo. However, there were
insufficient data on the safety of the live attenuated vaccine to render conclusions on safety
and efficacy over time.[28]
Global immunization appears to be prohibitively expensive. The hepatitis A vaccine is not yet
licensed for use in persons younger than 2 years.

Diet and Activity

Encourage patients to have an adequate diet. Patients should avoid alcohol and medications
that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary.
Bed rest during the acute illness may be important, although data to support this practice are
lacking. Restricting transmission is important, especially in the early phases of the illness.
Returning to work should probably be delayed for 10 days after the onset of jaundice.

Prevention
Control at the source, with treatment of contacts to prevent further cases of disease is the
primary goal. Long-term secondary goals include immunization, which increases herd
immunity and reduces the likelihood of further outbreaks in high-risk communities.
Education about transmission and prevention of transmission (eg, hand washing, safe food
sources) is also important.

Hepatitis A Medication
Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents
used include analgesics, antiemetics, vaccines, and immunoglobulins.
Although acetaminophen may be safely used to treat some of the symptoms associated with
hepatitis A virus (HAV) infection, the dosage should be no higher than 4 g/day.

Analgesic agents
Class Summary
Pain control is essential to quality patient care. Acetaminophen is useful for pain and/or fever.
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Acetaminophen (Tylenol, Tempra, Feverall)

Acetaminophen reduces fever by acting directly on the hypothalamic heat-regulating centers,

thereby increasing dissipation of body heat via vasodilation and sweating. It relieves mild to
moderate pain.

Antiemetics
Class Summary
Antiemetic agents are used to treat nausea and vomiting.
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Metoclopramide (Reglan)
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Metoclopramide is a dopamine antagonist that stimulates acetylcholine release in the

myenteric plexus. It acts centrally on chemoreceptor triggers in the floor of the fourth
ventricle, and this action provides important antiemetic activity.

Vaccines, viral, prevention

Class Summary
Hepatitis A vaccine is used for active immunization against disease caused by HAV.
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Hepatitis A vaccine, inactivated, and hepatitis B vaccine (Twinrix)

This combined hepatitis A–hepatitis B vaccine is used for active immunization of persons
older than 18 years against disease caused by HAV and infection by all known subtypes of
hepatitis B virus (HBV).
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Hepatitis A vaccine, inactivated (Havrix, Vaqta)

Hepatitis A vaccine may be administered with immunoglobulin injections without affecting

efficacy.

Immune globulins
Class Summary
Hepatitis A vaccine may be administered with immunoglobulin injections without affecting
efficacy.
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Immune globulin IM (Gamunex, Octagam, Gammaplex)

Immune globulin IM neutralizes circulating myelin antibodies through anti-idiotypic

antibodies; down-regulates proinflammatory cytokines, including interferon-gamma; blocks
Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T
cells; blocks the complement cascade; promotes remyelination; and may increase
cerebrospinal fluid immunoglobulin G (10%). It is effective when administered within 14
days of exposure.
If the patient is likely to be returning to areas of high endemicity, concurrent vaccination is
recommended. For situations in which exposure is likely to occur before vaccination would
be effective, both agents may be administered without reducing the efficacy of the HAV
vaccine.

Image 1. Hepatitis A virus as viewed through electron microscopy.

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Image 2. Hepatitis A. Time course of infection.

Image 3. Hepatitis A.

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