Late-onset combined immunodeficiency ( is a rare primary immunodeficiency characterized by hypogammaglobulinemia, T-cell lymphopenia, and susceptibility to opportunistic infections. While autoimmune liver involvement has been well documented in common variable immunodeficiency, no association with late-onset combined immunodeficiency has previously been reported. This case represents, to our knowledge, the first pediatric description of autoimmune hepatitis as the initial manifestation of late-onset combined immunodeficiency. We present the case report of a 15-year old North African Arabic Tunisian boy. A 15-year-old boy presented with severe hepatitis, clinically and histologically consistent with seronegative autoimmune hepatitis. Corticosteroid therapy led to clinical improvement and enabled a liver biopsy, which confirmed autoimmune hepatitis. Persistent hypogammaglobulinemia and lymphopenia involving T, B, and NK cells prompted further immunologic evaluation, confirming the diagnosis of late-onset combined immunodeficiency. The disease course was complicated by hepatitis-associated aplastic anemia and hemorrhagic events. Despite hematopoietic stem cell transplantation, the patient died from septic complications. This case highlights the importance of screening for underlying immunodeficiency in adolescents presenting with atypical or seronegative autoimmune hepatitis. Early recognition of late-onset combined immunodeficiency and related complications, such as hepatitis-associated aplastic anemia, is crucial for timely multidisciplinary management and may significantly impact patient outcomes.

Autoimmune hepatitis is an autoimmune liver condition of uncertain etiology. Environmental triggers have been involved in the pathophysiology of the disease. The triggers include viruses, immunizations, and drugs. Since the emergence of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been implicated in the development of various autoimmune diseases. We report the case of a 58-year-old patient who had persistent elevation in liver transaminase levels after COVID-19 infection. After undergoing a liver biopsy, he was diagnosed with seronegative autoimmune hepatitis with an excellent response to steroids. Our case highlights the importance of considering the diagnosis of autoimmune hepatitis in patients with persistent elevation of liver transaminases after COVID-19 infection.

Seronegative autoimmune hepatitis in children is a rare but potentially severe disease, sometimes requiring liver transplantation. This type of hepatitis may be associated with various immunological and hematological disorders, ranging from isolated lymphopenia to aplastic anemia. Precise pathophysiological mechanisms are still unknown, but the role of viruses cannot be excluded, either as directly pathogenic or as triggers, responsible for an inappropriate immune stimulation. Having the impression of an increasing number of seronegative autoimmune hepatitis since the beginning of SARS-CoV-2 pandemia period, we hypothesized that SARS-CoV-2 virus could be an infectious trigger. We conducted a retrospective, observational, descriptive study about children with seronegative autoimmune hepatitis, in a tertiary care center, between 2010 and 2022. Thirty-two patients were included. The overall incidence of seronegative autoimmune hepatitis increased 3.3-fold in 2020-2022, during the SARS-CoV-2 pandemia period (16 patients in 2.8 years) compared with 2010-2019 the pre pandemia period (16 patients in 9 years). Patients' clinical and biochemical liver characteristics did not differ between the two periods. Hematological damages were less severe during the pandemia period. Immunological studies revealed a dysregulated immune response. The initiation of immunosuppressive therapy (corticosteroids ± cyclosporine) was earlier during the pandemia period than before. In cases of undetermined acute hepatitis, an immune-mediated origin should be considered, prompting a liver biopsy. If the histological aspect points to an immune origin, immunosuppressive treatment should be instituted even though autoimmune hepatitis antibodies are negative. Close hematological monitoring must be performed in all cases. The 3.3-fold increase of cases during the SARS-CoV-2 pandemia will need to be further analyzed to better understand the underlying immunological mechanisms, and to prove its potential involvement.

Autoimmune hepatitis (AIH) is a rare, chronic, inflammatory, and necrotic liver disease characterized by the presence of autoantibodies. Its etiology is unknown. It affects 1 in 200 000 people annually in the US and occurs predominantly in women. Its presentation varies from asymptomatic forms to cirrhosis and acute liver failure and its diagnosis is based on the measurement of autoantibodies, such as antinuclear autoantibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti-liver and kidney microsomal antibodies (anti-LKM). 1). 10% of HAIs do not present antibodies, being called seronegative HAI, requiring a liver biopsy for diagnosis. To date the evidence remains limited and different societies have issued suggestions and recommendations. For this reason, we believe it is relevant to carry out a bibliographic review on the subject, capturing in this document the important information for the understanding and management of this pathology. La hepatitis autoinmune (HAI) es una enfermedad inflamatoria y necrótica del hígado, crónica e infrecuente caracterizada por la presencia de autoanticuerpos. Su etiología es desconocida. Afecta a 1 de cada 200 000 personas anualmente en los EE. UU. y se presenta predominantemente en mujeres. Su presentación varía desde formas asintomáticas hasta la cirrosis y falla hepática aguda y su diagnóstico se basa en la medición de autoanticuerpos, como los autoanticuerpos antinucleares (ANA), anticuerpos antimúsculo liso (ASMA) y anticuerpos antimicrosomales de hígado y riñón (anti-LKM-1). El 10% de las HAI no presentan anticuerpos, denominándose HAI seronegativa, necesitando biopsia hepática para el diagnóstico. Hasta la fecha la evidencia sigue siendo limitada y diferentes sociedades han emitido sugerencias y recomendaciones. Por tal motivo creemos relevante realizar una revisión bibliográfica sobre el tema plasmando en este documento la información importante para la compresión y el manejo de esta patología.