Liver & intrahepatic bile ducts

• Criteria and categories for the diagnosis of cAMR were defined by the Banff working group (Am J Transplant 2016;16:2816)

Probable chronic active AMR (all 4 criteria must be met)
1	Histopathologic evidence of injury consistent with cAMR (both required): Otherwise unexplained and at least mild mononuclear portal or perivenular inflammation with interface or perivenular necroinflammatory activity At least moderate portal / periportal, sinusoidal or perivenular fibrosis; see Liver allograft fibrosis score below
2	Recent evidence of circulating HLA DSA in serum samples
3	At least focal C4d positive (> 10% portal tract microvascular endothelia); see Acute AMR for C4d scoring
4	Reasonable exclusion of other insults that might cause a similar pattern of injury
Possible chronic active AMR
1	As above but C4d staining is negative or minimal (criteria 1, 2 and 4 met)

• Criteria are intended to be stringent to prevent overdiagnosis and do not include more recently described lesions (see Microscopic description); as more lesions are described, the criteria will likely be updated
• Banff suggests that liver allograft fibrosis scoring be performed in 3 separate compartments (portal, sinusoidal and perivenular) according to Venturi et al. (Am J Transplant 2012;12:2986)

Liver allograft fibrosis semiquantitative scoring system by Venturi et al. (Am J Transplant 2012;12:2986)

Compartment / score	0	1	2	3
Portal tracts	No fibrosis	Nonexpanding fibrosis in less than 50% of portal tracts	Fibrosis in more than 50% of portal tracts or expansion into short fibrous septa into periportal parenchyma	Marked expansion of most or all portal tracts with portal to portal or portal to central bridging fibrosis with or without occasional nodules
Sinusoids (zones 1 and 2)	No fibrosis	Little fibrosis with thin focal collagen deposits involving less than 50% of sinusoids	Little fibrosis with thin diffuse collagen deposits involving more than 50% of sinusoids or thicker but focal fibrosis in less than 50% of sinusoids	Thick, marked and diffuse sinusoidal fibrosis
Centrilobular vein	No fibrosis	Circular perivenular fibrosis involving less than 50% of central veins without invasion into the perivenular parenchyma	Circular perivenular fibrosis in more than 50% of central areas or expansion into short fibrous septa into perivenular parenchyma	Marked centrilobular fibrosis with bridging to other central or portal areas

• Scores from each compartment are added for a total score out of 9

Contributed by Mohamed El Hag, M.D., M.S.

• Inflammation (Clin Transplant 2018;32:e13227, Liver Transpl 2016;22:1593, Liver Transpl 2018;24:897):
  • Chronic hepatitis pattern of mononuclear inflammation with interface hepatitis or lobular and perivenular inflammation
  • Perivenulitis
• Vascular changes (Pediatr Transplant 2018; 22:e13124, Am J Transplant 2018;18:1534):
  • Obliterative portal venopathy with nodular regenerative hyperplasia-like changes
  • Obliterative arteriopathy or isolated arterial "V" lesions (age inappropriate arterial fibrointimal hyperplasia with no T cell mediated rejection) with or without intimal inflammation arterial lesions are associated with subsequent T cell mediated rejection (TCMR), graft failure and C4d positivity; most C4d positive cases show additional histologic features encountered in cAMR such as portal and perivenular inflammation (rejection activity index / RAI 1 - 2) and at least moderate periportal, perivenular or sinusoidal fibrosis (Am J Transplant 2018;18:1534)
• Bile duct changes (Liver Transpl 2018;24:897):
  • Biliary epithelial senescence and duct loss may be seen but at lower rates
• Distinct fibrosis patterns (Am J Transplant 2016;16:603, Transplantation 2017;101:2062, Clin Transplant 2018;32:e13227, Liver Transpl 2016;22:1593, Liver Transpl 2018;24:897):
  • Dense acellular portal collagen deposition: portal collagenization
  • Distinct subsinusoidal and perivenular fibrosis
  • Focal nodular hyperplasia-like changes: usually without the map-like glutamine synthetase staining pattern or dystrophic vasculature usually seen in classic focal nodular hyperplasia lesions

Contributed by Mohamed El Hag, M.D., M.S.

Banff criteria for the diagnosis of probable chronic active antibody mediated rejection include

1. Cholangitis and bile duct inflammation
2. Ductopenia
3. Focal to diffuse C4d uptake
4. Microvasculitis with dilated portal capillaries and marginating leukocytes
5. No to minimal allograft fibrosis

C. Focal to diffuse C4d uptake. Criteria for the diagnosis of chronic active antibody mediated rejection include presence of at least focal C4d uptake in addition to histologic features (at least mild necroinflammatory activity and moderate fibrosis). While microvasculitis with dilated portal capillaries can be seen with chronic active antibody mediated rejection, it is a feature seen with acute antibody mediated rejection. It is important to keep in mind that acute antibody mediated rejection may overlap with chronic active antibody mediated rejection. Cholangitis and bile duct inflammation are components of T cell mediated rejection rather than antibody mediated rejection. Classic chronic rejection is characterized by ductopenia; however, the concept of chronic rejection is evolving as its pathophysiology is further characterized.

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Reference: Liver - Chronic antibody mediated rejection

An isolated arterial "V" lesion is defined as age inappropriate arterial fibrointimal hyperplasia with or without associated inflammation without the presence of T cell mediated rejection. What is its significance in liver allografts?

1. Almost all are negative for C4d staining
2. It is not associated with T cell mediated rejection
3. It is only significant in kidney allografts and has no significance in liver allografts
4. It suggests underlying chronic active antibody mediated rejection

D.Isolated arterial lesions are rarely encountered in liver allografts and until recently their clinical significance was not known. A recent series of cases showed that isolated arterial "V" lesions are associated with subsequent T cell mediated rejection, graft failure and C4d positivity. The majority of C4d positive cases also showed additional histologic features encountered in chronic active antibody mediated rejection such as portal and perivenular inflammation (rejection activity index / RAI 1 - 2) and at least moderate periportal, perivenular or sinusoidal fibrosis (Am J Transplant 2018;18:1534).

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Reference: Liver - Chronic antibody mediated rejection