Epidemiology of Hepatitis A Infection

Hepatitis A virus (HAV) is the leading cause of acute viral hepatitis worldwide. Indeed, in some developing areas of the world, HAV seropositivity is close to 100%[1]. Overall, hepatitis A infection in the United States is much lower in industrialized countries[2]. Data from 1988 to 1994 in the NHANES III (National Health and Nutrition Examination Survey) revealed particularly high seroprevalence rates in the United States among poor, immigrant, and Latino populations[3]. In more recent surveillance data, the most frequent risk for HAV infection was travel outside the United States or Canada[4]. In the United States, HAV causes approximately 45% of all cases of acute viral hepatitis and 12% of all cases of acute liver failure[5]. The incidence of HAV in the United States has declined more than 90% since the availability of the hepatitis A vaccine in 1995. In 2010, the Centers for Disease Control and Prevention (CDC) received 1,670 reported cases of acute symptomatic hepatitis A infection and this represented the lowest number of cases per year ever reported[6]. The CDC estimates that the actual numbers of symptomatic acute HAV infections and total new infections in 2010 were 7,000 and 17,000, respectively.

Transmission, and Risk Factors

Hepatitis A virus is primarily transmitted via the fecal-oral route and is most commonly acquired via ingestion of contaminated food or during sexual activity[1]. Food can be contaminated at the time of harvesting, packaging, or meal preparation, and multi-state outbreaks have been associated with ingestion of fresh and frozen produce. Undercooked bivalves have also been implicated in hepatitis A outbreaks. Although transmission of HAV can occur through serum, blood products in the United States do not routinely undergo screening for HAV because transfusion-related hepatitis A infection rarely occurs. This low transmission rate is attributed to the virus' short incubation period and exclusion of patients with jaundice from blood donation. Vertical transmission is exceedingly rare. In the United States, the leading three risk factors for hepatitis A infection are (1) sexual or household contact, (2) international travel and (3) male-male sexual activity (Figure 1)[2]. In a more recent population-based surveillance study conducted during 2005 to 2007, the reported risk factors for HAV acquisition were international travel (48.5%), contact with a case (14.8%), employee or child in a day care center (7.6%), exposure to food or waterborne common-source outbreak (7.3%), illicit drug use (4.3%), and men who have sex with men (3.9%)[4]. Although needle sharing is likely responsible for transmission in some instances among injection drug users, poor hygiene, with resultant fecal-oral transmission, may play a role in the passage of hepatitis A among injection-drug users[7]. Children and employees at daycare facilities (and their contacts) are at higher risk for hepatitis A. No risk factor is identified in more than 30% of cases.

Clinical Course

The incubation phase lasts from 2 to 7 weeks (mean 28-30 days). Prodromal symptoms are non-specific and often include anorexia, fever, nausea, and malaise (Figure 2). Jaundice typically appears within 1 week after symptom onset and occurs in 70 to 80% of the adult population, but in less than 10% of children younger than 6 years of age. Bilirubinuria may precede jaundice by a few days and dark urine is a common presenting complaint. Jaundice and hepatomegaly are the most commonly observed physical examination abnormalities (Figure 3)[8]. Extra-hepatic manifestations may occur, but with less frequency than that observed in hepatitis B or C (Figure 4). The acute illness can be disabling; patients missed an average of 9 days of work in one food-borne outbreak[9] and 12 days in another outbreak that involved homosexual men[10]. After the onset of jaundice, most constitutional symptoms abate quickly, although some patients complain of residual fatigue for several weeks. Jaundice typically resolves within two weeks[11]. Most cases of hepatitis A are self-limited, and 85% of people show complete resolution of symptoms by 3 months[8]. Hepatitis A carries no risk for chronic hepatitis. Less common presentations of hepatitis A include cholestatic hepatitis, relapsing hepatitis, and acute hepatic failure. In recent years, fewer than 100 HAV-related deaths per year have been reported[6]. In rare instances, hepatitis A infection may trigger autoimmune hepatitis[12].

Relapsing Hepatitis A

Hepatitis A infection relapses in approximately 5 to 10% of cases (range 1.5 to 20%), typically within several weeks after apparent resolution of the original illness[1,13]. The severity of the relapse is variable and often resembles the initial presentation with manifestations that can include jaundice, elevated hepatic aminotransferase levels, and fecal shedding of the virus. Patients with relapse may have a greater risk of developing either short-term cholestasis[1] or immune-related manifestations, such as purpura, arthralgias, and nephritis[13]. Nevertheless, patients with relapsing hepatitis A infection should generally expect a full recovery. A review of several cases of relapsing hepatitis A suggested steroids may expedite recovery[13]. The existing published case series have involved too few patients to accurately identify risk factors for relapse. Available data suggest that multiple relapses appear to be highly unusual, but may be more common in children[14].

Cholestatic Hepatitis A

Cholestatic hepatitis A occurs in fewer than 10% of cases and is characterized by serum bilirubin greater than 10 mg/dL and a prolonged period of jaundice (usually greater than 12 weeks)[8]. Surprisingly, serum alkaline phosphatase is usually normal or only slightly elevated in patients with cholestatic hepatitis A infection[14]. In many cases, patients may experience a protracted clinical illness with pruritis, nausea, diarrhea, or malabsorption[1]. Most experts recommended treating cholestatic hepatitis A infection with oral prednisone at 40 mg/day, followed by a slow 4 week taper[15]. A marked decline in serum bilirubin typically occurs within several days of initiating corticosteroid treatment. In general, patients with a prolonged period of jaundice and serologic evidence of acute hepatitis A do not require an invasive work-up for jaundice; an abdominal ultrasound to exclude biliary obstruction should suffice.

Acute Liver Failure and Mortality

Acute liver failure associated with hepatitis A infection infrequently develops, but has profound clinical importance when it does occur. The most widely accepted criteria for the diagnosis of acute liver failure consists of (1) evidence of a coagulation abnormality (prolongation in prothrombin time by 4 to 6 seconds or an INR greater than or equal to 1.5); (2) any degree of altered sensorium; (3) no history of preexisting cirrhosis; and (4) a duration of illness less than 26 weeks[16]. The term acute liver failure is often used interchangeably with the terms fulminant hepatitis or fulminant hepatic failure, but the term acute liver failure is preferred. Patients with acute liver failure should be hospitalized and managed in an intensive care unit; moreover, the medical facility should have the capacity to perform liver transplantation. Among cases of HAV infection reported to the CDC in 2002, 25% were hospitalized[2]. In 2010, among the 1670 reported cases of acute HSV, approximately 1% died[6]. These CDC statistics (involving reported cases) probably vastly overestimate the true hospitalization and death rates when considering all patients with hepatitis A, since many patients with mild disease either remain undiagnosed or do not get reported. A recent review of hepatitis A-related deaths in California revealed an age-adjusted mortality of 1.2 deaths per 1 million person years[17]. Fatality is unusual in children, and the risk increases significantly in persons older than 40[1,17]. Mortality rates appear to be greater among patients with underlying liver disease, regardless of the cause[1]. Acute hepatic failure carries a high mortality rate, as only 35 to 40% of patients with acute hepatic failure caused by HAV infection will recover spontaneously[18,19]. Since more than 65% of patients with acute liver failure from hepatitis A will survive after liver transplantation[14], these patients with acute hepatic failure should receive an expedited evaluation for potential liver transplantation as soon as possible after presentation.

Laboratory Findings and Diagnosis of Acute HAV

Soon after inoculation, HAV is carried via the bloodstream to the liver where it replicates within hepatocytes. The virus is shed into the bile ducts and excreted in the stool. Viremia and fecal shedding of the virus peak in the two weeks prior to the onset of clinical symptoms (Figure 5). Fecal shedding of the virus likely continues for at least a week after symptoms begin, and the period of shedding can be longer in children (in some cases up to several months)[14]. Low-level viremia may persist for 18-30 days after the onset of symptoms[14]. Although PCR can detect HAV in blood and stool, the technique is time-consuming, costly, and rarely used outside of the research setting. Hepatocellular injury becomes evident by the marked elevation in hepatic aminotransferase levels (often greater than 500 units/L) which peak shortly after the prodromal period. After peaking, serum hepatic aminotransferase levels decline by approximately 75% per week[11]. Serum bilirubin levels are also elevated, but they do not usually exceed 10 g/dL. The decrease in serum bilirubin levels typically lags behind the fall in serum hepatic aminotransferase levels[11]. Serum IgM anti-HAV is almost always detectable at the onset of symptoms, and IgG anti-HAV levels rise soon thereafter (Figure 5). Measurement of serum IgM anti-HAV remains the diagnostic test of choice. In the setting of acute HAV infection, the IgM anti-HAV has a sensitivity of nearly 100%, specificity of 99%, and a positive predictive value of 88%[20]. Rarely, a patient with symptomatic early acute hepatitis A will have a negative result, but a repeat test should become positive in 1-2 weeks. The IgM levels characteristically peak before 3 months and gradually decline until they become undetectable. The IgG levels, however, remain elevated and confer lifelong immunity.

Monitoring and Treatment

Most experts would recommend that any patient with moderate to severe acute hepatitis should have immediate measurement of prothrombin time (PT) with international normalized ratio (INR) and should be evaluated for subtle signs of encephalopathy, including lethargy or irritability[14,16]. If liver function is normal or minimally abnormal, and there is no evidence for encephalopathy, patients and their family members or caregiver should be counseled to monitor for changes in sensorium, and close clinical follow-up should be arranged. There is no specific antiviral therapy for acute hepatitis A infection. Most patients can be treated symptomatically as an outpatient with laboratory and clinical follow-up. In general, patients with acute HAV infection who do not develop acute liver failure will have complete recovery without any permanent sequelae. For patients who present withor develop more severe disease, including PT INR of 1.5 or greater, or significant symptoms such as nausea and vomiting, hospitalization is usually required. Hospitalization is mandatory for patients with acute liver failure (PT INR of 1.5 or greater and encephalopathy); in this situation, the patient should be admitted to an intensive care unit (ICU) and contact inititated with a liver transplantation center, since patients with acute liver failure can rapidly deteriorate.

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    Figure 1 - Reported Risk Factors for Hepatitis A

    The chart is from CDC 2002 surveillance data and summarizes the percent of reported cases associated with each risk factor. If a case report was submitted with more than one risk factor, the case was attributed to the most common risk factor.

    Abbreviations: MSM = men who have sex with men; IVDU = intravenous drug use; HAV = hepatitis A virus

    From Centers for Disease Control and Prevention. Hepatitis surveillance report No. 59. Altanta, GA: U.S. Department of Health and Human Services, Centers for Disease Prevention, 2004.

    Figure 1
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    Figure 2 - Common Symptoms Among Patients with Acute Hepatitis A Virus Infection

    This graph summarizes the presenting symptoms among 59 patients with acute hepatitis A virus infection evaluated at a teaching hospital in California.

    Data from Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis. 1995;171 Suppl 1:S15-8.

    Figure 2
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    Figure 3 - Common Signs Among Patients with Acute Hepatitis A Virus

    This graph summarizes the presenting signs observed on physical examination among 59 patients evaluated at a teaching hospital in California.

    Data from Tong MJ, el-Farra NS, Grew MI. Clinical manifestations of hepatitis A: recent experience in a community teaching hospital. J Infect Dis. 1995;171 Suppl 1:S15-8.

    Figure 3
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    Extra-Hepatic Manifestations of Acute Hepatitis A Infection

    The table summarizes several extra-hepatic features of hepatitis A infection. It should be noted that these findings are not characteristic of the infection, and some have only been documented in case reports.

    Figure 4
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    Figure 5 - Course of Acute Hepatitis A Infection

    Abbreviations: HAV = hepatitis A virus; ALT= alanine aminotransferase

    Figure 5