自己免疫性肝炎

BACKGROUND: Psoriasis is a chronic, autoimmune skin disorder that can be associated with systemic comorbidities, including psoriatic arthritis (PsA). The coexistence of psoriasis, PsA, and autoimmune hepatitis (AIH) is uncommon and may present diagnostic and therapeutic challenges. This case report highlights a patient with psoriasis who developed both PsA and AIH without prior immunosuppressive therapy. CASE PRESENTATION: A 57-year-old Palestinian woman with longstanding plaque psoriasis presented with worsening skin lesions, progressive arthralgia involving both knees and ankles, chronic inflammatory low back pain, and persistently abnormal liver biochemistry. She had been diagnosed with psoriasis at age 49, which had been resistant to various treatments, including topical corticosteroids and phototherapy. One year before presentation, the patient developed progressive arthralgia, particularly in the knees, ankles, and lower back. Physical examination revealed swollen joints and limited range of motion. Laboratory tests indicated elevated liver enzymes, and autoimmune panel results were positive for antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), raising suspicion for autoimmune hepatitis. A liver biopsy confirmed type 1 AIH, characterized by lymphocytic infiltration and plasma cell predominance. Cyclosporine 100 mg daily was initiated, atorvastatin was discontinued, and the patient was monitored clinically and biochemically. After 6 weeks, psoriasis severity improved markedly, joint symptoms decreased, and liver enzyme levels normalized. No treatment-related adverse effects were documented during the reported follow-up period. CONCLUSIONS: This case highlights the importance of considering autoimmune hepatitis in patients with psoriatic disease who develop persistent liver enzyme abnormalities, even in the absence of prior systemic immunosuppressive therapy. A multidisciplinary approach is important in such complex presentations, and cyclosporine may be a useful therapeutic option in selected patients requiring concomitant control of dermatologic, rheumatologic, and hepatic disease.

Liver damage in autoimmune hepatitis (AIH) is perpetrated by T-effector lymphocytes that are not adequately restrained by regulatory T cells (Tregs). The goal of AIH treatment is to control inflammation and induce disease remission through administration of immunosuppressive drugs including corticosteroids, azathioprine, and, in difficult-to-treat cases, mycophenolate mofetil or tacrolimus (TAC). Despite TAC being a potent immunosuppressant, its use has been hampered by a narrow therapeutic window and systemic toxicity. In this study, we have tested the effects of lipid-core nanoformulations encapsulating TAC (NC-TAC) as a novel drug delivery system that would enable potentially favorable immunomodulatory effects compared with unencapsulated TAC. NC-TAC properties were assessed in vitro, in CD4 T cells and Tregs isolated from the peripheral blood of AIH patients and controls; and in vivo through a model of T cell-mediated liver injury induced by Concanavalin-A (Con-A) in NOD/scid/gamma mice, pre-emptively reconstituted with human CD4 T lymphocytes. Compared to unencapsulated TAC, NC-TAC favored a regulatory phenotype in CD4 T cells of AIH patients, enhanced the suppressive function and preserved AIH Treg phenotype in the presence of an inflammatory stimulus. Systemic administration of NC-TAC ameliorated liver injury in vivo, as indicated by decreased ALT levels, reduced lymphocyte infiltration on histology, and an increased frequency of intrahepatic CD4+FOXP3+ lymphocytes. NC-TAC could therefore be considered as a novel drug delivery system to be possibly explored for the treatment of AIH, having a beneficial immunomodulatory profile and effectively favoring Treg immune responses.

BACKGROUND: Fulminant hepatitis is a rare but highly lethal complication associated with various drugs, including antithyroid thionamides used for hyperthyroidism. While propylthiouracil (PTU) is more commonly linked to severe hepatotoxicity, methimazole can also cause acute liver failure and, rarely, bone marrow suppression such as aplastic anemia or agranulocytosis. Drug-induced liver injury accounts for a significant proportion of acute liver failure cases requiring transplantation, with antithyroid drugs occasionally implicated. The pathogenesis is thought to be immune-mediated and potentially dose-dependent, with cross-reactivity between thionamides. Simultaneous occurrence of severe hepatotoxicity and aplastic anemia is exceptionally rare, particularly with methimazole. CASE REPORT: A 37-year-old man with Graves' disease, on methimazole for 4 years without recent follow-up, presented in February 2024 with jaundice, choluria, and acholic stools. Investigations revealed hyperbilirubinemia, elevated transaminases, negative viral/autoimmune serologies, and normal imaging. Liver biopsy confirmed drug-induced injury with ductopenia, portal fibrosis, inflammation, and bilirubinostasis. Methimazole was discontinued. One month later, progressive pancytopenia developed, unresponsive to corticosteroids. Bone marrow biopsy showed hypocellularity consistent with aplastic anemia, requiring transfusions. Liver failure progressed to grade II encephalopathy, bilirubin 30.23 mg/dL (516.93 µmol/L), MELD 29, meeting King's College Criteria. He underwent urgent cadaveric orthotopic liver transplantation on June 13, 2024. Post-transplant, aplastic anemia was managed with erythropoietin, G-CSF, eltrombopag, and transfusions. An opportunistic CMV infection was treated with ganciclovir. Hematopoietic support was eventually discontinued without further transfusions, and the patient was discharged with stable graft and hematological recovery. CONCLUSION: This case illustrates the rare simultaneous occurrence of methimazole-induced fulminant hepatitis and aplastic anemia necessitating liver transplantation. It underscores the challenges in perioperative management of profound pancytopenia and posttransplant complications in such patients. Multidisciplinary care was key to successful outcome, highlighting the need for vigilant monitoring of antithyroid drug therapy and avoidance of cross-use in cases of severe adverse reactions.

RATIONALE: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially life-threatening hypersensitivity reaction. Its occurrence during pregnancy, especially secondary to anti-tuberculous therapy (ATT), is exceedingly uncommon and presents major diagnostic and therapeutic challenges. PATIENT CONCERNS: A 23-year-old pregnant woman (14 weeks gestation) presented with prolonged fever, jaundice, rash with desquamation, and respiratory symptoms while on first-line ATT for pulmonary tuberculosis. DIAGNOSES: Laboratory evaluation revealed severe eosinophilia, deranged liver function, hepatitis E virus co-infection, and autoimmune overlap (systemic lupus erythematosus with antiphospholipid antibody positivity). Based on clinical features and a Registry of Severe Cutaneous Adverse Reactions score of 6, a definite diagnosis of DRESS syndrome was established. INTERVENTIONS: ATT was discontinued, and she was treated with systemic corticosteroids, antihistamines, and topical therapy. Sequential drug challenges confirmed hypersensitivity to all 4 first-line agents, necessitating initiation of bedaquiline, clofazimine, and delamanid. OUTCOMES: The patient showed favorable clinical recovery with improvement in systemic manifestations and stabilization of pregnancy. She was discharged on modified ATT with multidisciplinary follow-up. LESSONS: This case highlights the complexity of diagnosing and managing DRESS in pregnancy, particularly in tuberculosis-endemic regions. Coexisting viral hepatitis and autoimmune disorders may mimic or exacerbate the syndrome, underlining the importance of high clinical suspicion, timely drug withdrawal, and individualized therapy.

Autoimmune hepatitis (AIH) is a chronic progressive liver disease that despite suggestive serum autoantibodies or plasma cell enrichment, remains functionally a diagnosis of exclusion. Whether the broader cellular composition of the liver might enable improved specificity of diagnosis has not been systematically tested. We prospectively recruited patients undergoing a clinically-indicated liver biopsy for suspected AIH and performed single-nucleus RNA sequencing (snRNA-seq) on biopsy tissue to map the cellular landscape of AIH and its diagnostic mimics. Unsupervised clustering on cell-type abundances alone largely separated AIH from non-AIH samples. Among individual populations, a subset of CD8⁺ T-cells marked by high TOX and PD1 expression was the most discriminating feature: its enrichment perfectly distinguished AIH by both snRNA-seq and in situ density (AUC = 1.00), outperforming plasma cell abundance (AUC = 0.83). CD8⁺TOX⁺ T-cell enrichment may therefore be the histologic lesion that marks the diagnosis of AIH.