Liver & intrahepatic bile ducts
Liver transplantation
Late onset graft injury
Chronic antibody mediated rejection

Deputy Editor-in-Chief: Raul S. Gonzalez, M.D.
Mohamed El Hag, M.D., M.S.

Minor changes: 18 February 2021

Copyright: 2020-2021,, Inc.

PubMed Search: Chronic antibody mediated rejection[title]

Mohamed El Hag, M.D., M.S.
Page views in 2020: 84
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Cite this page: El Hag M. Chronic antibody mediated rejection. website. Accessed March 3rd, 2021.
Definition / general
Essential features
  • Liver allograft fibrosis
  • Unexplained mononuclear, interface or perivenular inflammation / necroinflammatory activity
  • Evidence of circulating donor specific antibodies
  • C4d deposition
ICD coding
  • ICD-10: T86.41 - Liver transplant rejection
Clinical features
  • Mostly asymptomatic with normal or near normal liver function tests (Liver Transpl 2016;22:1593)
  • Mostly detected on protocol biopsies

 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
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
  • Evidence of DSA (HLA or non-HLA); mostly HLA class II DQ
  • Negative testing for hepatitis B, C and E (Liver Transpl 2016;22:1593)
  • Serum markers of fibrosis have been proposed, including hyaluronic acid and embryonic liver fodrin (Liver Transpl 2016;22:1593)
  • No serum markers of inflammation are currently recommended
Radiology description
Case reports
  • Retransplantation for failed allografts
Gross description
  • Explanted livers show a fibrotic multinodular and rubbery cut surface
  • May show a green cholestatic cut surface
Gross images

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

Explanted liver allograft

Microscopic (histologic) description
Microscopic (histologic) images

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

Chronic hepatitis pattern

Portal venopathy

Arterial lesions


Portal collagenization


Positive stains
  • Focal to diffuse C4d uptake by portal microvasculature (portal veins and capillaries) that may extend to inlet venules
Sample pathology report
  • Allograft liver, explant:
    • Chronic hepatitis, favoring chronic active antibody mediated rejection
      • C4d on paraffin tissue: diffuse uptake by portal microvasculature (portal vein and capillaries) and inlet venules
      • Strong DSA present (antidonor DQ)
    • Obliterative arteriopathy
    • Portal venopathy
    • Allograft fibrosis score (Am J Transplant 2012;12:2986):
      • Portal: 3/3
      • Central: 3/3
      • Sinusoidal: 1/3
Differential diagnosis
Board review style question #1

Banff criteria for the diagnosis of probable chronic active AMR 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
Board review style answer #1
C. Focal to diffuse C4d uptake. Criteria for the diagnosis of cAMR 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 cAMR, it is a feature seen with acute AMR. It is important to keep in mind that acute AMR may overlap with cAMR. Cholangitis and bile duct inflammation are components of T cell mediated rejection rather than AMR. 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: Chronic antibody mediated rejection
Board review style question #2

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

  1. Almost all are negative for C4d staining
  2. It is not associated with TCMR
  3. It is only significant in kidney allografts and has no significance in liver allografts
  4. It suggests underlying cAMR
Board review style answer #2
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 TCMR, graft failure and C4d positivity. The majority of C4d positive cases also showed additional histologic features encountered in cAMR such as portal and perivenular inflammation (RAI 1-2) and at least moderate periportal, perivenular or sinusoidal fibrosis (Am J Transplant 2018;18:1534).

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Reference: Chronic antibody mediated rejection
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