Liver & intrahepatic bile ducts

• Antibody mediated immune injury to liver allografts with short and long term consequences
• 3 distinct subtypes:
  • Hyperacute rejection (rare / mostly eliminated)
  • Acute antibody mediated rejection (aAMR)
  • Chronic active antibody mediated rejection (cAMR), see separate section

• DSA are associated with:
  • Decreased 5 year graft and patient survival
  • Increased incidence of TCMR and plasma cell rich rejection
  • Increased incidence of allograft fibrosis and chronic rejection (Am J Transplant 2014;14:779, J Immunol Res 2017;2017:3234906)

• Hyperacute rejection:
  • Portal edema, necrosis, neutrophilic infiltration and ductular reaction
  • Platelet fibrin thrombi in sinusoidal spaces, portal veins and central veins
  • Hepatocyte necrosis, hemorrhage and (if untreated) confluent necrosis
  • Necrotizing arteritis
• Acute antibody mediated rejection:
  • Microvascular injury with endothelial swelling, dilated capillaries and inlet venules and marginating leukocytes (eosinophils, neutrophils, monocytes, lymphocytes, macrophages)
  • Ductular reaction and cholestasis
  • Arteritis
  • May coexist with TCMR
• Histopathologic lesions are scored based on criteria described by the Banff working group (Am J Transplant 2016;16:2816):

h score	Histologic criteria
h score 1	Portal microvascular endothelial cell enlargement (portal veins, capillaries and inlet venules) involving a majority of portal tracts with sparse microvasculitis defined as 3 - 4 marginated or intraluminal monocytes, neutrophils or eosinophils in the maximally involved capillary with generally mild dilation
h score 2	Monocytic, eosinophilic or neutrophilic microvasculitis / capillaritis, defined as at least 5 - 10 leukocytes marginated or intraluminal in the maximally involved capillary, prominent portal or sinusoidal microvascular endothelial cell enlargement involving a majority of portal tracts or sinusoids, with variable but noticeable portal capillary and inlet venule dilatation and variable portal edema
h score 3	As above, with marked capillary dilatation, marked microvascular inflammation (10 or more marginated or intraluminal leukocytes in the most severely affected vessels), at least focal microvascular disruption with fibrin deposition and extravasation of red blood cells into the portal stroma or space of Disse (subsinusoidal space)

• Plasma cell rich rejection (de novo autoimmune hepatitis / plasma cell hepatitis) must meet criteria 1 and 3, criterion 2 is desirable (Am J Transplant 2016;16:2816):

	Criteria for plasma cell rich rejection
1	Plasma cell rich (> 30%) portal or perivenular infiltrates with easily identifiable interface and perivenular necroinflammatory activity; in most cases rejection activity index (RAI) score ≥ 5/9
2	Lymphocytic cholangitis is usually present but not required for diagnosis
3	Original disease other than autoimmune hepatitis

• C4d on paraffin tissue is a successful method for screening and diagnosing AMR in liver allografts (Hum Pathol 2018;73:144)
• To consider a portal tract positive, C4d has to be deposited in > 50% of the circumference of portal microvascular endothelium (portal vein and capillaries)
• C4d immunohistochemistry (performed on paraffin tissue) is scored based on criteria described by the Banff working group (Am J Transplant 2016;16:2816):
  
  

  C4d score	Criteria
  0	No C4d deposition in portal microvasculature
  1	Minimal: < 10% of portal tracts
  2	Focal: 10 - 50% portal tracts
  3	Diffuse: > 50% of portal tracts; often with extension; often with extension   into inlet venules and periportal sinusoids

  
  
• IgG4 positive plasma cells are increased in plasma cell rich variant

A 60 year old woman, 2 months post living donor liver transplantation from her son presented with jaundice, elevated transaminases and elevated bilirubin. A biopsy showed moderate T cell mediated rejection (TCMR) and the patient received steroids with no significant improvement. Assessment of pretransplant workup showed that the patient is sensitized and had a positive crossmatch. Posttransplant workup showed persistent Donor specific antibodies (multiple specificities, sum MFI 36,928). Imaging studies showed intact biliary tree and normal vascular flow. A repeat biopsy showed capillaritis, portal edema and focal luminal arteritis. According to Banff criteria, what else is needed to establish a definite diagnosis of acute antibody mediated rejection (aAMR)?


1. Banff criteria is met, the patient can be diagnosed with acute antibody mediated rejection (aAMR) and no additional requirements are needed
2. Diffuse C4d uptake by portal microvasculature (C4d score 3)
3. IgG4 staining and quantification of positive plasma cells
4. Presence of central perivenulitis and cholestasis

B. Diffuse C4d uptake by portal microvasculature. The patient otherwise met all criteria for a diagnosis of acute antibody mediated rejection (aAMR): 1) Evidence of histopathologic damage (capillaritis), 2) positive donor specific antibody (DSA), 3) reasonable exclusion of other causes by available diagnostic modalities (e.g. imaging) and finally 4) diffuse C4d uptake is needed to complete the criteria and establish the diagnosis. Increased IgG4 positive cells are seen in plasma cell rich rejection and are not part of the criteria in diagnosis of acute antibody mediated rejection (aAMR) or plasma cell rich rejection (Am J Transplant 2013;13:2966). Central perivenulitis and cholestasis can be seen with TCMR, aAMR and cAMR and are not part of the criteria. Central perivenulitis occurs most commonly with portal inflammatory changes but can also occur as an isolated lesion (Histopathology 2020;76:822).

Comment Here

Reference: Acute antibody mediated rejection including hyperacute rejection

A 65 year old man underwent liver transplant for Hepatitis C virus (HCV) induced cirrhosis with prior history of interferon treatment. The patient's posttransplant history was complicated by two episodes of early T cell mediated rejection (TCMR). The patient is now 2 years posttransplantation and presents with allograft dysfunction. A biopsy showed portal inflammation with mild cholangitis, interface activity and central perivenulitis. Plasma cells were visibly abundant and constituted about 45% of the inflammation. Hepatitis C virus (HCV) RNA was undetectable. What is the correct diagnosis?


1. Idiopathic posttransplantation hepatitis
2. Plasma cell rich rejection
3. Recurrent autoimmune hepatitis
4. Recurrent Hepatitis C virus (HCV)

B. Plasma cell rich rejection. The patient was transplanted for Hepatitis C virus (HCV) and treated with interferon (primary disease other than autoimmune hepatitis). While recurrent Hepatitis C virus (HCV) is a major differential, the central perivenulitis and negative RNA test essentially rule it out. Idiopathic posttransplantation hepatitis is a broad term used to describe chronic hepatitis changes in patients without clinical or serologic evidence of viral hepatitis, autoimmunity or drug induced liver injury (Liver Transpl 2001;7:285). More recently, however, late onset T cell mediated rejection (TCMR) and chronic active acute antibody mediated rejection (aAMR) have been identified as causes of chronic allograft inflammation and fibrosis (Gastroenterology 2018;155:1838, Liver Transpl 2016;22:1593, Liver Transpl 2009;15:S19, Liver Transpl 2018;24:897).

Comment Here

Reference: Acute antibody mediated rejection including hyperacute rejection