INTRODUCTION
Acute hepatitis A is an acute liver disease caused by the hepatitis A virus (HAV). This pathogen remains the leading cause of acute viral hepatitis globally, with an estimated 100 million infections and 1.5 million symptomatic cases each year, resulting in 15000 to 30000 deaths annually[1]. The burden is particularly high in developing countries, where inadequate sanitation facilitates transmission[2]. Infection is closely linked to unsafe water or food, poor sanitary conditions, inadequate personal hygiene, and, in some cases, oral-anal sexual contact[2]. HAV is spread primarily through the fecal-oral route, and its clinical manifestations vary widely, from completely asymptomatic infection to severe acute hepatitis. In most cases, however, HAV is self-limiting and resolves within a few weeks[3]. Unlike other hepatotropic viruses, HAV has not been shown to establish chronic infection[1]. Nevertheless, an increasing number of reports describe its potential role as a trigger for autoimmune hepatitis (AIH)[4]. AIH is a rare, chronic inflammatory liver disease of uncertain etiology[5]. Its pathogenesis is thought to involve a connection between genetic predisposition, environmental triggers, and a failure of immune tolerance, ultimately leading to sustained hepatocyte-directed immune responses, chronic inflammation, and progressive fibrosis[5,6]. AIH itself is rare, with an estimated annual incidence of 1-2 per 100000 and a prevalence of approximately 20 per 100000 in the general population, as reported from Europe, the Americas, and Asia, though somewhat lower rates are observed in Asian populations[6]. In all ethnic groups and at all ages, AIH affects women more often than men[7]. The clinical spectrum is remarkably broad. Patients may present at any age, from infancy to old age, and manifestations range from mild, intermittent transaminase elevations to fulminant hepatitis with acute liver failure[6]. This heterogeneity makes AIH a challenging diagnosis and necessitates considering it in virtually any patient with unexplained elevations in liver enzymes, with or without jaundice[6]. Diagnostic accuracy improved with the development of the International AIH Group (IAIHG) scoring system in 1999, followed by the simplified score introduced in 2008 for use in routine clinical practice[8,9]. No other liver disease demonstrates such a wide variation in presentation[6]. Here, we present the case of a 20-year-old male who developed AIH, diagnosed on the basis of liver biopsy, which appeared to be triggered by an acute HAV infection following a trip to Asia.
CASE PRESENTATION
A 20-year-old male was admitted on 29 January 2025 to the Department of Infectious Diseases with symptoms of acute hepatitis. Ten days before admission, he had developed his first symptoms, including fever, darkened urine, diarrhea with abdominal pain, and scleral icterus. His history revealed extensive travel to Asian and African regions: Three months prior to admission, he had visited Thailand, where he consumed fruit, seafood, and beverages with ice; in addition, over the previous six months, he had also stayed in Japan and the Cape Verde Islands. On admission, his general condition was good. Vital signs were stable with a heart rate of 70/minute and blood pressure of 120/70 mmHg. The abdomen was soft and non-tender, with no palpable pathological resistance. His weight was 92 kg and height 193 cm, corresponding to a body mass index of 24.7 kg/m2. Clinical examination revealed jaundice of the skin and sclera. The patient did not take any regular medications, had never been hospitalized, and reported no history of liver disease. His family history was also negative for liver conditions. He was vaccinated according to the Polish national immunization schedule, but had not received vaccinations against HAV or seasonal influenza. He denied a history of blood transfusions, sexual contacts, or the use of illicit drugs and new psychoactive substances. On admission, laboratory tests revealed markedly elevated markers of hepatic inflammation: Alanine aminotransferase (ALT) 1527 U/L (reference range 10-50 U/L) and aspartate aminotransferase (AST) 527 U/L (reference range 10-50 U/L). The patient also presented with hyperbilirubinemia of 5.59 mg/dL (reference range 0.10-1.20 mg/dL), as well as elevated alkaline phosphatase (ALP) at 138 U/L (reference range 40-129 U/L) and gamma-glutamyl transferase at 181 U/L (reference range 10-71 U/L). An abdominal ultrasound performed the day after admission showed no abnormalities. Notably, the patient’s anti-HBs antibody level was 5.49 mIU/mL (a value < 10 mIU/mL indicates lack of acquired immunity), despite having been vaccinated against hepatitis B virus (HBV) according to the national immunization schedule. For this reason, acute HBV infection was considered and subsequently excluded during diagnostic workup. Serological testing also ruled out past HBV, acute HEV, cytomegalovirus, and Epstein-Barr virus (EBV) infections. The 4th-generation human immunodeficiency virus (HIV) test was negative, as were anti-hepatitis C virus (HCV) antibodies supplemented with HCV RNA assessment. The presence of IgM antibodies against the HAV was detected, and based on this test, which correlated with the clinical picture, the patient was diagnosed with acute hepatitis A. Supportive hepatoprotective therapy was initiated, and after a documented downward trend in aminotransferases activity and bilirubin concentration, the patient was discharged home with recommendations for follow-up. The course of aminotransferases activity during the patient’s initial hospitalization is shown in Figure 1A.
Figure 1 Aminotransferases activity.
A: Aminotransferases activity during the patient’s initial hospitalization; B: Aminotransferases activity during the patient’s second hospitalization. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; U/L: Units per liter.
Two months after the initial hospitalization, the patient presented to the emergency department with symptoms similar to those at onset, the main complaint being fatigue. Following his first admission, he had returned to normal physical activity, but two weeks after resuming it, he developed an upper respiratory infection characterized by weakness and rhinorrhea without fever. No laboratory tests were performed at that time; however, follow-up tests recommended after the first hospitalization demonstrated a gradual decline in transaminases activity, culminating in a brief normalization of aminotransferases levels. During his second admission, laboratory evaluation revealed a marked increase in hepatic inflammation markers, with ALT reaching 1503 U/L and AST 575 U/L, both showing a progressive upward trend throughout the hospital stay (Figure 1B). In view of the clinical presentation, repeat testing was performed to exclude acute HBV, HCV, HIV, EBV, and cytomegalovirus infections, all of which returned negative results.
While awaiting liver biopsy results, the clinical possibility was raised that AIH had been induced by hepatitis A, based on the revised IAIHG scoring system. The preliminary score included: Male sex (0), ALP:AST ratio of 0.11 (+2), antinuclear (ANA) antibodies < 1:40 (0), IgG 21.1 g/L (+1), anti-HAV IgM positivity (-3), absence of recent hepatotoxic drug exposure (+1), and alcohol consumption < 25 g/day (+2). Following receipt of the histopathology report, additional points were assigned for biopsy findings, including interface hepatitis (+3) and predominantly lymphoplasmacytic infiltration (+1), with no rosetting of hepatocytes or biliary changes (0). Based on the final score and histological features, the diagnosis of AIH was established. Histology demonstrated portal tracts infiltrated by lymphocytes, plasma cells, and eosinophils, with clear evidence of interface hepatitis (Figure 2). Immunohistochemical staining allowed for further characterization of the infiltrate (Figure 3). CD138 staining highlighted an abundance of plasma cells, both as individual cells and in aggregates (Figure 4). These findings, interface hepatitis, lymphoplasmacytic infiltrates enriched with plasma cells, and mixed CD4/CD8 T-cell involvement, were consistent with the histological picture of AIH, leading to the diagnosis of AIH possibly induced by acute HAV infection.
Figure 2 Pathologic findings of the liver biopsy.
A: The portal tracts are infiltrated by lymphocytes, plasma cells and eosinophils. The interface hepatitis is evident; B: Close-up view to portal tract with interface hepatitis and parenchymal hepatitis with the contribution of eosinophils and plasma cells.
Figure 3 A double chromogen assay of immunohistochemistry for CD4 (3,3’-diaminobenzidine, brown colour) and CD8 (red colour).
Close to equal contribution of CD4 and CD8 lymphocytes. Numerous CD8+ cytotoxic lymphocytes in the portal tract.
Figure 4 CD138-positive singular and aggregates plasma cells in the portal tract (immunohistochemistry, CD138).
Corticosteroid therapy was initiated, which led to a marked reduction in aminotransferases activity. As steroid doses were gradually tapered, azathioprine was introduced[10]. Once a satisfactory downward trend in aminotransferases activity and a reduction in IgG concentration were achieved, the patient was discharged for outpatient follow-up, with instructions to continue therapy and to monitor aminotransferases activity regularly. During the nine-month follow-up period, a marked improvement in aminotransferases activity was achieved (Figure 5).
Figure 5 Aminotransferases activity during the nine-month follow-up period and corresponding treatment.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; U/L: Units per liter.
EPIDEMIOLOGY OF AIH
Data on AIH in the literature remain limited and are affected by important methodological shortcomings, making it difficult to establish precise epidemiological figures. One major limitation is that much of the available information was collected before the introduction of the first IAIHG scoring system in 1999, resulting in a lack of standardization in diagnosis[9]. Despite these challenges, several epidemiological trends have been identified. Of the three recognized types of AIH, type 1 (AIH-1) is by far the most common and, as with many autoimmune diseases, predominantly affects females[11]. Interestingly, the female-to-male ratio is estimated at approximately 4:1 in AIH-1[12]. Reported incidence also shows marked geographic variation, ranging from 0.5 cases per 100000 in the United States to 1.9 cases per 100000 in Norway[11,13,14]. To date, the most recent meta-analysis, which included 239 million participants and 55839 patients with AIH from 18 countries across five continents, reported a global pooled incidence of 1.28 cases per 100000 person-years[15]. Notably, the pooled prevalence of AIH has shown a gradual increase over time, rising steadily from 1970 to 2019[15]. In contrast, information from regions such as Africa is extremely limited, and much of the existing epidemiological literature remains outdated[12].
GENETIC PREDISPOSITION OF AIH
While the exact etiology of AIH remains elusive, genetic factors have been recognized as crucial contributors to disease susceptibility. Numerous studies have highlighted associations between AIH and specific human leukocyte antigen (HLA) alleles, as well as non-HLA genetic variants, indicating a polygenic nature of the disorder[16].
HLA genetic factors
HLA genes, located on chromosome 6p21, encode major histocompatibility complex molecules that present antigens to T lymphocytes, thus initiating adaptive immune responses[17]. Among these, class II HLA alleles are the most consistently implicated in AIH. Interestingly, these associations vary across ethnic groups[18]. Type 1 AIH, which is the most common form, shows strong associations with HLA-DRB103:01 and HLA-DRB104:01 in European populations[19]. In South America, AIH is mainly related to HLA-DRB113:01 alleles, while in Japan, it is more frequently associated with HLA-DRB104:05, *04:01, *08:02, and 08:03[20,21]. Of note, HLA-DRB107:01 has been reported to correlate with more rapid disease progression and poorer prognosis[18]. Type 2 AIH (AIH-2), which is less common and typically associated with liver kidney microsomal-1 antibodies, also demonstrates distinct HLA associations. In European populations, it is more frequently linked to HLA-DRB107:01 and HLA-DRB102:01. In contrast, HLA-DRB103:01 appears to predispose patients in both British and Brazilian cohorts, whereas HLA-DQB102:01 has been shown to be more common in Latin American cases[20,22].
Non-HLA genetic factors
Beyond the HLA region, genome-wide association studies have identified several non-HLA loci that may modulate susceptibility to AIH. Variants in genes involved in immune regulation, such as cytotoxic T-lymphocyte-associated protein 4, have been implicated. Polymorphisms in cytotoxic T-lymphocyte-associated protein 4, a negative regulator of T-cell activation, may impair immune checkpoint control, predisposing individuals to autoimmune reactions in the liver[23]. Similarly, TNF-α promoter polymorphisms can influence cytokine production, contributing to the inflammatory milieu characteristic of AIH[21]. Other candidate genes include those encoding Fas (CD95), programmed cell death protein 1, and interleukin-10, all of which are involved in maintaining immune homeostasis[18,21,24]. Although these associations are generally weaker than HLA links, they suggest that a combination of multiple minor-effect variants contributes to disease development.
Familial clustering and twin studies
Familial aggregation of AIH further supports the role of genetics in disease predisposition. First-degree relatives of affected individuals exhibit a higher risk of AIH, although concordance in monozygotic twins remains incomplete, indicating that environmental triggers, epigenetic modifications, or stochastic events also influence disease onset[25].
Understanding the genetic predisposition of AIH has practical implications. HLA typing can aid in risk stratification, particularly in populations with high allele prevalence. Furthermore, insights into immune-related genetic variants may facilitate the development of targeted therapies, such as immune checkpoint modulators or cytokine inhibitors, offering the prospect of precision medicine in AIH management.
CHARACTERISTICS OF AIH
The clinical picture of AIH is highly diverse. While the disease usually follows a chronic course, it may range from asymptomatic or mild forms to fulminant presentations, such as in our patient, who demonstrated markedly elevated aminotransferase activities[26]. Fatigue is the most common symptom, reported by approximately 85% of patients, while other frequent but non-specific long-term manifestations include weakness, abdominal pain, weight loss, nausea, and pruritus, several of which were present in our case[26]. Importantly, in many patients, physical examination and routine laboratory tests reveal no abnormalities, despite clear evidence of active hepatitis on liver biopsy[11]. In children and adolescents, AIH often takes a more aggressive course than in adults and may even be diagnosed in the acute phase, which is consistent with our findings[27]. Regardless of clinical presentation, laboratory tests typically show variable elevations in liver transaminases, with ALT activity predominating[27]. These values may remain only slightly above the normal range for prolonged periods, whereas in acute AIH, they can rise dramatically, sometimes exceeding 10 times the upper limit of normal (ULN)[26]. This was observed in our patient during his second hospitalization, when ALT and AST exceeded 1600 U/L and 500 U/L, respectively.
PATHOPHYSIOLOGICAL LINK BETWEEN HAV AND AIH
The pathophysiological link between HAV and AIH has been increasingly studied, and genetic factors appear to play a crucial role. Patients carrying histocompatibility complex (major histocompatibility complex) class II alleles HLA-DR3 and HLA-DR4 are considered at higher risk, with DRB10301 associated with a more severe disease course than DRB10401[4]. One of the most compelling studies comes from Vento et al[28], who prospectively followed 58 healthy relatives of 13 patients with AIH for four years. Participants were monitored every two months for serological markers and T-lymphocyte migration inhibitory activity. During follow-up, three cases of subclinical acute hepatitis A were identified, and notably, two of these individuals developed AIH within five months[28]. Authors concluded that HAV may act as a trigger for AIH in genetically susceptible individuals[28]. Importantly, a defect in suppressor-inducer T lymphocytes, responsible for controlling immune responses to the asialoglycoprotein receptor (ASGPR), a hepatocyte surface antigen, was identified in these patients prior to HAV infection[28]. After acute HAV, both helper T cells and antibodies against ASGPR persisted and increased, reinforcing the link between HAV and the breakdown of immune tolerance[28]. Although such observations remain rare, additional case reports support this hypothesis. For instance, Subramanian et al[29] described a 45-year-old woman from Mexico in whom HAV infection appeared to trigger AIH by initiating self-perpetuating, immune-mediated liver inflammation in that case, AIH manifested acutely after the resolution of viral hepatitis, mirroring the presentation observed in our patient. Additionally, several immunopathogenic mechanisms have been proposed to explain how acute viral infections may trigger AIH, although direct evidence involving HAV remains scarce and warrants further investigation. Fujinami et al[30] suggested that viral infections can initiate autoimmunity through mechanisms such as molecular mimicry and bystander activation. In the context of HAV, molecular mimicry could occur if viral epitopes share structural similarities with hepatocyte-specific antigens, such as the ASGPR, thereby activating autoreactive T and B lymphocytes[31]. Bystander activation may also play a role, as HAV-induced hepatic inflammation promotes cytokine release and enhanced antigen presentation, potentially activating self-reactive lymphocytes that have escaped normal immune tolerance[32]. Although HAV itself has not been systematically examined within this mechanistic framework, these immunological concepts offer a plausible explanation for the transition from acute viral hepatitis to AIH observed in our patient and in previously reported cases. Although HLA-DR3 and HLA-DR4 alleles are considered major genetic susceptibility factors for AIH triggered by HAV, HLA class II typing in our patient was negative for both alleles. This observation suggests that HAV-associated AIH may also develop in the absence of classical HLA risk factors. In addition, ASGPR-specific antibodies and helper T-cell responses, previously proposed as mechanistic links between HAV infection and loss of immune tolerance, were not assessed in this case due to limited availability of these tests in routine clinical practice. Despite these limitations, the close temporal association between acute HAV infection and the onset of biopsy-proven AIH, along with typical histological features and a favorable response to immunosuppressive therapy, supports the role of HAV as a triggering factor in this patient.
TYPES OF AIH
The distinction between the two primary subtypes of AIH was first proposed in 1995 by Czaja and Manns[33], who based the classification on the presence of specific serum autoantibodies. AIH-1 is the more prevalent form, characterized by the presence of ANA and smooth muscle antibodies (SMA). It typically manifests later in life and is therefore regarded as the adult-onset form of AIH. In contrast, AIH-2 occurs more frequently in pediatric populations and is associated with anti-liver kidney microsome (LKM1) and anti-liver cytosol (anti-LC1) antibodies[9]. Although AIH-2 is predominantly observed in children, studies indicate that AIH-1 still accounts for at least two-thirds of pediatric cases, particularly among adolescents[34]. A third subtype, AIH-3, was later proposed and linked to antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP). Initially, the presence of anti-SLA/LP antibodies was thought to indicate a more severe disease course and poorer prognosis. However, subsequent studies demonstrated that anti-SLA/LP autoantibodies almost always coexist with antibodies against ribonucleoprotein (Ro52). Since Ro52 autoantibodies themselves are considered an independent prognostic factor for unfavorable outcomes in AIH, irrespective of anti-SLA/LP status, the distinct classification of AIH-3 has been called into question[35].
The validity of distinguishing the third type of AIH in adult patients has been questioned because AIH-1 and AIH-3 are clinically indistinguishable. Therefore, anti-SLA/LP antibodies should be regarded as an additional serological marker of AIH-1 rather than as a defining feature of a separate subtype[36,37]. Similarly, a recent long-term observational study in the pediatric population found no significant differences in disease activity, treatment response, or overall prognosis among children with various antibody profiles or AIH subtypes[38]. In line with these findings, the current European Association for the Study of the Liver guidelines recommend that, in adult patients, the classification of AIH into subtypes should not influence clinical management or therapeutic decisions[10].
DISTINGUISHING AIH FROM OTHER LIVER DISEASES
AIH should always be considered in cases of elevated liver enzymes or cirrhosis of unknown origin, particularly when accompanied by increased IgG levels and circulating autoantibodies[10]. The diagnosis must be established after excluding all other known causes of liver disease, both acute and chronic, since several differential diagnoses may coexist with AIH. Extrahepatic etiologies most commonly manifest as acute hepatic injury and include viral infections such as EBV and HIV. In these cases, a thorough medical history and physical examination should be conducted to assess for extrahepatic manifestations, followed by appropriate molecular and serological tests to confirm or exclude these infections. Another extrahepatic cause, celiac disease, may result in either acute or chronic liver injury and can coexist with AIH. Given its increased prevalence among AIH patients (3.5%) compared with the general population (1%), serological testing for celiac disease should be performed at least once in the diagnostic process[39]. The evaluation of intrahepatic causes should likewise involve detailed patient anamnesis (including family history, current medications, vaccinations, alcohol intake, and risk factors for blood-borne infections) and physical examination (assessment for obesity, xanthomas, or Kayser-Fleischer rings). In all cases, hepatitis A-E viruses should be excluded through molecular and serological testing[10]. Given the high and rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the general population (over 30%), hepatic steatosis may complicate AIH diagnosis[40]. Steatosis can be identified via imaging or non-invasive modalities such as transient elastography, which assesses both controlled attenuation parameter and liver stiffness. MASLD is typically associated with at least one additional cardiometabolic risk factor, such as obesity, dyslipidemia, or diabetes mellitus, the latter being recognized as an independent risk factor for severe fibrosis and inflammation in patients with AIH[41]. Markers suggesting iron overload, including elevated transferrin saturation and ferritin, should prompt further evaluation for hereditary hemochromatosis through HFE genotyping and, if needed, liver biopsy[42]. Similarly, in cases where copper accumulation is suspected, as in Wilson disease, assessment of copper metabolism and extrahepatic features should be undertaken, with ATP7B genetic testing recommended for diagnostic confirmation[43]. Potential drug-induced liver injury (DILI) must also be excluded. This assessment should include not only prescribed medications but also over-the-counter preparations and dietary supplements, as up to 9% of all DILI cases may evolve into drug-induced AIH[44]. In addition, alcohol-related liver disease can mimic or coexist with AIH, presenting with elevated gamma-glutamyltransferase, increased mean corpuscular volume, hypertriglyceridemia, and elevated IgA levels. In specialized settings, ethyl glucuronide testing in hair samples can serve as a biomarker of chronic excessive alcohol use[45]. In both DILI and alcohol-related injury, accurate history-taking and patient cooperation are fundamental for diagnosis. A liver biopsy, correlated with clinical findings and autoantibody profiles, may help distinguish AIH from autoimmune cholangiopathies such as primary biliary cholangitis or primary sclerosing cholangitis. Primary biliary cholangitis typically affects women, involving small intrahepatic bile ducts, and is characterized by elevated ALP and the presence of antimitochondrial antibodies. In contrast, primary sclerosing cholangitis is more common in young men and is marked by segmental fibrosis and structuring of bile ducts, leading to cholestasis. Testing for IgG4-related cholangitis should also be performed, and clinicians must remain aware of the possibility of overlap syndromes[10]. The differential diagnosis of AIH is a complex and nuanced process that often yields ambiguous results and should therefore be conducted by an experienced multidisciplinary diagnostic team.
DIAGNOSTICS OF AIH
Laboratory tests
AIH is typically associated with increased serum aminotransferases activity, with ALT levels usually exceeding those of AST in both acute and chronic disease presentations. The degree of aminotransferase elevation is highly heterogeneous, ranging from marginal increases to values surpassing 50 times the ULN[46]. Importantly, the magnitude of ALT elevation does not necessarily reflect the severity of histological inflammation[47]. Biochemical cholestasis is observed less frequently in AIH. Fewer than one-fifth of patients demonstrate mild increases in ALP (typically < 2 × ULN) or gamma-glutamyl transferase (< 5 × ULN). Marked elevations in these parameters should prompt consideration of cholestatic variants of AIH or alternative hepatobiliary disorders[10]. Serological testing frequently reveals hypergammaglobulinemia, with 85-95% of patients presenting with elevated serum IgG[48]. Historically, high IgG levels have been considered a marker of more aggressive histological activity and poorer therapeutic outcomes. However, a study conducted in 2020 changed this paradigm, showing no significant differences in clinical presentation, histopathology, or the likelihood of achieving complete biochemical remission between patients with normal and elevated IgG concentrations at the time of diagnosis[49]. The detection of autoantibodies represents a cornerstone in the diagnostic process of AIH. Both non-organ-specific autoantibodies, such as ANA and SMA, as well as organ-specific antibodies including anti-SLA/LP, anti-LKM1, and anti-LC1, are recognized as characteristic serological markers of this disease[50]. Although their presence provides strong diagnostic support, these markers alone are insufficient to establish a definitive diagnosis. Notably, a subset of patients, approximately 20%, may present with seronegative AIH, defined by the absence of ANA, SMA, and LKM1 antibodies[51]. The diagnostic performance of these antibodies has been systematically evaluated. A meta-analysis reported moderate sensitivity and specificity for ANA, moderate sensitivity but higher specificity for SMA, and low sensitivity yet strong specificity for anti-SLA/LP[52]. Importantly, diagnostic reliability improves when two or more autoantibodies are identified simultaneously[53]. Nevertheless, none of these autoantibodies is entirely unique to AIH, as they may also occur in other liver conditions, highlighting the need for careful differential assessment[50]. It is crucial to note that autoantibodies are primarily valuable for diagnostic purposes; they do not provide prognostic information or predict treatment outcomes. According to the 2025 guidelines of European Association for the Study of the Liver, initial screening should include testing for ANA, SMA, anti-LKM1, and anti-LC1 by indirect immunofluorescence on triple rodent tissue sections, supplemented by anti-SLA/LP testing using solid-phase[10]. However, comprehensive autoimmune serology testing remains limited in availability across many laboratories, which may restrict its practical application.
Liver biopsy
Liver biopsy remains a cornerstone for confirming the diagnosis of AIH. Diagnosing AIH without histological confirmation should be considered only in exceptional cases, given that the label carries significant implications, including long-term immunosuppressive therapy[51]. The pathology report should provide a comprehensive assessment, encompassing the grading of necroinflammatory activity and the staging of fibrosis[54]. For optimal evaluation, biopsy specimens should include a minimum of eight complete portal tracts. This is best achieved using needles of at least 18G in diameter, preferably 16G or larger, with a biopsy length of at least 1.5 cm[55]. Notably, the diameter of the biopsy, which determines the number of fully represented portal tracts, often has a greater impact on diagnostic yield than the length alone. Considering the patchy distribution of AIH lesions, longer biopsies or sampling from multiple liver segments can reduce the risk of sampling error[54]. Histological evaluation should systematically assess key liver structures, including portal tracts, parenchyma, sinusoids, and terminal hepatic veins, while noting the presence, maturity, and extent of fibrosis. The histological assessment begins by identifying the dominant inflammatory pattern, whether portal or lobular. Typical morphological features include portal inflammation rich in plasma cells, interface hepatitis (previously termed piecemeal necrosis), emperipolesis (penetration of lymphocytes into hepatocytes), hepatocyte rosettes, and variable fibrosis[56]. Lobular necroinflammatory activity is generally observed alongside portal and periportal inflammation. Approximately 10% of patients may show no fibrosis at initial presentation. Recent studies indicate that hepatocyte rosettes and emperipolesis are not specific to AIH and may be seen in other liver conditions[57]. The final report should provide a weighted interpretation of all histological features and classify the likelihood of AIH according to the 2022 IAIHG criteria as likely, possible, or unlikely[54].
Diagnostic criteria
The IAIHG introduced the first diagnostic criteria in 1993, later revised in 1999[9,58]. To make the tool more practical, a simplified scoring system was proposed in 2008, which remains widely used today[59]. According to this system, 1-2 points are assigned for the presence of autoantibodies, elevated serum IgG, typical histological features, and the exclusion of viral hepatitis. A score of ≥ 6 indicates probable AIH, while ≥ 7 supports a definite diagnosis. The simplified criteria demonstrate high diagnostic accuracy, with a sensitivity of about 95%, a specificity of 90%, and an overall accuracy of 92%[60]. Nonetheless, no single feature, such as autoantibody positivity or hypergammaglobulinemia, is sufficiently specific to establish the diagnosis on its own. The coexistence of conditions like MASLD or alcohol-related liver injury further complicates the evaluation. Recent studies suggest that replacing the histological component of the simplified score with the updated 2022 IAIHG histological criteria could further enhance sensitivity in adult populations, potentially improving diagnostic accuracy[61]. Moreover, for pediatric patients, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Hepatology Committee proposed in 2018 a dedicated scoring system tailored to autoimmune liver diseases in children, aiming to address age-specific diagnostic challenges[34].
TREATMENT OF AIH
The primary goal of AIH management is to achieve complete biochemical, clinical, and histological remission. Successful treatment reduces disease-related morbidity and mortality, prevents progression to end-stage liver disease, and decreases the risk of hepatocellular carcinoma and the need for liver transplantation[62]. Long-term immunosuppression is often required, as only a minority of patients achieve sustained remission following treatment withdrawal[48]. Immunosuppressive therapy is recommended for all patients with active disease, including those with advanced fibrosis or compensated cirrhosis[10]. Treatment should be individualized according to disease activity, comorbidities, and tolerance. Predniso(lo)ne in combination with azathioprine remains the standard first-line regimen, while mycophenolate mofetil is a widely accepted alternative in patients intolerant to or unresponsive to azathioprine[51]. In our patient, predniso(lo)ne was initiated as induction therapy; however, after hospital discharge, budesonide (9 mg daily) was introduced. Although budesonide is not considered a first-line agent in current guidelines, its favorable pharmacokinetics, including a higher first-pass metabolism and reduced systemic exposure, made it an appropriate option in this case[10,63]. The general treatment algorithm is summarized in Figure 6.
Figure 6 Simplified algorithm of first-line and subsequent therapeutic management in autoimmune hepatitis (according to European Association for the Study of the Liver Clinical Practice Guidelines, 2025).
1Low-dose predniso(lo)ne monotherapy can be suggested only in patients with mild disease who achieved complete biochemical response and are intolerant to both azathioprine and mycophenolate mofetil. AZP: Azathioprine; MMF: Mycophenolate mofetil; CBR: Complete biochemical response; TG: Thioguanine; TGN: Thioguanine nucleotides; MMP: Methylmercaptopurine.
Therapeutic response should be monitored biochemically, aiming for complete normalization of aminotransferases and IgG within six months. In cases of insufficient response or intolerance, adherence and drug metabolite levels should be assessed before switching to second-line options[10]. Because AIH is a chronic and relapsing disease, most patients require long-term maintenance therapy with azathioprine or mycophenolate mofetil, either as monotherapy or combined with low-dose corticosteroids[48]. A trial of treatment withdrawal may be considered only in patients who have maintained stable remission on low-dose therapy for at least two years; however, relapse occurs in the majority, and further withdrawal attempts are generally discouraged[10]. Long-term corticosteroid therapy is associated with metabolic and bone complications. Therefore, patients should ensure adequate calcium intake and receive vitamin D supplementation as part of routine management to mitigate the risk of osteoporosis and other steroid-related adverse effects[51].
CONCLUSION
The onset of AIH due to acute hepatitis A is rare, but this etiology of liver inflammation should be considered in patients who have recently had hepatitis A, as timely and correctly targeted diagnosis will enable appropriate treatment to prevent the progression of liver disease.
Peer review: Externally peer reviewed.
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Specialty type: Gastroenterology and hepatology
Country of origin: Poland
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P-Reviewer: Zhang JH, Professor, China S-Editor: Bai Y L-Editor: A P-Editor: Zhang YL
