eMedicine Specialties > Gastroenterology > Liver

Hepatitis A

Richard K Gilroy, MBBS, FRACP, Associate Professor, Medical Director of Liver Transplantation and Hepatology, Department of Internal Medicine, Kansas University Medical Center
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

Updated: Aug 26, 2008

Introduction

Background

One of the more common causes of acute hepatitis is hepatitis A virus (HAV). The hepatitis A virus was isolated by Purcell in 1973. Since the application of accurate serologic investigations in the 1980s, the epidemiology, clinical manifestations, and natural history of hepatitis A have become apparent.

The relative frequency of the hepatitis A virus 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 this disease, and vaccination and passive immunization have successfully led to some reduction in illness in high-risk groups. Reduced encounters with the hepatitis A virus at a young age have resulted in both a decline in herd immunity and a change to the epidemiology of the illness, with increases in the mean age of occurrence of illness attributed to acute hepatitis A virus 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.

Humans appear to be the only reservoir for the hepatitis A virus.

Pathophysiology

The hepatitis A virus is a single-stranded, positive-sense, linear RNA enterovirus and a member of the Picornaviridae family. In humans, viral replication depends on hepatocyte uptake and synthesis, and assembly occurs exclusively in liver cells. Acquisition results almost exclusively from ingestion (ie, fecal-oral transmission), although isolated cases of parenteral transmission have been reported.

The hepatitis A virus is an icosahedral nonenveloped virus measuring approximately 28 nm in diameter. 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, and chlorine and iodine are similarly effective (see Media file 1). 

Various genotypes of the hepatitis A virus 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.

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.¹ The demonstration of the hepatitis A virus in saliva has raised questions about this exclusivity. After entry into the cell, viral RNA is uncoated, and host ribosomes bind to form polysomes. Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase. Assembled virus particles are shed into the biliary tree and excreted in the feces (see Media file 3).
 
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 varying degree of necrosis. 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 the hepatitis A virus is during the anicteric prodrome (14-21 d) of infection and corresponds to the time when transmission is highest. Recognizing that the active virus is shed after the development of jaundice is important, although amounts fall rapidly (see Media file 2).

Outbreaks of acute hepatitis A have received international attention. The most notable report of transmission is that which appeared in The New England Journal of Medicine. Here was described a point source epidemic of hepatitis A virus 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 prior to the vegetable arriving in the United States.

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.

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 following hepatitis A virus 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. In this age range, the illness is more often mild or subclinical; however, severe disease, including fulminant hepatic failure, does occur.

Frequency

United States

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 virus disease. This, in turn, may result in more clinically apparent and severe disease.

Persons aged 5-14 years are most likely to acquire acute hepatitis A virus infection prior to vaccination programs. Over the last 40 years, the average age of infected persons has been noted to steadily increase. Evidence of past infection differs between adults (approximately 40%) and children (approximately 10%) and supports acquisition during school-aged years.

Individuals in high-risk populations currently account for many sporadic cases of hepatitis A virus 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 hepatitis A virus 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 the hepatitis A virus.

International

The hepatitis A virus has a worldwide distribution. The highest seropositivity (antibody to hepatitis A virus) is observed in adults in urban Africa, Asia, and South America, where evidence of past infection is nearly universal.

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 hepatitis A virus antibody in the older population; accordingly, sporadic cases may be observed in some individuals.

Until recently, US 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.

In Shanghai in 1988, a large shellfish-related epidemic occurred. This provided a unique opportunity to study the incubation and natural history of acute hepatitis A virus infection in a large population.

The differential diagnosis for acute hepatitis A virus infection is acute hepatitis E virus infection. Both viruses have a similar clinical presentation, are common in the third world, and have the same mode of transmission. Dual infection is believed to occur. Data on this implication (ie, prognosis, disease course) are not available.

Mortality/Morbidity

In the United States, most cases are symptomatic, with the frequency of icteric cases approaching 80%. Globally, hepatitis A virus 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; a direct correlation between increasing age and likelihood of adverse events (ie, morbidity and mortality) is present. Most deaths from acute hepatitis A virus infection occur in persons older than 50 years, despite the fact that acute hepatitis A virus infection is 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. The overall case fatality for acute hepatitis A virus infection is 0.02-0.1%. The current older population has a large number of individuals who are immune by virtue of exposure in early life; however, this pattern has been changing.
• Other populations with increased likelihood of adverse sequelae caused by acute hepatitis A virus 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, along with case reports of acute hepatitis A virus infection deaths in persons with hepatitis C.
• Infection in early life occurs commonly in developing countries. Therefore, symptomatic disease is uncommon in natives and is most often observed in visitors to these countries. Seropositivity for hepatitis A virus antibody 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 reported to occur, reinfection is not associated with clinical disease. A rapid rise in immunoglobulin G (IgG) antibody to hepatitis A virus in the absence of immunoglobulin M (IgM) is the hallmark of this event (anamnestic response).

Race

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.

Sex

Except for persons in high-risk populations (eg, sewage workers, childcare workers, aid workers, male homosexuals), no sexual predilection is apparent.

Age

With increasing age of acquisition, both symptomatic disease and adverse sequelae increase.

In the Shanghai outbreak, 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.

Clinical

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 drug use) along with excluding other possible causes for acute hepatitis (eg, accidental Tylenol overdose). The incubation period is 2-6 weeks, with a mean of 4 weeks. Shorter incubation periods may result from higher total dose of viral inoculum.

• Discussion focusing on excluding other etiologies should be undertaken early in order to guide further investigation. Not every patient with fever, hepatomegaly, and jaundice has hepatitis A virus infection. Some of the important differential diagnoses for acute hepatitis warrant early and specific management.
• 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, similar to those presenting with appendicitis.
• 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 hepatitis A virus infection. Jaundice 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.
  • Itch (pruritus), although less common than jaundice, is generally accompanied by jaundice.
  • Arthralgias and skin rash, although associated, 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.
  • This phenomenon is further discussed in Complications, along with some of the less commonly associated features of the disease.

Physical

The physical examination focuses on detecting features to support a diagnosis of acute hepatitis and should include assessment for features of chronic liver disease or similarly assessment for evidence of decompensation.

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

Causes

Most patients have no defined risk factors for hepatitis A. Risk factors for acquisition of hepatitis A include the following:

• Personal contacts
• Institutionalization
• Occupation (eg, daycare)
• Foreign travel
• Male homosexuality
• Illicit parenteral drug use

Differential Diagnoses

Budd-Chiari Syndrome
Cytomegalovirus
Hepatitis, Viral

Other Problems to Be Considered

Acute drug-induced liver injury (eg, Tylenol, ecstasy)
Acute HIV infection
Drug-induced hypersensitivity reactions (eg, sulfasalazine hypersensitivity)

Workup

Laboratory Studies

• Anti–hepatitis A virus immunoglobulin M
  • The diagnosis of acute hepatitis A virus infection is based on serologic testing for IgM antibody to the hepatitis A virus. Test results for anti-hepatitis A virus IgM are positive at the time of onset of symptoms and usually accompany the first rise in alanine aminotransferase (ALT) level. This test is sensitive and specific, and the results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients.
  • False-positive results are uncommon and should be considered in the event that anti-hepatitis A virus IgM persists.
  • IgM persists in patients with relapsing hepatitis for the duration of this pattern of disease.
• Anti–hepatitis A virus immunoglobulin G
  • Anti-hepatitis A virus IgG appears soon after IgM and generally persists for many years.
  • The presence of anti-hepatitis A virus IgG in the absence of IgM indicates past infection or vaccination rather than acute infection.
  • IgG provides protective immunity.
• Liver enzymes
  • Rises of levels in ALT and aspartate aminotransferase (AST) assays are sensitive for this disease. Levels may exceed values of 10,000 mIU/mL, with ALT levels generally greater than AST levels. Levels usually return to reference ranges over 5-20 weeks.
  • Rises in alkaline phosphatase accompany the acute disease and may progress during the cholestatic phase of the illness following the rises in transaminase levels.
• 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 hepatitis A virus infection.
  • Older individuals have higher bilirubin levels.
  • Both direct and indirect fractions increase because of hemolysis, which often occurs in acute hepatitis A virus infection.
• Modest falls in serum albumin level may accompany the illness.
• Prothrombin time
  • Prothrombin time usually remains within or near the reference range. Significant rises should raise concern and support closer monitoring.
  • In the presence of encephalopathy, an elevated prothrombin time has ominous implications (eg, fulminant hepatic failure).
• CBC count
  • Mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely accompany infection.
  • Indices of low-grade hemolysis are not uncommon.

Imaging Studies

• Imaging studies are usually not indicated in hepatitis A virus infection.
• An ultrasound scan may be required when alternative diagnoses warrant exclusion and should assess vessel patency and evaluate any evidence supporting unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with fulminant hepatic failure.

Other Tests

• Molecular diagnostic techniques performed on blood and feces for hepatitis A virus RNA are purely research tools.
• Other investigations (eg, serum acetaminophen) may be necessary as suggested by history and clinical examination findings.

Procedures

• Liver biopsy has a minimal role in acute hepatitis A virus infection. This procedure may play a part in chronic relapsing hepatitis A virus infection or when the diagnosis is uncertain.

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 with infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). In fulminant hepatic failure, biopsy findings may show extensive cell loss with ballooning in many of the remaining hepatocytes. Immunofluorescent stains for hepatitis A virus antigen provide positive results.

Treatment

Medical Care

For acute cases of hepatitis A virus 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 require hospital admission and intravenous fluids.
• In most instances, hospitalization is unnecessary. Most children have minimal symptoms; adults are more likely to require more intensive care, including hospitalization.
• Between 3-8% of cases of fulminant hepatic failure are caused by hepatitis A virus; however, only 1-2% of hepatitis A virus infections in adults lead to fulminant hepatic failure.
• Tylenol may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/d in adults.
• Other treatments are directed by specific complications.

Surgical Care

Consider patients with fulminant hepatic failure for referral for liver transplantation. Recurrent disease after liver transplantation has not been reported. Selection of patients who require liver transplantation may be difficult because 60% of them recover from fulminant hepatic failure without a need for liver transplantation (similar to 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.

Consultations

Consider liver transplantation in patients with fulminant hepatic failure. Liver transplantation for chronic relapsing hepatitis A virus infection has occurred in the context of decompensation with good results; however, there is a report of clinical recurrence after liver transplantation.

Diet

Encourage an adequate diet. Patients should avoid alcohol and medications that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary.

Activity

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.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Analgesic agents

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

Acetaminophen (Tylenol, Tempra, Feverall)

Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating. Relieves mild to moderate pain.

Dosing

Adult

325-650 mg PO q4-6h or 1 g PO tid/qid; not to exceed 4 g/d

Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h

Interactions

Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity; caution in G-6-PD deficiency or PKU

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; contained in many OTC products and combined use with these products may result in cumulative doses exceeding recommended maximum dose

Antiemetics

Used to treat nausea and vomiting.

Metoclopramide (Reglan)

Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, which provides important antiemetic activity.

Dosing

Adult

5-10 mg PO tid/qid
5-20 mg IV/IM tid

Pediatric

Not established

Interactions

Anticholinergic agents antagonize effects; opiate analgesics may increase CNS toxicity

Contraindications

Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in history of mental illness and Parkinson disease

Vaccines, viral, prevention

Hepatitis A vaccine is used for active immunization against disease caused by hepatitis A virus.

Hepatitis A vaccine, inactivated, and hepatitis B vaccine (Twinrix)

For active immunization of persons >18 years against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus.

Dosing

Adult

0.5 mL IM; repeat at 1 and 6 mo

Pediatric

Dose is as per that for product Twinrix Junior (half dose of antigen administered)

Interactions

Immunosuppressants may reduce effectiveness; when concomitant administration of other vaccines or IG required, give different syringes and different injection sites

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in individuals on anticoagulant therapy; may not prevent hepatitis A infection in individuals with unrecognized hepatitis A infection at the time of vaccination; caution when administering to women who are breastfeeding and people with thrombocytopenia or a bleeding disorder as bleeding may occur following IM use; immunosuppressed people or those receiving immunosuppressive therapy may not obtain expected immune response (may require additional doses)

Hepatitis A vaccine, inactivated (Havrix, Vaqta)

May be administered with immunoglobulin injections without affecting efficacy.

Dosing

Adult

Havrix: 1440 U IM once; booster dose at 6-12 mo
Vaqta: 50 U IM once; booster dose at 6 mo

Pediatric

<2 years: Not recommended
>2 years:
Havrix: 360 U IM days 0 and 30; 360 U booster dose at 6-12 mo; alternatively, 720 U day 0 and 720 U booster dose at 6-12 mo
Vaqta: 25 U IM once; booster dose at 6-18 mo

Interactions

May decrease effects of immunosuppressive agents

Contraindications

Documented hypersensitivity; IV/SC/ID administration

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in acute infection or febrile illness; duration of effect has not been fully established; efficacy >85%; caution in individuals taking anticoagulant therapy; vaccine does not protect against hepatitis B, C, or E viruses

Immune globulins

Purified preparation of gamma globulin. Derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum. Used for postexposure prophylaxis or when inadequate time is available for immunization to be effective before potential exposure.

Immune globulin, intramuscular (BayGam 15-18%)

Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Effective when administered within 14 d of exposure.
If 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 may be administered without reducing the efficacy of hepatitis A virus vaccine.

Dosing

Adult

0.02-0.06 mL/kg IM for exposed contacts or individuals traveling to areas for up to 6 mo; use higher dose if subject will be in the area for up to 6 mo (ie, where hepatitis A is common)
0.06 mL/kg IM q4-6mo for travelers staying > 3 mo

Pediatric

Not established

Interactions

Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine

Contraindications

Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

First check serum IgA (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory study result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Follow-up

Inpatient & Outpatient Medications

• Tylenol may be safely used to treat some of the symptoms associated with the hepatitis A virus infection. However, the dose should be no greater than 4 g/d.

Transfer

• Refer patients with fulminant hepatic failure to facilities with expertise in liver transplantation.

Deterrence/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.
• The efficacy of immunization has been clearly demonstrated in high-risk groups.  
• In the United States, vaccination programs targeting children during urban outbreaks have demonstrated significant benefits.
• Immunization programs applied to high-risk groups show morbidity and cost benefits. Approximately 20% of individuals with acute hepatitis A virus infection may require hospitalization.
• Global immunization appears to be prohibitively expensive. The hepatitis A vaccine is not yet licensed for use in persons younger than 2 years.
• The efficacy of the hepatitis A vaccine ranges from 80-100% after 1-2 doses compared to placebo. The current dosing recommendations for the available vaccinates are provided in Medication. 
• 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 hepatitis A virus 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.
• Annually, an estimated 100 people die in the United States as a result of acute liver failure due to the hepatitis A virus. The frequency of acute hepatitis appears more common in states neighboring Mexico. Although the case-fatalities from fulminant hepatitis A virus 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.
• Passive immunization with Gammagard reduces infection when administered within 14 days of exposure (ie, postexposure prophylaxis).
• In many instances, preexposure prophylaxis has been somewhat replaced by 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.
• Postexposure prophylaxis is recommended for nonimmunized close contacts of those recently diagnosed with acute hepatitis A virus infection.
• Immunization is indicated for individuals traveling to areas of high endemicity who have less than 2 weeks before departure. Both the vaccination and intramuscular immunoglobulin should be administered to provide long-term immunity, particularly in persons who intend to travel to these areas repeatedly.
• Notify the appropriate public health authority following diagnosis of hepatitis A virus infection.
• Initiate contact tracing after diagnosis of hepatitis A virus infection.
• 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. Vaccination is highly effective at preventing hepatitis A virus disease.
• In any suspected food handler transmission, it is imperative that health department officials are notified immediately. As many as 10% of cases of acute hepatitis A virus are seen in commercial food handlers in the United States. Recommendations for providing post-exposure prophylaxis are developed based upon risk. To be effective in preventing disease, immunoglobulin needs to be administered within 14 days of exposure.
• See related CME at Hepatitis A Vaccine and Immune Globulin Offer Protection Against HAV Exposure. 
• See related CME at Updated Guidelines for Preventing Hepatitis A Virus Infection After Exposure to the Virus.
• See related CME at Hepatitis A & B Vaccines.

Complications

• Generally, hepatitis A virus infection elicits no lasting sequelae. Death is rare, occurring in fewer than 0.2% of cases.
• Death is more frequent in elderly patients and in those with underlying liver disease. In children, liver transplantation has been performed for fulminant hepatic failure. In France, 10% of cases of fulminant hepatic failure in children are caused by hepatitis A virus 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.
• Prolonged cholestasis may follow the 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 greater 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, lupuslike syndrome, and Sjögren syndrome have been reported in association with hepatitis A virus infection. These complications are all rare.
• Autoimmune hepatitis following hepatitis A virus infection has received substantial discussion in the literature. A postulated mechanism involves molecular mimicry and genetic susceptibility, in much the same way as that proposed in type 1 diabetes. Steroid therapy for this condition was associated with good clinical response and improvement in biochemical and clinical parameters, in a way similar to that of traditional autoimmune hepatitis. However, these findings are confined to isolated case reports, and the results of larger clinical trials are not available.
• Relapsing hepatitis A virus infection
• This complication occurs in 3-20% of patients with acute hepatitis A virus infection and uncommonly takes the form of multiple relapses.
• Following a typical acute course of hepatitis A virus 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 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.

Prognosis

• Prognosis is excellent. Long-term immunity accompanies hepatitis A virus infection. Recurrence and chronic hepatitis do not usually occur.

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 hepatitis A virus infection who are treated at home and those around them should follow strict enteric precautions.
• For excellent patient education resources, visit eMedicine's Hepatitis Center, Liver, Gallbladder, and Pancreas Center, and Public Health Center. Also, see eMedicine's patient education articles Hepatitis A and Foreign Travel.

Miscellaneous

Medicolegal Pitfalls

• 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 Tylenol, as a cause of acute liver injury. After establishing a diagnosis of hepatitis A virus 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.
• Patients at risk for developing acute hepatitis A virus infection should receive immunization for hepatitis A virus. In addition, immunization of those at greater risk for morbidity from acute hepatitis A virus 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. It is not difficult to identify a low risk-benefit ratio in patients with chronic liver disease, and the author would recommend vaccination for hepatitis A virus in all who have no contraindication.
• Liver transplantation, in selected cases, is an option if the patient has fulminant hepatic failure.

Multimedia

Media file 1: Hepatitis A virus as viewed through electron microscopy.

Media file 2: Hepatitis A. Time course of infection.

Media file 3: Hepatitis A.

References

1. Kaplan G, Totsuka A, Thompson P et al. Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus. EMBO J. Aug 15 1996;15(16):4282-96. [Medline].

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Keywords

hepatitis A, infectious hepatitis, hepatitis A virus, acute hepatitis, hepatitis A vaccine, hepatitis A vaccination, hep A, HAV, HAV infection, fulminant hepatic failure, liver transplant, liver transplantation, hepatomegaly, jaundice, hepatitis B virus, HBV, hepatitis C virus, HCV, hepatitis D virus, HDV, hepatitis E virus, HEV, Picornaviridae

Contributor Information and Disclosures

Author

Richard K Gilroy, MBBS, FRACP, Associate Professor, Medical Director of Liver Transplantation and Hepatology, Department of Internal Medicine, Kansas University Medical Center
Disclosure: Nothing to disclose.

Coauthor(s)

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: Nothing to disclose.

Medical Editor

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, and Association of American Physicians
Disclosure: Humana Press Consulting fee Consulting; Novartis Consulting fee Review panel membership

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

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