Continuing Education Activity

The hepatitis A virus (HAV) is a positive-sense, single-stranded RNA virus that belongs to the family Picornaviridae. It replicates primarily within hepatocytes and is a common infectious etiology of acute hepatitis worldwide. Symptoms of acute infection include nausea, vomiting, fatigue, malaise, abdominal pain, poor appetite, and fever. This activity reviews the evaluation and management of hepatitis A and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Summarize the epidemiology of hepatitis A infection.
• Review the pathophysiology of hepatitis A infection.
• Describe the use of serologic tests to evaluate hepatitis A infection.
• Outline the importance of improving care coordination among the interprofessional team members to educate the patient on the importance of the hepatitis A vaccine to enhance the delivery of care for those with hepatitis A infection.

Introduction

The hepatitis A virus (HAV) is a common infectious etiology of acute hepatitis worldwide. HAV is most commonly transmitted through the oral-fecal route via exposure to contaminated food, water, or close physical contact with an infectious person. According to the World Health Organization (WHO), infection rates in developed countries are low. However, high-risk groups include injection-drug users, men who have sex with men, people traveling to endemic areas, and isolated communities. HAV does not cause chronic liver disease unlike hepatitis B or C. Acute hepatitis usually presents as a self-limited illness; development of fulminant hepatitis is rare. Typical symptoms of acute infection include nausea, vomiting, abdominal pain, fatigue, malaise, poor appetite, and fever; management is with supportive care. Alternate clinical patterns include cholestatic, prolonged, and relapsing disease. Vaccination against HAV is recommended for children 12 months or older and adults with the risk of exposure including travelers to endemic countries, men who have sex with men, illicit drug users, potential occupational exposure, and/or chronic liver disease.[1][2][3][4]

Globally, the rates of HAV have decreased due to improvements in public healthcare policies, sanitation, and education, but infection rates of other hepatitis viruses appear to be increasing.

Etiology

HAV is one of the most common causes of acute hepatitis infection worldwide. The WHO estimates that approximately 1.5 million people are infected with HAV each year. Endemic rates are high in developing countries with low socioeconomic conditions and poor sanitation and hygiene practices. Exposure in these developing countries usually occurs in childhood. Infection rates are low in developed countries such as the United States, Canada, and Western Europe. High-risk groups in low endemicity countries have been identified as injection-drug users, men who have sex with men, people traveling to endemic areas, and isolated communities such as nursing homes and even day-care centers. The incidence of HAV in a given population correlates with socioeconomic properties such as income, the density of housing, sanitation, and water quality. With the implementation of vaccination, the incidence of HAV in the United States has significantly decreased. The incidence of acute HAV infection has decreased by 92% from 12 cases per 100,000 in 1995 to 1 case per 100,000 in 2007.[5]

Most cases of transmission are from person to person and limited to close contacts. Blood transfusion is a very rare cause of hepatitis A.

Risk factors for HAV include

• Institutionalization
• Close personal contact
• Travel to a foreign country
• Occupation
• Parenteral drug abuse
• Homosexuality

Epidemiology

Improved sanitation has resulted in a shift in the age group that acquires hepatitis A. In recent years there has been a decline in the incidence of a new infection.

The United States has a low endemicity. Mexico has a high prevalence of individuals with the anti-HAV antibody indicating a previous infection. The frequency of acute hepatitis is higher in those U.S. states that are adjacent to Mexico.

The reported hepatitis A incidence has declined by 90% to as low as 1.2 cases per 100,000 population. The greatest reductions are seen in children and in those states where routine vaccination was started in 1999. Over the last 4 decades, the average age of hepatitis A infected individuals has increased.

Individuals in high-risk populations account for most cases of HAV infection. These groups include foreign travelers to developing nations, gays, childcare workers, institutionalized individuals, and those living in poverty.

Food handlers are an infrequent source of outbreaks in the United States. Virtually any food may be contaminated with HAV.

International

HAV is highest in resource-poor regions such as Africa, Asia, and South America, where evidence of past infection is nearly universal. Acquisition often occurs in childhood, and it is usually asymptomatic. 

Sex

There is no sexual predilection. It is most common in aid workers, gays, and around sewage.

Age

With increasing age symptomatic disease and adverse sequelae increases. Mortality from fulminant hepatic failure increases with increasing age.

Pathophysiology

HAV, first identified in 1973 by Feinstone et al., is classified in the family Picornaviridae and genus Hepatovirus. It is a positive-sense, single-stranded RNA virus which replicates primarily within hepatocytes. Animal studies showing HAV antigen in the epithelial cells of intestinal crypts and cells of the lamina propria in the small intestine suggest replication might also occur at these sites. Once ingested orally, the virus is taken up from the gastrointestinal tract and the HAV particles are carried to the basolateral membrane of the hepatocyte via the portal circulation. The hepatocellular injury in acute HAV infection is mediated by various immune mechanisms. It has been shown that patients with acute HAV infection have the virus-specific T-cell mediated release of cytotoxic interferon-gamma. Additionally, recent mice-models have demonstrated HAV-induced hepatocellular apoptosis and inflammation associated with the innate immune response.  The humoral immune response is responsible for the diagnostic serologic assays. Following replication in the liver, HAV is excreted in bile and released into the stool. The concentration of the virus is highest in the stool during the 2 weeks before the onset of jaundice, at which point the individual is most infectious. Most people are no longer infectious 1 week after jaundice appears at which time stool shedding and viremia are decreased.

History and Physical

Acute HAV infection is typically a self-limited illness characterized by nausea, vomiting, right upper quadrant abdominal discomfort, malaise, anorexia, myalgia, fatigue, and fever. Patients may develop dark urine and pale stools within a week, followed by jaundice, icteric (yellow-tinted) sclera, and pruritus. Patients usually have elevated levels of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, and lambda-glutamyl transpeptidase. These lab abnormalities typically resolve within 1 to 6 weeks following the onset of symptoms. The incubation period usually ranges from 14 to 28 days but can last up to 50 days. The severity of symptoms varies with age and comorbidities, particularly underlying chronic liver disease. Most children with acute HAV infection are asymptomatic.

Extra-hepatic manifestations rarely occur but may include pancreatitis, rash, acute kidney injury with interstitial nephritis or glomerular nephritis, pneumonitis, pericarditis, hemolysis, and acute cholecystitis. Neurologic complications have also been reported such as mononeuritis, Guillan-Barre, encephalitis and central myelitis. There were two reported cases in 1991 of autoimmune hepatitis triggered by acute HAV infection. Lemon et al. describe five clinical patterns: 

1. Asymptomatic infection
2. Symptomatic infection with jaundice, dark urine, and clay-colored stool
3. Cholestatic hepatitis with prolonged alkaline phosphatase and bilirubin elevation and pruritus
4. Relapsing infection
5. Fulminant hepatitis.

Evaluation

Acute hepatitis A is diagnosed by serologic testing to detect HAV-specific immunoglobulin (IgM) antibodies in the blood. Additional testing can include reverse transcriptase-polymerase chain reaction to detect the viral RNA. Immunoglobulin G (IgG) anti-HAV emerges soon after infection and remains present for the person’s lifetime.

Blood work will reveal a mild lymphocytosis and normal prothrombin time. If the prothrombin time is elevated, it should raise suspicion of severe liver damage including risk for encephalopathy.

Hepatitis A is associated with an elevation in aspartate aminotransferase, which returns to normal in 4-6 months. Bilirubin levels are also elevated and if they persist one should suspect cholestatic liver disease.

Ultrasound is not done in routine cases of HAV.

Treatment / Management

No specific treatment is needed for most patients with acute, uncomplicated HAV infection beyond supportive care. Complete recovery from symptoms may take several weeks to months. In the rare case of fulminant hepatitis from HAV infection, liver transplantation may be a life-saving measure. Extrahepatic complications are managed routinely.[5][6][7]

According to the WHO, the most effective way to prevent HAV infection is to improve sanitation, food safety, and immunization practices. In the United States, vaccination against hepatitis A is available as inactivated, single-antigen vaccines (HAVRIX and VAQTA) or in combination with hepatitis B (TWINRIX). The Centers for Disease Control and Prevention recommends vaccination for children 12 months or older, travelers to endemic countries, gays, illegal drug users, individuals with occupational risk exposure, persons with clotting factor disorders or chronic liver disease. Standard adult dosing recommends administration of two doses of the vaccine 6 to 12 months apart. These vaccines are highly efficacious were seroconversion rates approaching 100%.

Until more recently, immunoglobulin was the only treatment for post-exposure prophylaxis again HAV. However, animal studies and clinical trials demonstrated the efficacy of post-exposure immunization with an inactivated HAV vaccine has led the CDC to recommend the vaccine instead of immunoglobulin for exposure to HAV in healthy individuals aged 1 to 40 years. For individuals 41 years and older, immunoglobulin administration is preferred due to the risk of more severe clinical presentation and limited evidence of vaccine efficacy in this age group. Children less than 12 months, individuals with chronic liver disease, and immunocompromised persons should also receive immunoglobulin.[8][9][10]

Differential Diagnosis

• Alcoholic hepatitis
• Other Viral hepatitis (B, C, D, E)
• Autoimmune hepatitis

Prognosis

The outcomes for most patients with HAV are excellent. After an infection, long term immunity is common and unlike the other viral hepatitis infections, recurrence of symptoms is rare.  Death is rare but may occur in older individuals or those with underlying liver disease. In the US, there are about a hundred deaths from HAV every year. Rarely in children with fulminant disease, liver transplant has been undertaken. The most important prognostic factor is age; the older the individual, the more likely that an adverse reaction or event may occur. Long term sequelae are very rare.

Complications

• Prolonged cholestasis
• Acute renal failure
• Autoimmune hepatitis

Enhancing Healthcare Team Outcomes

Hepatitis A is not life-threatening but in older people, it can be associated with adverse outcomes. Thus, the condition is usually managed by an interprofessional team that includes an infectious disease expert, emergency department physician, nurse specialist, primary care provider, and the internist.

There is no specific treatment for this infection. Supportive care helps recovery in most patients.

For people who travel to endemic areas, the primary care providers including the pharmacist, nurse practitioner and clinician should educate the patient about the hepatitis A Vaccine. In addition, the patient should maintain good personal hygiene, wash all fruits and vegetables, drink boiled water and avoid sexual encounters with strangers. Patients with HAV should follow strict enteric precaution at home and limit personal contact with other members of the family until the symptoms subside. Finally, the infectious disease nurse should educate male patients from abstaining from anal sex.

The prognosis for most patients with hepatitis A is excellent.[11][12]