Liver & intrahepatic bile ducts

• Alloimmune injury to the allograft driven primarily by effector T cells (with varying accompaniment by monocytes and macrophages), usually occurring > 3 - 6 months posttransplantation with the potential to produce clinically significant, progressive and chronic structural changes that include vascular, biliary, fibrotic and parenchymal remodeling transformation of the liver architecture (Banff Foundation: Banff Liver Group 2022 [Accessed 3 January 2024])
• Leads to worse patient and graft survival after liver transplantation (Arq Bras Cir Dig 2015;28:212)

• ICD-10: T86.41 - liver transplant rejection

Grading descriptors of late onset T cell mediated rejection presenting as isolated central perivenulitis (Hepatology 2006;44:489)

Description	Biopsy findings
Minimal or indeterminate	Perivenular inflammation involving a minority of terminal hepatic veins, with patchy perivenular hepatocyte loss but without confluent perivenular necrosis
Mild	As above but involving most terminal hepatic veins
Moderate	As above, with focal confluent perivenular hepatocyte dropout and mild or moderate inflammation but without bridging necrosis
Severe	As above, with confluent perivenular hepatocyte dropout and inflammation involving most hepatic venules and with central to central bridging necrosis

Banff working group proposed scoring of late TCMR for further development (Banff Foundation: Banff Liver Group 2022 [Accessed 3 January 2024])

Subscore	Component	Contribution	Criteria
Alloimmune activity grade	Portal inflammation	0 - 3	Existing Banff criteria
	Bile duct damage	0 - 3	Existing Banff criteria
	More severe lesion: subendothelial inflammation or central perivenulitis	0 - 4	Banff rejection activity index (RAI) "v" score or Banff 2006 isolated CP score
	Interface hepatitis	0 - 4	Proposed criteria (see below)
Fibrosis stage	Periportal	0 - 3	Venturi: LAFS
	Subsinusoidal	0 - 3
	Perivenular	0 - 3

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• May be asymptomatic and detected on surveillance / protocol biopsies
• Some patients present with fever, malaise, abdominal pain, hepatosplenomegaly and rarely, increasing ascites; because most patients are asymptomatic, TCMR is suspected primarily by an increase in values on liver biochemical tests
• Biochemical tests measuring liver function may show a rise in transaminase levels in cases with more prominent lobular changes, contrasting with the cholestatic profile that is more typically seen in early portal based acute TCMR
• Presence of cholestasis may signify a more severe form of late onset TCMR, which is less likely to be steroid responsive
• Associated increased risk of developing a number of adverse outcomes including further episodes of TCMR and progression to chronic rejection or allograft failure
• References: Clin Transplant 2008;22:316, Transplant Proc 2001;33:1525

Contributed by Nigar Anjuman Khurram, M.D. and Muhamed Elhag M.D.

• Late onset TCMR must be differentiated from recurrent hepatitis B or C and autoimmune hepatitis (AIH)
• Hepatitis B / hepatitis C:
  • Features that suggest rejection rather than viral etiology include
    • More prominent lymphocytic cholangitis
    • Interface hepatitis
    • Perivenular inflammation involving a majority of bile ducts and central veins
    • Low grade or absent lobular and interface necroinflammatory activity
    • Correlation with serum viral nucleic acid and autoantibody studies is essential
• Autoimmune hepatitis:
  • Shows aggressive plasma cell rich interface activity
  • Autoantibodies positivity (ASMA, anti-LKM, ANA, etc.)
  • More prominent lobular necroinflammatory activity

What is late onset T cell mediated rejection usually associated with?

1. Excessive immunosuppression
2. Focal to diffuse C4d uptake
3. Immunosuppression noncompliance
4. No fibrosis of the allograft
5. Old age

C. Immunosuppression noncompliance. Late onset TCMR often presents in patients > 1, 3 or 6 months after transplantation; however, it is mostly believed to present after 6 months of transplantation often as a result of noncompliance with immunosuppressive medications. Answer E is incorrect because late onset TCMR has no negative association with age of the recipient. Answer A is incorrect because excessive immunosuppression would lower immune cell counts, decreasing the risk for T cell mediated rejection but would cause other side effects. Answer B is incorrect because C4d deposition is more commonly seen in vascular walls of portal areas and hepatic sinusoidal walls in cases with antibody mediated rejection. Answer D is incorrect because late onset TCMR is associated with atrophy and fibrosis.

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Reference: Late T cell mediated (cellular) rejection

Per Banff rules, what would perivenular inflammation involving a minority of terminal hepatic veins, with patchy perivenular hepatocyte loss but without confluent perivenular necrosis be regarded as?

1. Mild late T cell mediated rejection
2. Minimal late T cell mediated rejection
3. No rejection
4. Severe late T cell mediated rejection

B. Minimal late T cell mediated rejection. Answer C is incorrect because late onset TCMR can involve minority of terminal hepatic veins and that is considered rejection. Answer A is incorrect because mild late T cell mediated rejection involves most terminal hepatic veins. Answer D is incorrect because severe late T cell rejection shows confluent perivenular hepatocyte dropout with inflammation involving most hepatic venules along with central to central bridging necrosis.

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Reference: Late T cell mediated (cellular) rejection