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.
The United States is an area of low endemicity. In contrast, the nearest southern neighbor, Mexico, has a high prevalence of anti-hepatitis A virus antibody, indicating previous infection.In 1988, the number of reported cases of hepatitis A was 27,000; in 1995, approximately 32,000 infections were reported. The US Centers for Disease Control and Prevention (CDC) estimated the actual number of infections in 1995 to be approximately 150,000.
More recent data from the CDC show the number of reported acute clinical cases of hepatitis A virus in 2003 to be 7653, with the estimate of actual clinical cases to be 33,000. The estimated number of new infections in the United States for that same year was 61,000. During 1995-2006, reported hepatitis A incidence declined 90% to the lowest rate ever recorded (1.2 cases per 100,000 population). Much in the same way, a decline in the incidence of hepatitis A virus disease was also seen 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 this, 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 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
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Further Reading
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
