HLA One-Way Mismatch As a Definitive Risk Factor for Graft-versus-Host Disease and Mortality in Living Donor Liver Transplantation

BACKGROUND:Graft-versus-host disease (GVHD) is a rare but highly lethal complication following liver transplantation (LT). Human Leukocyte Antigen one-way mismatch (HLAOWMM), defined as a donor possessing alleles entirely contained within the recipient's profile, is a known significant risk factor for GVHD. It is important to compare HLAOWMM with other known risk factors to contextualize its relative importance in clinical decision-making. The role of factors such as recipient age over 65 years, recipient-donor age difference of 22 years or more, and underlying conditions like autoimmune hepatitis and alcoholic liver disease has been explored in other studies. However, HLAOWMM appears to pose a definitive and critical risk when compared to these factors. Hypothesized immunological mechanisms suggest that HLAOWMM-induced GVHD results from donor T-cell activation against host antigens, leading to an aggressive immune response. This study examines a single-center series of liver transplantation cases to evaluate the association between HLAOWMM and the development of GVHD as well as patient mortality. PATIENTS AND METHODS:This was a retrospective analysis of 2398 LT procedures (2357 LDLT) performed at our institution between August 2006 and October 2018. Eight cases involving HLAOWMM were identified. HLAOWMM was defined as the situation in which all donor alleles are present in the recipient, whereas the reverse is not true. Clinical outcomes were analyzed, and a detailed Case 8 is presented to illustrate a recent HLAOWMM case resulting from the accidental omission of pre-transplant HLA testing. RESULTS:Eight patients underwent LT with HLAOWMM, giving an incidence of 3.3 per 1,000 LT procedures (8/2398). Five out of the 8 patients (62.5%) developed confirmed or highly suspected GVHD, resulting in a 100% mortality rate for the entire HLAOWMM cohort. The typical presentation was delayed (median onset 6 weeks post-LT) with cutaneous and mucosal symptoms. The detailed case demonstrated a classic histopathologic pattern of severe interface dermatitis with necrotic keratinocytes on skin biopsy, strongly supporting the diagnosis of acute GVHD. Diagnosis of GVHD was based on a combination of clinical presentations, including skin rash and oral ulcers, laboratory findings, including elevated liver enzymes and cytopenias, and histopathological examination showing interface dermatitis. The presence of apoptotic keratinocytes and basal-layer degeneration was a key histological criterion for diagnosing GVHD in these patients. CONCLUSION:HLAOWMM is a definitive and critical risk factor for GVHD in LDLT, associated with devastating outcomes and uniform mortality in this series. In response to the adverse outcome observed in Case 8, the policy of mandatory HLA matching was formally reinforced and reintroduced as a non-negotiable component of the evaluation protocol for all cases. The exclusion of such high-risk donor-recipient pairs should be established as the standard of care to prevent this fatal complication.