The earliest description of an illness consistent with viral hepatitis dates back to the second century. During the centuries that followed, epidemics of jaundice were reported, and outbreaks plagued military campaigns, both ancient and modern.
In the 1920s, a viral etiology was suggested for what was then known as infectious hepatitis. Various viral agents were isolated from urine, blood, and stool from patients with hepatitis in the first half of the 20th century; however, the 27 nm particles of the hepatitis A virus (HAV) were not described until 1973.[1]
This finding led to the development of serologic testing and, more recently, molecular techniques, such as polymerase chain reaction (PCR). These events resulted in greater knowledge of the epidemiology, transmission, and infectivity of HAV, as well as in the development of preventive measures, including active and passive immunization. Hepatitis A is now the target of routine childhood immunizations, starting at age 1 year (see Recommendations Updated for Universal Administration of Hepatitis A Vaccination in US Children).
Go to Hepatitis A, Pediatric Hepatitis B, Pediatric Hepatitis C, and Viral Hepatitis for complete information on these topics.
HAV infection is transmitted via the fecal-oral route, and viral replication occurs in the liver, leading to hepatic injury. The entire liver exhibits necrosis, which is most marked in the centrilobular areas, as well as increased cellularity in the portal areas. The regional lymph nodes and spleen may become enlarged. Liver injury is represented in 3 ways:
Direct cellular injury that elevates serum liver enzyme levels
Cholestasis that causes jaundice and hyperbilirubinemia
Inadequate liver function that lowers serum albumin levels and prolongs the prothrombin time (PT)
Hepatitis A is caused by HAV, a positive-sense, single-stranded, nonenveloped RNA virus that belongs to the Picornaviridae family and the Hepatovirus genus. After fecal-oral transmission, the virus is then excreted into the bile. Its concentration is highest in the stool, especially during the 2 weeks preceding the onset of jaundice. This correlates with the period of peak infectivity. Children and adults can be assumed to be noninfectious 1 week after the appearance of jaundice.
Common-source outbreaks from contaminated food or water may occur.[2] HAV is concentrated in filter-feeding shellfish, which may thrive close to sewage outlets, and widespread outbreaks can occur from a single contaminated source, such as uncooked vegetables that are distributed to restaurants or grocery stores. Statistically, eating out is actually less risky than home cooking.
Childcare centers may be sources of outbreaks from contaminated changing tables. These outbreaks may not be identified until an adult contact has a recognizable HAV infection, because young children are often asymptomatic or have anicteric illnesses.
Nosocomial outbreaks have occurred because of HAV shedding. Outbreaks of HAV infection have been increasingly reported among illicit drug users. International travel is another risk factor for HAV infection.
Vertical transmission of HAV (ie, from mother to neonate) and transmission by means of blood transfusion are extremely rare. Sexual transmission is possible, especially between homosexual men. Spread of HAV from nonhuman primates to humans has been reported.
In 2006, the national annual incidence in the United States was 1.2 cases per 100,000 population (see the image below).[3] Before vaccination became widespread, rates were higher than 9 cases per 100,000 population.[4]
View Image
Incidence of acute hepatitis A virus in the United States from 1982-2006. (Image from "Surveillance for Acute Viral Hepatitis --- United States, 2006.....
Nearly one third of adults have serologic evidence of prior HAV infection. Higher rates are associated with lower socioeconomic status, crowding, and poor sanitation. Outbreaks may occur in association with poor food hygiene or undercooked food.
International statistics
In developing countries, infection is highly endemic; nearly 100% of the population in some countries has serologic evidence of past HAV disease during childhood.
In a surveillance study of 1156 HAV cases from 6 sites in the United States’ Emerging Infections Program, from 2005 through 2007, the majority of infections were due to international travel or exposure to travelers. Many of the cases that implicated travel or contact with travelers as a risk factor involved travel to Mexico.[5]
Age-related differences in incidence
In the United States, prior to targeted vaccination programs, the highest rate of infection occurred in children aged 5-14 years. Since the advent of widespread vaccination, as many as 80% of infections have been in adults. Interestingly, the classic symptoms of hepatitis are less likely in younger patients. Young children, especially those younger than 5 years, may be asymptomatic or may have anicteric illness that appears to be a nonspecific viral infection.
Sex-related demographics
HAV has no sex predilection. Homosexual males may have a higher risk of infection than heterosexual males.
Race-related demographics
Before targeted vaccination programs, certain well-defined populations were considered high-risk groups, including Native Americans, Alaskan natives, and some Hispanic people. Epidemics occurred in these groups every 5-10 years, as susceptible people entered or were born into the population. In addition, overall rates of infection in nonepidemic years were also greater in these populations than in the United States as a whole.
Since 2003, racial and ethnic differences have virtually disappeared. For example, a nearly 99% decrease was noted in the incidence of HAV among Native Americans as the result of a widespread targeted vaccination campaign among high-risk groups.
The prognosis is excellent. In most patients, HAV infection is self-limited, and complete recovery occurs. In fact, many cases are asymptomatic. Except in the setting of fulminant hepatitis, sequelae are rare. Fulminant hepatitis due to HAV is uncommon and has a case-fatality rate of 0.4%.
Relapsing HAV infection occurs in approximately 10% of patients 1-4 months after the initial episode and results in full recovery.
Chronic active hepatitis, which can be seen in hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, does not occur in HAV infection. A chronic carrier state is not seen with HAV infection.
Patients and parents should be educated regarding the transmission of HAV and instructed in proper hygiene. Indications for postexposure prophylaxis should be explained, and affected individuals should be identified and treated appropriately. Local and state health departments are instrumental in epidemiologic identification of the appropriate contacts who need postexposure prophylaxis.
Physicians should be prepared to explain transmission and prevention issues to the staff at the patient’s school and childcare center. This can help identify individuals who may need prophylaxis, as well as alleviate unnecessary worries for those who are not at risk.
For patient education resources, see the Hepatitis Center and the Liver, Gallbladder, and Pancreas Center, as well as Hepatitis A.
The incubation period from the time of exposure to hepatitis A virus (HAV) to the appearance of symptoms is around 28 days (range 2 wk to 6 mo). The patient’s initial symptoms during the prodromal period include low-grade fever, nausea, vomiting, decreased appetite, and abdominal pain. Older children and adults are more likely to report pain in the right upper quadrant.
Diarrhea may occur in young children, whereas constipation is more common in adults. If present, jaundice, dark urine, and light-colored stool develop several days to a week after the onset of systemic symptoms. Anicteric infections are common in young children.
Physical examination
The general appearance is that of mild-to-moderate illness. A patient who appears severely ill is likely to have hepatitis of another cause or an atypical course. Mild hepatomegaly and right upper quadrant tenderness may be present. Clinical jaundice is present in two thirds of symptomatic patients. Splenomegaly may occur in 10-20% of patients.
Complications
Complications are few. Fulminant hepatitis with massive hepatic necrosis and liver failure due to HAV infection is rare. Cholestatic hepatitis occurs in a small percentage of patients. It is identified by persistent hyperbilirubinemia, pruritus, and constitutional symptoms that last for 12-16 weeks in the absence of biliary obstruction on sonograms.
Liver inflammation during hepatitis A virus (HAV) infection can be identified by elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltranspeptidase (GGTP; also known as gamma glutamyltransferase [GGT]) levels. Increases in ALT and AST levels are seen most consistently, and the values are usually 4-100 times the normal levels. Elevations in ALT and AST levels may precede the onset of symptoms by a week or more and usually peak within 3-10 days after onset of clinical illness.
Serum bilirubin levels, although elevated, usually remain below 10 mg/dL and peak after 1-2 weeks of illness. Prolongation of the prothrombin time (PT) and a significant decrease in the albumin level suggest a more severe course.
Specific antibody tests for HAV confirm infection. Anti-HAV immunoglobulin M (IgM) is present at the onset of symptoms, and its level remains high for 4-8 weeks. It usually disappears by 4-6 months, but occasionally it persists for a longer period.
Anti-HAV immunoglobulin G (IgG) becomes detectable shortly after the IgM titer appears and usually increases as the IgM level decreases. IgG persists for life and provides ongoing immunity against reinfection.
Ultrasonography of the liver may be helpful when cholelithiasis is a consideration. However, imaging studies are generally not necessary. The history and physical examination and laboratory findings are used to establish the diagnosis in most cases of HAV infection.
Histologic findings are similar to those in other forms of acute viral hepatitis and include inflammatory cell infiltration, hepatocellular necrosis, and liver cell regeneration.
Liver biopsy is not indicated, because of the self-limited nature of HAV infection and the absence of a chronic infectious state.
No specific therapy is available. The investigational antienteroviral drug pleconaril (Disoxaril; ViroPharma) has no activity against hepatitis A virus (HAV). Treatment is therefore supportive.
Hospitalization is indicated for patients with significant dehydration due to vomiting or those with fulminant hepatitis.
Consultation with a subspecialist is generally not required. Fulminant hepatitis warrants care by a pediatric gastroenterologist and, possibly, an intensive care specialist.
Go to Hepatitis A, Pediatric Hepatitis B, Pediatric Hepatitis C, and Viral Hepatitis complete information on these topics.
Inpatient care is not needed for most patients with HAV infection. Some patients may require hospitalization for intravenous (IV) rehydration. Once emesis subsides and the patient can tolerate oral fluids, discharge is appropriate. In the rare case of fulminant hepatitis, transfer to a facility with pediatric subspecialty care is indicated.
Follow-up liver enzyme studies should be performed at monthly intervals until levels normalize. If elevations persist for longer than 3 months, complications or additional diagnoses should be considered.
Medications that have known liver toxicity should be avoided.
Pre-exposure prophylaxis with HAV vaccine is recommended for persons aged 1 year or older who are traveling to countries where HAV infection is endemic. If the trip is shorter than 2 weeks, or if the patient is younger than 1 year, IG should be given. If the trip is longer than 3 months, a larger dose of IG (0.06 mL/kg) is needed for those who cannot receive the vaccine. Repeat dosing is recommended if the trip lasts longer than 5 months.
HAV vaccine is currently licensed for use in children aged 12 months or older.[6, 7] One dose of vaccine leads to seroconversion in 88% of adult patients by 15 days and in 99% of adult patients by 1 month. When followed with a second dose 6 months later, the vaccine leads to 100% seroconversion. In those treated with immunosuppressive agents, protective antibody levels appear to be significantly lower, and a single dose does not afford much protection (only 33% after the first dose in one study of patients treated for rheumatoid arthritis).[8] Immunity from the HAV vaccine in healthy people appears to last several decades and is probably life-long.[9]
Others who should receive the vaccine include children aged 12-35 months, patients with chronic liver disease, homosexual or bisexual men, users of injectable illicit drugs, and those with a high occupational risk (those who work with nonhuman primates and HAV laboratory workers).[10]
Vaccination in areas of extremely high incidence of infection may only be cost-effective if prevaccination serology is obtained to target nonimmune individuals.[11]
The Advisory Committee on Immunization Practices (in the United States) (ACIP) has recommended universal immunization in all children older than 1 year (the lower limit of the approved age range) and catchup immunization in those who have not been vaccinated.[12] A 2016 study by Murphy et al reported that ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ≥1-dose and ≥2-dose vaccine coverage.[13]
Postexposure prophylaxis consists of the administration of HAV vaccine (preferred if the patient is >1 y and < 40 y) or immune globulin (IG) to contacts as soon as possible, but no later than 2 weeks after exposure. IG is given as an intramuscular injection of 0.02 mL/kg. It is 80-90% effective in preventing HAV infection by means of passive immunity.
Candidates for postexposure prophylaxis include household and sexual contacts of infected patients, contacts in childcare centers during outbreaks, and, if the patient is a food handler, others who work at the same establishment. Information regarding administration of hepatitis A vaccine after exposure (either alone or in addition to IG) is currently available.[14, 15, 12]
No specific dietary changes are needed. In euvolemic patients with vomiting (but without dehydration that necessitates IV fluid therapy), appropriate intake of oral fluid is recommended, as with other viral illnesses.
Patients should not return to school or work for 1 week after the onset of illness. Hospitalized patients who use diapers or those who are incontinent should have contact isolation for 1 week after the onset of illness. Otherwise, activity can be resumed as tolerated.
General prevention measures consist of good personal hygiene, handwashing, ingestion of safe drinking water, and proper sanitation. Prevention specific to hepatitis A infection includes the use of IG and HAV vaccine[16] (see Postexposure Prophylaxis and Immunization).
The use of contact precautions is recommended for hospitalized patients for 1 week after the onset of symptoms.
People with chronic liver conditions, such as infection with HBV or HCV, should also be vaccinated against hepatitis A virus.
No specific treatment for hepatitis A virus (HAV) exists. Accordingly, treatment is supportive rather than directly curative. Agents used include analgesics, antiemetics, vaccines, and immunoglobulins. Prevention (either before or after exposure to HAV) is important.
Long-term studies indicate that seropositivity conferred by hepatitis A vaccine lasts at least ten years in children under the age of 2 years, although titers are somewhat lower in those children whose mothers were hepatitive A-positive by serology, presumably through interference with the vaccine. The significance of these lower titers is uncertain.[17]
Clinical Context:
For active immunization against disease caused by hepatitis A virus (HAV). Complete primary immunization at least 2 wk prior to expected exposure to HAV. Primary immunization series consists of 2 doses.
Vaccination is indicated for primary immunization to prevent hepatitis A. It is also used for postexposure prophylaxis, either alone or in conjunction with immune globulin (IG).
Clinical Context:
Acetaminophen reduces fever by acting directly on hypothalamic heat-regulating centers, thereby increasing dissipation of body heat via vasodilation and sweating. It relieves mild to moderate pain.
Clinical Context:
Immune globulin IM neutralizes circulating virus. It is effective for pre-exposure protection and for post-exposure protection when administered within 14 days of exposure. It should be used in place of vaccination in those children too young (< 1 y) for vaccination when the child is traveling to an endemic area.
These are purified preparations of gamma globulin. They are derived from large pools of human plasma and are composed of 4 subclasses of antibodies, approximating the distribution of human serum. They are used for postexposure prophylaxis or when inadequate time is available for immunization to be effective before potential exposure.
Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP, Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's Medical Center
Disclosure: Received research grant from: Cubist<br/>Received income in an amount equal to or greater than $250 from: Horizon Pharmaceuticals, Shire<br/>Medico legal consulting for: Various.
Coauthor(s)
Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University
Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Chief Editor
Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation
Disclosure: Nothing to disclose.
Acknowledgements
Leslie L Barton, MD Professor Emerita of Pediatrics, University of Arizona College of Medicine
Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
CDC. Notice to readers: FDA approval of Havrix (hepatitis A vaccine, inactivated) for persons aged 1-18 years. MMWR. December 9, 2005. 54(48):1235-1236.
CDC. Notice to readers: FDA approval of VAQTA (hepatitis A vaccine, inactivated) for children aged >1 year. MMWR. October 14, 2005. 54(40):1026.
Incidence of acute hepatitis A virus in the United States from 1982-2006. (Image from "Surveillance for Acute Viral Hepatitis --- United States, 2006." MMWR March 21, 2008. 57(SS02);1-24)
Incidence of acute hepatitis A virus in the United States from 1982-2006. (Image from "Surveillance for Acute Viral Hepatitis --- United States, 2006." MMWR March 21, 2008. 57(SS02);1-24)
){kind=link}