Atypical presentation of pediatric acute hepatitis A: Is the situation alarming?

Abstract

Hepatitis A virus (HAV) infection remains a significant public health concern in many developing countries. The annual incidence of HAV infection is 1.5 million, though this figure may be underestimated owing to the infection’s asymptomatic nature and the presence of milder disease variants. The clinical spectrum of HAV infection now ranges from asymptomatic infection to fulminant hepatitis. Despite the availability of safe and highly effective vaccines, HAV infections remain a major contributor to acute viral hepatitis worldwide.

Key Words: Acute hepatitis A; Acute viral hepatitis; Atypical manifestation; Children; Prolonged cholestasis

Core Tip: Although pediatric hepatitis A is usually self-limiting, atypical presentations, such as cholestatic, relapsing, and autoimmune-triggered forms, can prolong morbidity and, occasionally, be life-threatening. This mini-review summarizes the clinical spectrum, highlights warning signs of severe disease, and outlines practical management and prevention strategies, with a particular emphasis on vaccination.

INTRODUCTION

Hepatitis A virus (HAV) is a nonenveloped, single-stranded RNA virus of the Picornaviridae family, Hepatovirus genus[1]. Transmission occurs predominantly via the fecal-oral route through contaminated food or water, with potential person-to-person transmission[2]. In low- and middle-income countries, HAV is endemic, with most children being infected early in life, usually asymptomatically. In highly endemic areas, infection before the age of five leads to lifelong immunity and low rates of symptomatic disease[3].

With improvements in socioeconomic conditions, sanitation, and hygiene, several regions have transitioned from high to intermediate endemicity[4,5]. The typical pediatric presentation involves a brief prodrome of fever, malaise, anorexia, and vomiting, followed by jaundice and dark urine, resolving spontaneously within 2-6 weeks[6]. In contrast, atypical forms differ in duration, severity, or systemic involvement and include cholestatic, relapsing, or autoimmune-triggered hepatitis, as well as extrahepatic manifestations affecting hematologic, renal, or neurologic systems[7]. Atypical HAV now accounts for a notable proportion of pediatric hepatitis-related hospitalizations[8].

Recognizing these forms is essential, as they often mimic other endemic infections such as dengue, malaria, or typhoid, leading to misdiagnosis and inappropriate treatment[9]. Severe hemolysis or thrombocytopenia may be life-threatening if not detected early, and greater clinical awareness can help prevent unnecessary investigations and prolonged empirical therapy[10]. This review summarizes current knowledge on the epidemiology, pathophysiology, diagnosis, management, and prevention of atypical pediatric HAV.

EPIDEMIOLOGY

HAV remains a notable cause of acute viral hepatitis (AVH) in children worldwide, with approximately 1.5 million symptomatic cases being reported annually. However, seroprevalence data suggest that the actual annual infection rate exceeds 100 million cases[10]. In regions with high endemicity, such as parts of South Asia, sub-Saharan Africa, and certain areas of Latin America, nearly all children acquire infection before the age of 10 years, with most cases being asymptomatic or subclinical[10,11]. In intermediate-endemicity regions, including parts of the Middle East, Eastern Europe, and parts of Latin America, socioeconomic advancements and improved sanitation delayed the age of primary infection into late childhood or adolescence[4,5]. This change is related to a higher proportion of clinically apparent disease, including atypical and severe presentations, since older children tend to mount a more vigorous immune response[5,9].

Atypical HAV manifestations are increasingly reported in intermediate-endemicity countries, where conditions such as prolonged cholestasis, relapsing hepatitis, and other nonclassical forms are more prevalent[8]. For example, a prospective study from Bangladesh identified atypical features, including prolonged cholestasis, ascites, pleural effusion, and encephalopathy, in 15% of pediatric HAV cases[12]. Similarly, an Indian tertiary-care cohort reported atypical presentations in 14% of 229 affected children, with prolonged cholestasis and relapsing hepatitis being the most common[13]. Outbreaks in schools and daycare centers continue to pose public health challenges in areas without universal HAV vaccination programs[14]. Seasonal variation is observed in multiple regions, often peaking during the rainy season or warmer months when the risk of food and water contamination increases[15]. Sociodemographic and environmental risk factors in children include household crowding, inadequate hand hygiene, limited parental education, and insufficient access to safe water[16]. The introduction of universal HAV vaccination in the late 1990s has significantly decreased incidence rates in numerous countries, although it has resulted in increased susceptibility among older age demographics. Vaccines are safe, with only mild local reactions or transient fever. Serious adverse events are exceedingly rare, underscoring their safety and importance[3].

PATHOPHYSIOLOGY OF HEPATITIS A AND THE BASIS FOR ATYPICAL PRESENTATIONS

HAV is a hepatotropic, nonenveloped, positive-sense RNA virus that enters the host through the gastrointestinal tract. After ingestion, the virus replicates in the oropharynx and small intestine before spreading through the bloodstream to the liver[9]. Within the liver, HAV targets hepatocytes but is considered noncytopathic; hepatocellular injury results primarily from immune-mediated mechanisms rather than direct viral cytotoxicity[4]. In a typical HAV infection, the adaptive immune response, particularly involving cytotoxic CD8⁺ T lymphocytes and natural killer cells, recognizes HAV-derived antigens presented on the surfaces of hepatocytes. This recognition triggers inflammation and hepatocyte apoptosis, leading to the release of aminotransferases[11]. This immune-mediated hepatocellular injury is responsible for the development of jaundice, dark urine, and other hallmark clinical features of HAV infections.

MECHANISMS OF ATYPICAL OR SEVERE HAV INFECTIONS IN CHILDREN

Several immunological and host factors influence the pathogenesis of atypical HAV presentations in the pediatric population. In older or genetically predisposed children, an exaggerated immune response (overactive T-cell-mediated response) may prolong hepatocellular injury, resulting in cholestatic hepatitis or relapsing disease[7]. Circulating immune complexes that contain HAV antigen and antibodies may deposit in various tissues, leading to extrahepatic manifestations such as rash, arthritis, nephropathy, or vasculitis. Endothelial dysfunction and capillary leak cause inflammatory damage to the vascular endothelium and may result in conditions such as ascites, pleural effusion, and generalized edema[17]. Elevated levels of proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6, have been associated with multisystem involvement and lead to severe complications, such as hepatic encephalopathy and acute respiratory distress syndrome[18]. Factors such as malnutrition, concurrent bacterial or parasitic infections, and genetic polymorphisms affecting immune regulation may predispose children to atypical disease courses[16].

DEFINING ATYPICAL HAV INFECTION IN THE PEDIATRIC POPULATION

The clinical manifestations of typical pediatric HAV infections encompass mild constitutional symptoms such as low-grade fever, malaise, anorexia, and nausea; transient jaundice lasting less than or equal to 2 weeks; and elevated serum alanine aminotransferase and aspartate aminotransferase, along with mild hyperbilirubinemia. Recovery is complete, without any relapse or extrahepatic organ injury[11,19].

Atypical pediatric HAV infections are characterized by prolonged jaundice or cholestatic symptoms exceeding 12 weeks; relapsing hepatitis following an initial symptom-free recovery; severe hepatic dysfunction, potentially leading to acute liver failure or encephalopathy; and significant extrahepatic involvement affecting the renal, respiratory, hematologic, neurologic, pancreatic, or musculoskeletal systems. Clinical overlap with other endemic tropical infections, such as dengue, typhoid, and leptospirosis, may result in diagnostic errors[20,21].

PROLONGED CHOLESTASIS

Cholestasis is a well-known but generally temporary aspect of AVH. In typical AVH, the cholestatic phase resolves within 3-4 weeks. Prolonged cholestasis, defined as persistence of jaundice and cholestatic features beyond 12 weeks, often with serum bilirubin > 10 mg/dL and aminotransferases < 500 IU/L, represents an atypical course that can be distressing for patients and caregivers and diagnostically challenging for physicians. Clinical features comprise worsening jaundice, pale stools, intractable pruritus, vitamin deficiency, fatigue, reduced quality of life, and psychosocial issues[22].

HAV infection may trigger polymorphisms in ATP-binding cassette proteins that are involved in bile secretion. In cases of prolonged cholestasis, HAV RNA clearance from serum can take 46-105 days, compared to just 11-20 days in typical hepatitis. This suggests that genetic susceptibility and immune response may play a role in the persistence of cholestasis[23,24]. When a child presents with prolonged jaundice, pruritus, or pale stools, it is crucial to differentiate prolonged cholestasis of AVH from chronic cholestatic disorders. Intrahepatic causes of cholestasis are progressive familial intrahepatic cholestasis, Alagille syndrome, cystic fibrosis, and alpha-1 antitrypsin deficiency. Common extrahepatic causes are choledochal cyst, biliary stricture or mass compression, and portal cavernoma cholangiopathy[25]. Moreover, a few genetic or metabolic disorders may cause prolonged cholestasis. Mutations in ATP8B1, ABCB11, and TJP2 genes are linked to cholestasis in early infancy with low or normal gamma-glutamyl transferase levels. Mutations in the ABCB4 gene can lead to dysfunctional multidrug-resistant protein 3, triggering cholestasis during AVH[26,27]. Furthermore, benign recurrent intrahepatic cholestasis may present with recurrent episodes of cholestasis in adolescence[28].

Alagille syndrome, an autosomal dominant disorder, commonly manifests as cholestasis in early infancy. Characteristic clinical features and appropriate investigations, including genetic testing, can help identify the underlying disease[29]. Smooth muscle actin and antinuclear autoantibodies can be incidentally detected in AVH as part of an autoimmune response. Cholestatic presentations can mimic autoimmune sclerosing cholangitis or overlap syndromes[30].

Drug-induced liver injury can complicate AVH, leading to flares of transaminases, liver failure, or cholestasis. A careful history of drug intake—especially herbal or alternative medicines—is crucial, as many “liver tonics” and “immune boosters” popular in Asia are falsely believed to aid recovery[31]. While many cases of cholestatic pruritus resolve on their own, severe occurrences may require pharmacologic treatment. Ursodeoxycholic acid is beneficial in 80% of cases because it increases bile flow and reduces toxicity. Rifampicin is used in 18% of cases as a pregnane-X-receptor agonist, and cholestyramine is required in approximately 4% of cases, acting as a bile acid binder. Refractory cases may necessitate treatment with naltrexone or sertraline. The benefit of steroids remains uncertain, although some reports show prednisolone improving resistant pruritus[32,33]. Multivitamin supplementation is crucial for preventing vitamin deficiencies. Figure 1 illustrates an approach to a child with prolonged cholestasis in AVH.

Figure 1 Approach to a child with prolonged cholestasis in acute hepatitis A. ALT: Alanine aminotransferase; LFT: Liver function test; PFIC: Progressive familial intrahepatic cholestasis; ASC: Autoimmune sclerosing cholangitis; A1TT: Alpha 1 anti-trypsin deficiency; CF: Cystic fibrosis; DILI: Drug-induced liver injury; IgG: Immunoglobulin G; ANA: Anti-nuclear antibody; ASMA: Anti-smooth muscle antibody; LKM1: Liver kidney microsomal antibody; MRCP: Magnetic resonance cholangiopancreatography.

RELAPSING HEPATITIS

Relapsing HAV infections can occur in 2%-4% of children and often mimic the initial presentation. This condition is characterized by an acute HAV episode followed by a remission period of 4-15 weeks, after which symptoms may reappear. During relapse, IgM anti-HAV antibody titers and the fecal HAV virus load typically increase[22]. Typically, the recurrent episode is mild and can recur intermittently over a period of 3-9 months. The relapse is thought to be due to a renewed immune-mediated attack on hepatocytes that still harbor residual or reemerging viral antigens. Genetic and immunological factors may contribute to the body’s inability to eliminate HAV. During a relapse, patients may present with jaundice, fatigue, and elevated aminotransferases, and HAV RNA may reappear in the serum or stool[9]. Notably, patients who experience a relapse should be considered potentially infectious, as viral shedding may reappear. Additionally, IgM anti-HAV antibodies can persist for 3-4 months, or, in some cases, up to 12 months following the initial infection. Therefore, their continued presence alone does not confirm that new symptoms are due to HAV relapse; polymerase chain reaction evidence is necessary for confirmation[34].

Recurrent jaundice develops in approximately one-third of pediatric patients with autoimmune hepatitis (AIH), often persisting for 6-24 months. The absence of acute viral markers and features of chronic liver disease should prompt an evaluation for AIH[22]. Primary sclerosing cholangitis may also cause episodes of relapse and spontaneous remission. In contrast, children with extrahepatic biliary obstruction usually present with a history of recurrent fever and cholangitis without a prodromal phase, distinguishing this condition from relapsing viral hepatitis[35]. Genetic cholestatic disorders are significant causes of recurrent jaundice in children. ATP8B1 and ABCB11 deficiencies account for episodic jaundice in approximately 8% of cases and are almost always accompanied by pruritus[36]. Additionally, the Dubin-Johnson syndrome, caused by ABCC2 mutations, is characterized by recurrent conjugated hyperbilirubinemia, which can develop in early childhood[37]. Management of these conditions is primarily supportive, as there is no definitive cure. Ursodeoxycholic acid may be prescribed for cases of cholestasis, pruritus, or bile-induced liver injury owing to its cytoprotective and immunomodulatory effects on hepatocytes. However, its application is not standardized and is generally tailored to individual cases, with pruritus being the most frequent indication. The role of steroids for relapsing hepatitis is still controversial[34].

TRIGGER OF AIH

HAV infection is typically a self-limiting acute illness. However, in some individuals, it can trigger autoimmune responses. There are currently no standardized criteria to define the time interval during which AIH can be attributed to HAV infection in patients diagnosed with acute HAV. The virus can induce immune dysregulation through mechanisms such as molecular mimicry, wherein viral antigens resemble host proteins, resulting in cross-reactive immune responses against the body’s own tissues. In genetically predisposed individuals, HAV infection can disrupt immune tolerance, resulting in the activation of autoreactive T cells and B cells that persist even after viral clearance. This has been linked to the development of autoimmune conditions such as AIH, Guillain-Barré syndrome, and autoimmune thyroid disease in rare cases[38,39]. In pediatric populations, HAV infection may also unmask latent autoimmunity. Up to 63% of children with HAV exhibit detectable autoantibodies, primarily anti-smooth muscle antibodies, occasionally antinuclear antibodies, and rarely, anti-liver-kidney microsomal antibodies. These autoantibodies are believed to arise from the release of intracellular antigens during hepatocyte necrosis. Genetic susceptibility also plays a role, with the HLA II DRB1*0301 allele, which is strongly associated with type 1 AIH, being observed in individuals with persistent HAV infection, which suggests a genetic predisposition for autoimmunity in response to HAV exposure[22].

ASCITES IN AVH

Ascites develops in approximately 3%-30% of children with AVH. Among these, around 38% have clinically detectable ascites[40,41]. Children with ascites tend to be younger and exhibit lower serum albumin and total protein levels, as well as prolonged prothrombin time, indicating more severe liver dysfunction than those with uncomplicated AVH. Several mechanisms have been proposed to explain the development of ascites and pleural effusion in hepatitis A. A reduction in serum albumin level decreases plasma oncotic pressure, whereas compression of the portal vein and lymphatics by swollen hepatic sinusoids may temporarily increase pressure. Both factors contribute to the accumulation of ascitic fluid. More importantly, patients with ascites do not exhibit features of chronic liver disease or portal hypertension, such as varices, nodular liver, or portosystemic collaterals[42].

Fluid restriction and dietary sodium restriction (2 mEq/kg/day) are the primary treatment options. Ascites usually resolves entirely within 8 weeks, without recurrence, along with improvement in liver function tests and normalization of liver size for age. Diuretics are necessary in about 44% of cases[22].

INTRAVASCULAR HEMOLYSIS IN AVH

Hemolysis of mild-to-moderate severity is a recognized complication in AVH. However, in some cases, individuals may experience severe hemolysis, which tends to occur more often in those with underlying glucose-6-phosphate dehydrogenase (G6PD) deficiency. It has been suggested that viral infections can directly trigger significant hemolysis in G6PD-deficient patients. Additionally, exposure to certain medications or specific foods may exacerbate the hemolytic process[43]. Among patients who develop hemolysis, 36% are found to have G6PD deficiency, while 7% have a positive direct Coombs’ test[40]. Hemolysis can occur with chronic liver disease, particularly in Wilson’s disease and AIH. In acute hemolysis with suspected G6PD deficiency, it is critical to avoid contraindicated drugs, ensure hydration and diuretics to prevent kidney injury, and evaluate for Wilson’s disease or AIH. If acute kidney injury occurs, plasmapheresis and dialysis may be necessary (Table 1)[44].

Table 1 Atypical pediatric hepatitis A virus manifestations.

Presentation	Key features	First-line tests	Initial management	When to escalate
Prolonged cholestasis	Jaundice > 12 weeks, pruritus, pale stools	LFTs, GGT, USG	UDCA ± rifampicin, vitamins A-D-E-K	Rising INR > 1.5 or bilirubin ↑ > 3 months
Relapsing HAV	Recurrence 4-15 weeks after recovery	LFT, HAV PCR	Supportive, monitor	Persistent > 3 months → exclude AIH/DILI
Autoimmune-triggered	Prolonged hepatitis, ANA/ASMA+, high IgG	Autoantibody panel, IgG	Immunosuppression (AIH protocol)	Liver failure or biopsy AIH pattern
Hemolysis (G6PD)	Anemia, dark urine	CBC, LDH, reticulocyte, G6PD	Hydration, avoid oxidants	AKI → dialysis
Ascites/effusions	Abdominal distension	Ultrasound, albumin	Sodium restriction ± diuretics	Non-resolving > 8 weeks
Neurologic/pancreatitis	Confusion or epigastric pain	LFTs, amylase/Lipase	Supportive	Persistent deficits

HAV: Hepatitis A virus; LFT: Liver function test; GGT: Gamma-glutamyl transferase; USG: Ultrasonography; UDCA: Ursodeoxycholic acid; PCR: Polymerase chain reaction; ANA: Anti-nuclear antibody; ASMA: Anti-smooth muscle antibody; IgG: Immunoglobulin G; AIH: Autoimmune hepatitis; CBC: Complete blood count; LDH: Lactate dehydrogenase; INR: International normalization ratio; DILI: Drug-induced liver injury; AKI: Acute kidney injury.

Aside from the atypical features noted above, systemic complications of AVH can include acute kidney injury, low platelet count, acute pancreatitis, hemophagocytic lymphohistiocytosis, aplastic anemia, and transverse myelitis. Neurological involvement in hepatitis A is uncommon, with encephalitis being particularly rare. Nevertheless, a few documented cases of hepatitis A complicated by encephalitis have been recorded in the literature[45].

Several factors contribute to the restricted development of antiviral medicines against HAV. First, the infection is typically self-limiting and lacks a chronic phase, reducing clinical demand for therapy. Second, restricted viral replication in standard cell cultures and animal models impedes experimental studies. Third, HAV’s noncytopathic replication and dependence on host factors make identification of selective viral targets difficult. Furthermore, the availability of safe and effective vaccines lowers research incentives[9].

CONCLUSION

Acute hepatitis A is generally a benign and self-limiting illness; however, clinicians should be vigilant for atypical presentations. Recognizing conditions such as relapsing hepatitis, prolonged cholestasis, ascites, and intravascular hemolysis is essential for guiding management and avoiding unnecessary or low-yield investigations. Invasive procedures and aggressive therapies should be reserved for cases with a strong clinical suspicion of underlying chronic liver disease. Awareness of these unusual presentations is crucial, as timely recognition and appropriate intervention can considerably influence patient outcomes. The cornerstone of hepatitis A control is active immunization.