Graft-versus-host disease after liver transplantation: A global review of pathogenesis, diagnosis, and treatment strategies

Graft-versus-host disease (GVHD) following liver transplantation (LT) (GVHD-LT) is a rare but highly lethal complication, occurring in 0.1–2 % of recipients with mortality rates exceeding 75 %. GVHD-LT develops when donor-derived lymphocytes transferred within the hepatic allograft recognize recipient tissues as foreign and mount an immune attack, primarily targeting the skin, gastrointestinal tract, and bone marrow while characteristically sparing the donor liver graft itself. This comprehensive review synthesizes current knowledge of GVHD-LT pathogenesis, clinical manifestations, diagnostic approaches, and therapeutic strategies based on systematic literature analysis of cases reported from 1988 to 2025. Clinical presentation typically occurs 2–12 weeks post-transplant with the classic triad of fever, maculopapular rash, profuse diarrhea, and progressive pancytopenia. Diagnosis relies on tissue biopsy demonstrating characteristic histopathological changes combined with molecular chimerism analysis confirming donor lymphocyte persistence. Risk factors include recipient age > 50 years, hepatocellular carcinoma as underlying disease, and specific donor-recipient immunologic mismatches. Management remains challenging due to the delicate balance required between intensifying immunosuppression to control donor lymphocyte activity while preventing overwhelming infection. Conventional high-dose corticosteroids yield poor outcomes, with emerging therapies including JAK inhibitors, extracorporeal photopheresis, and targeted cytokine blockade showing promise in steroid-refractory cases. The hyperinflammatory state frequently overlaps with hemophagocytic lymphohistiocytosis, requiring specialized therapeutic approaches. Despite therapeutic advances, prognosis remains poor, with sepsis from opportunistic infections representing the leading cause of death. Future directions emphasize the urgent need for risk stratification models, preventive strategies, and multi-institutional collaborative trials to improve outcomes for this devastating post-transplant complication.