Hepatitis A

Etiology

HAV is one of the most common causes of acute hepatitis infection worldwide. The discovery of a virus-like antigen in 1973 via immune electron microscopy marked a pivotal advancement in comprehending acute infectious hepatitis, culminating in identifying HAV.[6] Initially categorized as enterovirus type 72, HAV is now classified as the sole member of the Hepatovirus genus within Picornaviridae.[7] Despite sharing structural similarities with insect-infecting picornaviruses and having evolutionary roots in bats, rodents, and shrews, HAV exhibits distinctive features in its life cycle and hepatotropism.[8] 

This nonenveloped, icosahedral virus, measuring 27 to 32 nm, is transmitted fecal-orally and displays notable differences in its physical form when excreted versus circulating in the blood. Genomic analysis reveals 6 genotypes, 3 infecting humans and 3 found in primates. Genotype distribution varies geographically, with human infections predominantly involving genotype 1. The HAV genome, a 7.5 kb positive-sense single-stranded ribonucleic acid, contains an internal ribosome entry site, modified capsid proteins, and specific replication elements. 

Hepatitis A Risk Factors

Factors that increase an individual's risk of HAV infection include:

• Close personal contact with infected persons (eg, household members, caretakers, sexual partners)
• Close contact with international adoptees from high endemicity regions
• Occupational exposure (eg, laboratory workers and primate handlers)
• Injection and non injection drug use
• High-population group settings (eg, homeless shelters, syringe service programs, and correctional facilities)
• International travel to regions with high or intermediate HAV endemicity

Additionally, risk factors for severe HAV disease include:

• Immunocompromised persons (eg, human immunodeficiency virus, chronic renal failure, transplant recipients, and those on immunosuppressive therapy),
• Chronic liver disease (eg, hepatitis B or C infection, cirrhosis, fatty liver disease, and elevated liver enzymes)
• Adults older than 40 
• Pregnancy

Epidemiology

Improved sanitation has resulted in a shift in the age group that acquires hepatitis A, which has led to a decline in the incidence of new cases in recent years. The United States has a low endemicity; however, Mexico has a high prevalence of individuals with anti-HAV antibodies, indicating a previous infection. The frequency of acute hepatitis is higher in countries 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, with the most significant reductions seen in children and countries where routine vaccination started in 1999.[9] 

Over the last 4 decades, the average age of hepatitis A-infected individuals has increased, and those in high-risk populations account for most cases of HAV infection. The classification of HAV endemicity is based on the age-specific seroprevalence of anti-HAV immunoglobulin G (IgG). Age-associated seroprevalence surveys of anti-HAV IgG are essential for elucidating historical infection rates and population susceptibility. However, incidence studies relying on case reports are often faced with data incompleteness and bias.

Geographical Incidence and Transmission Patterns

Individuals in high-endemicity regions such as sub-Saharan Africa and certain parts of South Asia exhibit 90% or more anti-HAV IgG positivity by age 10. These areas experience low disease rates, with most infections occurring in early childhood (ie, younger than 5). Transmission is predominantly interpersonal, facilitated by inadequate sanitation.

Patients in medium-endemicity areas, including Asia, Latin America, Eastern Europe, and the Middle East, demonstrate 50% or more seroprevalence by age 15 but less than 90% by age 10. These regions face high disease rates, affecting late childhood and young adulthood. Transmission occurs via person-to-person contact and through contaminated food and water sources during outbreaks.

Economically advanced regions, including Western Europe, Australia, New Zealand, Canada, the United States, Japan, and Singapore, are low endemicity areas with 50% or more seroprevalence by age 30 but less than 50% by age 15. These areas experience low disease rates, with infections primarily occurring in susceptible individuals. Transmission modes include interpersonal contact, food and water-related outbreaks, and travel-associated infections. Individuals in very low-endemicity regions (eg, Northern Europe) exhibit less than 50% seroprevalence by age 30. These areas experience low disease rates, with infections predominantly affecting susceptible individuals, similar to low-endemicity regions (CDC. Hepatitis A, https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/hepatitis-a).

Acute Liver Failure Incidence and Hepatitis A Infection

In regions with low endemicity and developed settings, HAV contributes to less than 2% of acute liver failure (ALF) cases.[10] However, in medium and high endemicity regions, the incidence is highly variable, ranging from around 2% in some adult studies to approximately 30% in certain series.[11][12] Recent observational studies from India indicate a concerning trend of symptomatic HAV infections in adolescents and adults, accompanied by an increased incidence of ALF and higher mortality rates among adolescents.

Age-Dependent Variations of Hepatitis A Infection

The clinical manifestations and outcomes of HAV infection exhibit significant age-dependent variations. In adults, symptomatic acute hepatitis A occurs in more than 70% of cases, with 3% to 20% experiencing relapsing or prolonged hepatitis.[13] ALF is rare, with less than 1% of adult cases, but when it does occur, approximately 30% may require liver transplantation. In contrast, children demonstrate a markedly different clinical profile, with fewer than 30% exhibiting symptomatic acute hepatitis A.

Adults and children share a high spontaneous recovery rate exceeding 99%, underscoring the self-limiting nature of HAV infection. However, children generally experience a more benign course, rarely progressing to ALF or developing prolonged or relapsing hepatitis. Despite these age-related differences, the overall prognosis remains favorable for both groups with appropriate supportive care. Most patients recover without significant medical intervention, although severe outcomes such as ALF and the need for liver transplantation are slightly more prevalent in adults.

These age-dependent clinical patterns highlight the generally milder course of HAV infection in pediatric populations and emphasize the importance of age as a factor in predicting disease progression and outcomes. The epidemiological impact of HAV is intricately linked to the average age of infection, with high-endemicity regions experiencing early, often asymptomatic infections in children. As incidence decreases and the average age of infection rises, more severe symptoms and increased healthcare costs are observed. 

Pathophysiology

Following oral transmission, the virus enters the bloodstream from the gastrointestinal tract and is carried to the basolateral membrane of the hepatocyte via the portal circulation.[7] HAV exhibits 2 infectious forms: naked, nonenveloped virions (nHAV) and quasi-enveloped virions (eHAV). The naked virions, characterized by a highly conserved antigenic structure, are shed in feces, while eHAV, a distinctive feature of HAV, is secreted from infected cells and found in blood. The dual nature of HAV virions plays a crucial role in its pathogenesis and transmission, highlighting the virus's adaptation to different host environments. 

HAV infection of hepatocytes occurs via the HAV cellular receptor-1, also known as the T-cell immunoglobulin mucin domain-1 receptor, in the space of Disse. Results from recent studies suggest alternative entry pathways.[14] A complex interplay of innate and adaptive immune mechanisms characterizes the host response to HAV infection. HAV employs strategies to evade innate immunity, wherein the viral proteases target key signaling molecules and thereby suppress the type I interferon response. However, innate immunity is not completely evaded as the plasmacytoid dendritic cells produce significant type I interferons in response to HAV-infected cells or eHAV.[15] 

The adaptive immune response, particularly T-cell–mediated immunity, appears crucial in viral clearance, potentially causing hepatocellular injury. While human studies have identified virus-specific cytotoxic CD8 T cells, results from recent research in chimpanzee models suggest a more prominent role for CD4 helper T cells in infection resolution.[16][17] The dynamics of regulatory T cells during acute infection have also been implicated in the modulation of liver injury. Diagnosing acute hepatitis A primarily relies on detecting serum IgM antibodies to HAV or observing seroconversion in symptomatic individuals. Humans and primates exhibit delayed B-cell response due to the sequestration of viral antigens. A rapid, dominant, neutralizing IgG response targets conserved viral capsid protein epitopes, providing lifelong protection postinfection. Passive immunization or postexposure vaccination within 2 weeks can prevent liver disease, likely through post-endocytic neutralization of eHAV. Multifunctional virus-specific CD4 T cells correlate with declining intrahepatic viral ribonucleic acid, indicating their primary role in controlling infection and interferon-stimulated genes.[18] 

Following replication in the liver, HAV is excreted in bile and released into the stool. The virus concentration is highest in the stool during the 2 weeks before the onset of jaundice, at which point the individual is most infectious (see Image. Hepatitis A Replication Cycle).[19] Most people are no longer contagious 1 week after jaundice appears, at which time stool shedding and viremia are decreased.

Histopathology

Liver biopsy is rarely performed in uncomplicated acute hepatitis A infections. When a biopsy is performed, histopathological examination reveals inflammation and necrosis in the periportal regions with varied levels of apoptosis.[20][21] While cholestasis accompanied by an increased presence of plasma cells in the portal and periportal areas can be more indicative of hepatitis A, definitive diagnosis necessitates laboratory confirmation. In cases of severe hepatitis, necrotic bridges may form between portal areas.

History and Physical

Hepatitis A Clinical Features

The following clinical presentations are frequently associated with HAV infection:

• Asymptomatic infection
• Symptomatic infection with jaundice, dark urine, and clay-colored stool
• Cholestatic hepatitis with prolonged alkaline phosphatase and bilirubin elevation and pruritus
• Relapsing infection
• Fulminant hepatitis [15]

HAV infection usually presents with an acute onset, similar to other hepatotropic virus infections, following an average incubation period of approximately 28 days (15-50 days).[22] The clinical course is characterized by initial prodromal symptoms, including malaise, vomiting, anorexia, fever, and right upper quadrant abdominal pain, followed by a more severe symptomatic phase. This phase, typically manifesting 1 week after the initial symptoms, may include fever, malaise, anorexia, nausea, abdominal discomfort, and jaundice, persisting for a median duration of 8 weeks.[23] 

The most prevalent symptoms include jaundice, observed in 40% to 80% of cases, and dark urine, reported by 68% to 94% of patients. Fatigue affects 52% to 91% of individuals, while loss of appetite or anorexia is noted in 42% to 90% of cases during the prodromal phase. Abdominal pain or discomfort is experienced by a third during the various stages. Half of the patients report cholestatic symptoms, including acholic stools. The severity and manifestation of symptoms demonstrate a notable age-dependent pattern, with children younger than 6 years often presenting asymptomatically or with mild symptoms. In contrast, older children and adults exhibit more pronounced symptomatology, including jaundice, in more than 70% of cases. Peak infectivity occurs 2 weeks before and at least 1 week following symptom onset. The acute illness typically resolves within 2 months, with a median duration of 2 weeks. 

Physical examination reveals icterus and tender hepatomegaly. Acute HAV is associated with self-limiting pleural effusion, usually mild and undetected on examination. In the cholestatic phase, scratch marks and shiny nails can be observed. Extrahepatic manifestations are rarely associated with splenomegaly, rash, lymphadenopathy, and arthritis. A high index of suspicion must be kept for identifying hepatic encephalopathy and signs of coagulopathy, though it is a rare complication. 

Cholestatic hepatitis presentations

Marked by prolonged jaundice, cholestatic symptoms, including pruritus and acholic stools, with the labs showing elevated serum bilirubin and alkaline phosphatase levels, occur in less than 5% of patients. Cholestatic hepatitis typically resolves spontaneously without sequelae. Rarely, patients with intractable pruritus might require specific therapy.

Relapsing infection presentations

Although HAV does not progress to a chronic stage or result in chronic viral shedding, cases of prolonged illness with recurrent symptoms or ALF have been documented and affect up to 10% of patients, with episodes of relapse lasting up to 12 months. These protracted cases may involve delayed viral clearance, persistent symptoms, elevated liver enzymes, and severe cholestasis, with some instances of relapsing hepatitis and detectable HAV ribonucleic acid.

Up to 10% of patients experience a relapse of symptoms within 6 months after the acute illness. Clinical relapse generally lasts less than 3 weeks, though biochemical relapse can persist for up to 12 months. The cause of relapsing hepatitis remains unknown, and no predisposing factors have been identified. Clinical relapse typically follows apparent recovery, with near normalization of serum aminotransferases, followed by biochemical and sometimes clinical relapse.

Manifestations during relapse are often milder than the initial episode, but serum aminotransferases can exceed 1000 IU/dL, and serum anti-HAV IgM antibodies persist throughout the disease. HAV can be recovered from stool during relapses, indicating continued infectivity. During relapses, extrahepatic manifestations such as arthritis, vasculitis, nephritis, and cryoglobulinemia have been reported. Autoimmune hepatitis may be triggered by HAV infection in susceptible individuals, characterized by hyperglobulinemia, circulating autoantibodies, and inflammatory liver changes on histology, which might be another cause for this pattern.

Acute liver failure and fulminant hepatitis presentations

Individuals with ALF and fulminant hepatitis frequently present with coagulopathy and altered sensorium after the onset of jaundice. The risk of ALF and mortality increases with age and preexisting liver conditions, with an overall case-fatality ratio of approximately 0.3%. Superinfection with HAV in patients with chronic hepatitis C can lead to severe outcomes, including ALF, and may trigger autoimmune mechanisms exacerbating liver damage. Coinfection with other viruses (eg, hepatitis G) has been observed, although the role of HAV in severe cases remains unclear.

Hepatitis A and Pregnancy

Acute HAV infection is associated with increased risks of preterm labor and gestational complications.[24] Extrahepatic manifestations, occurring in 10% to 15% of cases, include rash, arthralgias, leukocytoclastic vasculitis, arthritis, glomerulonephritis, cryoglobulinemia, optic neuritis, transverse myelitis, toxic epidermal necrolysis, myocarditis, thrombocytopenia, aplastic anemia, and red cell aplasia.[25]

Evaluation

In patients presenting with the syndrome of acute hepatitis with characteristic clinical features as mentioned above, an HAV infection is suspected, and laboratory tests and exclusion of other conditions are necessary for the diagnosis. Biochemical parameters include a characteristic pattern in the liver function tests observed across various acute viral hepatitis presentations. Elevated bilirubin, serum aminotransferases, and alkaline phosphatase (ALP) are noted. The chronology of this derangement and the pattern of aminotransferase elevation are essential. Among the transaminases, the alanine aminotransferase level (ALT) is generally higher than in cases of other viral hepatitis and can rise 10- to 100-fold. Typically, the bilirubin level starts to increase later. Blood work usually reveals mild lymphocytosis and normal prothrombin time. If the prothrombin time becomes deranged, severe liver damage, including the risk for encephalopathy, should be suspected.

Shortly after the ALT levels increase, HAV particles can be detected in the stool, though stool is not routinely tested. Anti-HAV IgM starts to rise after this, and the clinical symptoms appear shortly after the initial excretion of particles. When differential diagnoses are excluded, the presence of anti-HAV IgM and characteristic clinical features confirms the diagnosis of hepatitis A. Anti-HAV IgM usually remains positive for 4 to 6 months. Additional testing can include reverse transcriptase-polymerase chain reaction to detect viral ribonucleic acid, which can show false negative results in an acute infection. Anti-HAV IgG emerges soon after infection and remains present for the person’s lifetime.

An abdominal ultrasound can help exclude other causes, including differentiating between extrahepatic and intrahepatic cholestasis and evaluating fever with abdominal pain. However, findings are frequently nonspecific (eg, gallbladder wall and periportal edema). Pleural effusion and perihepatic fluid are seen on rare occasions while visualizing the liver.

Acute liver failure should be suspected in cases with deranged prolonged prothrombin time and monitoring for minimal hepatic encephalopathy. Close monitoring of prothrombin time and liver function tests are mandated. Signs of raised intracranial pressures (ICT) should be carefully monitored, as bradycardia, hypertension, and altered breathing patterns can indicate raised ICT. ICT can be monitored by transcranial Doppler, optic nerve sheath diameter, and reverse jugular monitoring. Moreover, a noncontrast computed tomography (CT) of the brain can demonstrate changes secondary to increased ICT. Deranged kidney function tests are a poor prognostic marker. Clinicians should also exclude sepsis. Evaluation and management are like any other case of ALF.

In the cholestatic variant of hepatitis A infection, ALP and gamma-glutamyl transferase are raised along with cholestatic symptoms, typical of intrahepatic cholestasis. Pruritus can be worrisome; testing of individuals with pruritus will typically have findings that show elevated bile acid levels. Usually, cholestasis does not persist long enough to cause a severe deficiency of fat-soluble vitamins. 

Treatment / Management

Supportive Management

No specific treatment is needed for most patients with acute, uncomplicated HAV infection beyond supportive care. In individuals with fulminant hepatitis within regions where universal immunization is not possible, antiviral treatment would be helpful; this type of therapy is currently not available for HAV. Cholestatic hepatitis A is also self-limiting; if pruritus is severe, antipruritic measures, including cholestyramine, rifampicin, or ondansetron, may be used. Refractory pruritus, though a self-limiting condition, can rarely require plasma exchange.

Severe HAV infections with ALF should be managed like other ALF cases. The Kings College criteria give a lower priority to ALF due to acute viral hepatitis as these are less severe. Despite the implementation of priority scoring systems like the Model for End-Stage Liver Disease (MELD) score or King’s College criteria for liver transplantation referrals, it remains challenging to determine which patients with hepatitis A-associated ALF will need a transplant due to the lack of reliable biomarkers. However, Kings College criteria may not apply to high endemicity regions with higher prevalence where dynamic prognostication models have been developed.[26] 

Patients exhibiting worsening hepatic synthetic function require special considerations. Hepatic synthetic dysfunction is indicated by coagulopathy with prolonged international normalized ratio, increasing creatinine, serum albumin levels below 3%, rising blood ammonia levels, and clinical signs of hepatic encephalopathy, necessitating prompt transfer to an intensive care unit, ideally at a liver transplant center. Patients should be classified using the United Network for Organ Sharing liver failure medical urgency classification (eg, MELD 1 or PELD 2) or by assigning a status (eg, 1A or 1B) for liver allocation based on country-specific guidelines and the availability of access to a transplant center. Extrahepatic complications are managed accordingly. 

In rare cases of severe relapse and cholestatic symptoms, patients have been given a short course of corticosteroids based on anecdotal evidence and limited case reports, but randomized controlled trials are lacking.[27] Corticosteroids are also used for pure red cell aplasia caused by hepatitis A and have been tried in children with fulminant liver failure from hepatitis A.[28][29][30][31][32][33][34][35] N-acetyl cysteine was not found to be useful.[36](B2)

Differential Diagnosis

Differential diagnoses that should also be considered include:

• Other acute hepatitis viral infections (eg, hepatitis E virus and hepatitis B virus)
• Non-hepatotropic viral infection (eg, dengue virus, cytomegalovirus infection, herpes simplex virus infection, Ebstein-Barr virus)
• Parasitic and zoonotic infectious diseases (eg, leptospiral and rickettsial infections, Q fever, malaria, and tropical fever syndromes)
• Drug-induced liver injury 
• Autoimmune hepatitis 
• Ischemic hepatitis 
• Alcohol-associated hepatitis 
• Wilson disease
• Acute Budd-Chiari syndrome

Prognosis

The outcomes for most patients with HAV are excellent. After an infection, long-term immunity is common, and unlike 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 United States, approximately 100 deaths from HAV occur every year. Liver transplant is rarely undertaken in children with fulminant disease. The most important prognostic factor is age; the older the individual, the more likely an adverse reaction or event may occur. Long-term sequelae are very rare.

Complications

Complications of HAV include:

• Acute liver failure and fulminant hepatitis 
• Acute liver injury 
• Prolonged cholestasis 
• Acute-on-chronic liver failure in patients with preexisting hepatitis C virus infection or metabolic dysfunction associated steatotic liver disease
• Severe complications associated with HAV infection including pericarditis, renal failure, thrombocytopenia, acute pancreatitis, aplastic anemia, autoimmune hemolytic anemia, Guillain-Barré syndrome, vasculitis, and arthritis