Chronic rejection after liver transplantation: Opening the Pandora’s box

Table 1 Histological definition and clinical features of chronic rejection

	T cell-mediated chronic rejection	Antibody-mediated chronic rejection
Histological definition (according to the 2016 Banff Group[1])	Presence of bile duct atrophy/pyknosis affecting the majority of bile ducts; OR Bile duct loss in more than 50% of the portal tracts; OR Foam cell obliterative arteriopathy	At least mild mononuclear portal and/or perivenular inflammation with interface and/or perivenular necroinflammatory activity; AND At least moderate portal/periportal, sinusoidal or perivenular fibrosis; AND Positive C4d staining in at least 10% of the portal tracts; AND Circulating DSAs in serum samples collected within 3 months of biopsy; AND Other causes have reasonably been excluded
Incidence	2%-5%	Unknown
Risk factors	(1) History of T cell-mediated acute rejection episodes; (2) Autoimmune aetiology of the primary liver disease; (3) Non-compliance with IS therapy; (4) Cyclosporine-based IS regimens as opposed to tacrolimus-based regimens; (5) Previous re-transplantation for rejection; (6) Donor/recipient gender mismatch; and (7) Donor age greater than 40	(1) Donor-specific antibodies (especially de novo anti-HLA class II antigens); (2) Inadequate IS (cyclosporine regimens or low CNI concentrations); (3) MELD score > 15; (4) Young age at transplantation; and (5) Re-transplantation
Clinical implications	15%-20% graft loss	Increased fibrosis and graft failure in an unknown percentage of patients

CNI: Calcineurin inhibitors; DSA: Donor-specific antibody; IS: Immunosuppressive; HLA: Human leukocyte antigen; MELD: Mayo End-Stage Liver Disease.