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.

Table 2 Histological features of early and late chronic T cell-mediated rejection according to the Banff schema[2]

Structure	Early CR	Late CR
Small bile ducts (< 60 μm)	(1) Degenerative changes involving the majority of ducts: Eosinophilic transformation of the cytoplasm; Increased nucleus: Cytoplasm ratio; nuclear hyperchromasia; uneven nuclear spacing; ducts only partially lined by biliary epithelial cells; and (2) Bile duct loss in < 50% of the portal tracts	(1) Degenerative changes in remaining bile ducts; and (2) Loss in > 50% of the portal tracts
Terminal hepatic venules and zone 3 hepatocytes	(1) Intimal/luminal inflammation; (2) Lytic zone 3 necrosis and inflammation; and (3) Mild perivenular fibrosis	(1) Focal obliteration; (2) Variable inflammation; and (3) Severe (bridging) fibrosis
Portal tract hepatic arterioles	Occasional loss involving < 25% of the portal tracts	Loss involving > 25% of the portal tracts
Other	So-called "transition" hepatitis with spotty necrosis of hepatocytes	Sinusoidal foam cell accumulation and marked cholestasis
Large perihilar hepatic artery branches	Intimal inflammation and focal foam cell deposition without luminal compromise	(1) Luminal narrowing by subintimal foam cells; and (2) Fibrointimal proliferation
Large perihilar bile ducts	Inflammation damage and focal foam cell deposition	Mural fibrosis

CR: Chronic rejection.