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emedicine.medscape.com

Hepatitis A
Updated: May 08, 2019
Author: Richard K Gilroy, MD, FRACP; Chief Editor: BS Anand, MD 

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.

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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.

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 that 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 the hepatocytes.[3] The demonstration of HAV in the 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.

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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 the
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 corresponds to the time when transmission is the highest (see the image below).
Recognizing that the active virus is shed after the development of jaundice is important, although the quantity falls 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 in 2005.[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 the onset of symptoms may be dose related. The presence of
disease manifestations and the severity of symptoms after HAV infection directly correlate with the patient's 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

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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 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 that the number of reported acute clinical cases of hepatitis A in 2003 was 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 the 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 the 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 the outbreaks of infection. In this setting, the affected individuals tend to be infants born since the last

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outbreak or susceptible adults who moved to the area.

Age-related demographics

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 with 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 the 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 the 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

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 the biochemical and clinical parameters.
However, these findings are confined to isolated case reports, and the results of larger clinical trials are not available.

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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.

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 (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

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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.

DDx

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

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 (CMV)

Viral Hepatitis

Workup
 

Workup

Approach Considerations
Nucleic acid testing (NAT) is the gold standard for the diagnosis of viremic stages of hepatitis infection.[17]

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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 the diagnosis acute of 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 the 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 its 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

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 the 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.
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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 seen in 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.

Treatment

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.

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

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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.

Liver transplantation for chronic relapsing HAV infection has been performed in the context of acute 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.

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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, better water purification 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.

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.

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.
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Analgesic agents

Class Summary
Pain control is essential to quality patient care. Acetaminophen is useful for pain relief and/or fever.

Acetaminophen (Tylenol, Tempra, Feverall)

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

Metoclopramide (Reglan)
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.

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).

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.
 

Questions & Answers

Overview

When was hepatitis A virus (HAV) first identified?

What advancements have reduced the incidence of hepatitis A?

What is the virology of hepatitis A virus (HAV)?

What have phylogenetic and recombination analyses revealed about hepatitis A virus (HAV) genomes?

What is the pathophysiology of viral replication in hepatitis A virus (HAV)?

What is the most common means of transmission of hepatitis A virus (HAV)?

What is the incubation period of hepatitis A virus (HAV)?

What are the risk factors for the acquisition of hepatitis A?

What has shifted the burden of hepatitis A?

What are the incidence and prevalence of hepatitis A in the US?

What are the age-related demographics of acute hepatitis A virus (HAV)?

What causes sporadic cases of hepatitis A virus (HAV) infection?

What is the international prevalence of hepatitis A virus (HAV)?

Which risks are associated with an older age of acquisition in hepatitis A virus (HAV) infection?

What are the sex-related demographics of hepatitis A virus (HAV) infection?

What is the prognosis of hepatitis A virus (HAV) infection?

What is the outcome of liver transplantation for fulminant hepatic failure (FHF) caused by hepatitis A virus (HAV) infection?

What is the association between age and illness severity in hepatitis A virus (HAV) infection?

Which populations have an increased risk of adverse sequelae caused by acute hepatitis A virus (HAV) infection?

What is the relationship between acute hepatitis A virus (HAV) infection and cholestasis and how is it characterized?

What are the rare complications of hepatitis A virus (HAV) infection?

What mechanism is involved in autoimmune hepatitis after hepatitis A virus (HAV) infection?

How common is relapsing hepatitis A virus (HAV) infection?

What is the indication for liver transplantation in hepatitis A infection?

How should travelers be educated about hepatitis A?

How should patients with hepatitis A virus (HAV) infection be educated?

Presentation

What should be included in the history of patients with suspected hepatitis A virus (HAV) infection?

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What are the early symptoms of hepatitis A virus (HAV) infection?

How is the icteric phase of hepatitis A virus (HAV) infection characterized?

How is relapsing hepatitis A virus (HAV) infection characterized?

What is the focus of the physical exam in patients with suspected hepatitis A virus (HAV) infection?

What are the typical physical findings in patients with suspected hepatitis A virus (HAV) infection?

DDX

Which condition has a similar presentation as acute hepatitis A virus (HAV) infection?

Which conditions should be considered in the diagnosis of acute hepatitis A virus (HAV) infection?

What are the differential diagnoses for Hepatitis A?

Workup

What is the gold standard for diagnosis of viremic stages of hepatitis A infection?

What are the approach considerations in the workup of hepatitis A?

What does a CBC reveal in the workup of hepatitis A?

What does a prothrombin time (PT) indicate in the workup of hepatitis A?

Which liver enzyme measurements are associated with hepatitis A?

Which hepatic synthetic function measurements are consistent with hepatitis A?

What is the role of anti-hepatitis A virus (HAV) IgM testing in the workup of hepatitis A?

What is the role of anti-hepatitis A virus (HAV) IgG in the workup of hepatitis A?

When is ultrasonography indicated in the workup of hepatitis A?

What are histologic findings in hepatitis A?

Treatment

What is the treatment for hepatitis A?

Which patients should undergo immunization for hepatitis A virus (HAV)?

Should hepatitis A virus (HAV) vaccination be provided to patients with autoimmune liver disease?

Which therapeutic agents are available for the treatment of hepatitis A virus (HAV)?

What does supportive care for hepatitis A consist of?

Which patients with hepatitis A virus (HAV) infection are candidates for liver transplantation and what are the
considerations?

What are the recommendations for prophylaxis against hepatitis A virus (HAV) infection?

How effective is the hepatitis A virus (HAV) vaccination?

When in immunization against hepatitis A indicated?

What factors are associated with changes in hepatitis A virus (HAV) infection rates?

What are the benefits of hepatitis A vaccination?

What dietary recommendations are indicated in the treatment of hepatitis A?

What activity restrictions are indicated in the treatment of hepatitis A?

How is hepatitis A prevented?

Medications

What are the goals of drug treatment forhepatitis A?

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What is the maximum dosage of acetaminophen in the treatment of hepatitis A?

Which medications in the drug class Immune globulins are used in the treatment of Hepatitis A?

Which medications in the drug class Vaccines, viral, prevention are used in the treatment of Hepatitis A?

Which medications in the drug class Antiemetics are used in the treatment of Hepatitis A?

Which medications in the drug class Analgesic agents are used in the treatment of Hepatitis A?

Contributor Information and Disclosures

Author

Richard K Gilroy, MD, FRACP Gastroenterologist, Intermountain Healthcare

Disclosure: Received salary from gilead, NPS pharmaceuticals, salix pharmaceuticals, AbbVie for speaking and teaching.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases,
American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal
Endoscopy

Disclosure: Nothing to disclose.

Additional Contributors

George Y Wu, MD, PhD Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in
Hepatitis Research, University of Connecticut School of Medicine

George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver
Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical
Investigation, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of
Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology
and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians
and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

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