Case Presentation: Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare immune-dysregulation disorder caused by defective apoptosis, most often from FAS-pathway mutations. Impaired lymphocyte deletion leads to chronic non-malignant lymphoproliferation, elevated double-negative T cells, and immune-mediated cytopenias. While hematologic autoimmunity is characteristic, hepatic and dermatologic manifestations are seldom described. We report a decade-long case of ALPS complicated by autoimmune hepatitis and bullous pemphigoid, emphasizing diagnostic reasoning and individualized immunosuppression.A 26-year-old male with genetically confirmed ALPS (FAS c.332A>G, p.H11R; 6.7% double-negative T cells) had been followed since 2012 for anemia and splenomegaly (initial 14.7 cm). Between 2014–2020, splenomegaly progressed to 25 cm with chronic leukopenia and thrombocytopenia but no lymphadenopathy. In 2018, he developed acute transaminitis, with ALT/AST in the ~500 U/L range and bilirubin ~6 mg/dl. Infectious (hepatitis A/B/C, EBV, CMV), metabolic (Wilson disease, hemochromatosis, α1-antitrypsin deficiency), and drug-induced causes were excluded. Autoimmune serologies (ANA, anti-LKM, AMA) were negative, and IgG was normal. Liver biopsy demonstrated portal chronic inflammation with eosinophils and mild periportal fibrosis, compatible with autoimmune hepatitis–like injury despite negative serologies.Sirolimus was started for ALPS-related cytopenias but later discontinued when liver enzymes worsened and the patient developed pruritic blistering lesions consistent with bullous pemphigoid. In late 2023, sirolimus was replaced with mycophenolate mofetil. Over the next year, liver enzymes improved with ALT decreased ~160 U/L; AST ~85 U/L, bilirubin 2.4 mg/dL, skin lesions resolved, and spleen size decreased to 22 cm. He remains clinically stable on mycophenolate.
Discussion: This case illustrates the broad clinical spectrum of ALPS, in which defective Fas-mediated apoptosis promotes the persistence of autoreactive lymphocytes and predisposes to delayed multi-organ autoimmunity. Although hepatic involvement has been described, autoimmune hepatitis is rare, and bullous pemphigoid is exceptionally uncommon, with only isolated cases reported. Rigorous exclusion of infectious, metabolic, and medication-related etiologies was essential before attributing hepatic injury to ALPS-associated immune dysregulation.Sirolimus is typically first-line for ALPS-related cytopenias, but it may not adequately address extra-hematologic manifestations. In this patient, mycophenolate successfully controlled hepatic inflammation and dermatologic autoimmunity while reducing steroid exposure. His marked improvement highlights the importance of individualized immunosuppression, as organ-specific responsiveness can vary widely.
Conclusions: ALPS can evolve into multi-organ autoimmunity involving hepatic and cutaneous systems long after hematologic stabilization. Thorough evaluation to exclude secondary causes is crucial before diagnosing ALPS-associated autoimmune hepatitis. Mycophenolate may offer superior systemic disease control when sirolimus is inadequate, however long-term surveillance is critical, particularly when rare hepatic or dermatologic complications emerge in ALPS.