Table of contents
  1. Learning objectives
  2. Core diagnostic framework
  3. RAI score: what it is and how to use it
  4. Acute T-cell–mediated rejection (acute TCMR)
  5. Late T-cell–mediated rejection (late TCMR)
  6. Plasma cell-rich rejection (PCR)
  7. Chronic ductopenic rejection (CDR)
  8. Acute antibody-mediated rejection (acute AMR)
  9. Chronic antibody-mediated rejection (chronic AMR)
  10. High-yield comparison and clinical pearls
  11. References

GI/Hepatology · Hepatology Topics

Liver Transplant Rejection

Back to GI/Hepatology →Open presenter mode

Liver Transplant Rejection

Liver allograft rejection is best understood as a group of distinct clinicopathologic syndromes, because the timing, biopsy pattern, reversibility, and treatment differ by subtype. In the current AASLD/AST practice guideline, the key rejection phenotypes are acute T-cell–mediated rejection (acute TCMR), late TCMR, plasma cell-rich rejection (PCR), chronic ductopenic rejection (CDR), acute antibody-mediated rejection (acute AMR), and chronic AMR. The most practical principle is that liver biopsy remains the diagnostic gold standard, and for acute TCMR the Rejection Activity Index (RAI) is used to grade severity and guide initial treatment intensity. In the current guideline, late TCMR is treated using the same severity-based framework as acute TCMR, but it is identified mainly by its distinct histologic pattern rather than by a separate late-specific scoring system. [Te et al. 2026]

Learning objectives

  • Classify liver allograft rejection into acute TCMR, late TCMR, PCR, CDR, acute AMR, and chronic AMR. [Te et al. 2026]
  • Explain the typical timing, pathophysiology, and hallmark biopsy findings of each subtype. [Te et al. 2026] [Demetris et al. 2016]
  • Use the RAI correctly: explicitly defined for acute TCMR, while the same severity-based treatment logic is applied to late TCMR. [Te et al. 2026]
  • Build a focused workup for suspected rejection, including when to obtain DSA testing and C4d staining. [Te et al. 2026] [Demetris et al. 2016]
  • Apply guideline-consistent treatment for each rejection phenotype. [Te et al. 2026]

Core diagnostic framework

  • Liver biopsy is the gold standard for diagnosis of rejection. [Te et al. 2026]
  • Peripheral blood biomarkers alone should not be used to diagnose or exclude TCMR or other allograft injury. [Te et al. 2026]
  • Review the pattern of liver test abnormality, synthetic function, drug exposure, and adherence before assuming a specific rejection subtype. [Te et al. 2026]
  • For suspected AMR or mixed rejection, obtain donor-specific antibody (DSA) testing and request C4d staining on biopsy. [Te et al. 2026] [Demetris et al. 2016]
  • If the course is refractory, atypical, or mixed, repeat biopsy and review the case closely with pathology. [Te et al. 2026]
  • Check AST, ALT, ALP, bilirubin, and synthetic function.
  • Review tacrolimus or cyclosporine exposure, recent dose changes, and adherence.
  • Exclude common competing causes of graft dysfunction such as vascular, biliary, infectious, or recurrent disease processes.
  • Obtain liver biopsy when rejection is meaningfully in the differential.
  • Add DSA testing and C4d staining when AMR, PCR with possible AMR overlap, or a mixed rejection phenotype is suspected.
  • If the patient does not respond as expected, obtain a repeat biopsy rather than repeatedly assuming steroid-resistant TCMR.

RAI score: what it is and how to use it

  • The Rejection Activity Index (RAI) is the Banff semiquantitative grading system used for TCMR histology, and the current guideline gives explicit treatment cutoffs for acute TCMR. [Te et al. 2026] [Höroldt et al. 2006] [AASLD Pathology Pearls 2022]
  • It scores 3 histologic domains, each 0 to 3:
    • Portal inflammation
    • Bile duct inflammation/damage
    • Venous endothelial inflammation (endotheliitis)
  • Total score ranges from 0 to 9. [Höroldt et al. 2006] [AASLD Pathology Pearls 2022]
  • In the current guideline:
    • Mild acute TCMR: RAI <4
    • Moderate/severe acute TCMR: RAI ≥4
    • The management figure further separates RAI 4–6 and RAI 7–9 within the moderate/severe range. [Te et al. 2026]
  • Late TCMR does not have a separate late-specific RAI system in the guideline. Instead, it is recognized by a distinct histologic pattern, and the guideline applies the same severity-based treatment approach used for acute TCMR. [Te et al. 2026]
  • Practical bedside question: Do I intensify baseline immunosuppression alone, or do I give high-dose IV steroids now? The guideline uses the same treatment logic for acute and late TCMR, even though late TCMR is identified by pattern rather than a distinct score. [Te et al. 2026]
  • Best wording:
    • RAI is explicitly defined for acute TCMR in the current guideline.
    • Late TCMR is distinguished mainly by its histologic pattern.
    • The guideline applies the same severity-based treatment approach to late TCMR as it does to acute TCMR.
  • Avoid saying:
    • “RAI is only for acute TCMR” → too narrow.
    • “Late TCMR has its own separate RAI system” → not supported by the guideline.

Acute T-cell–mediated rejection (acute TCMR)

  • Typical timing: Usually within the first 3 months after transplant. [Te et al. 2026]
  • Pathophysiology: Recipient T-cell alloimmune activation targets portal tracts, bile ducts, and venous endothelium. The preferred current term is TCMR rather than “acute cellular rejection.” [Te et al. 2026] [Demetris et al. 2016]
  • Biopsy pattern:
    • Diffuse lymphohistiocytic or polymorphous infiltrate in portal or perivenular areas
    • Bile duct inflammation and damage
    • Subendothelial inflammation / endotheliitis of veins
    • Fibrosis uncommon
    • Severity graded with the RAI. [Te et al. 2026] [AASLD Pathology Pearls 2022]
  • Initial workup:
    • Liver biopsy with RAI scoring
    • Review calcineurin inhibitor exposure and adherence
    • Do not rely on blood biomarkers alone
    • Repeat biopsy if the response is suboptimal or the pattern becomes atypical. [Te et al. 2026]
  • Management:
    • Mild (RAI <4):
      • Augment existing immunosuppression
      • If on cyclosporine, switch to tacrolimus if feasible
      • Consider adding an antimetabolite or mTOR inhibitor
    • Moderate/severe (RAI ≥4):
      • IV methylprednisolone 500–1000 mg daily for 1–3 days
      • Follow with steroid taper
      • Augment baseline immunosuppression
      • Consider adding a second immunosuppressive class
    • Infection prophylaxis should be administered concurrently with high-dose corticosteroids
    • If refractory: consider a second corticosteroid course or lymphocyte-depleting therapy. [Te et al. 2026]
  • Recheck drug exposure and adherence.
  • Repeat biopsy to assess for late TCMR, PCR, CDR, AMR, or a non-rejection mimic.
  • Reassess whether the original biopsy reflected mild versus moderate/severe disease.
  • Do not keep giving repeated steroids indefinitely without re-establishing the diagnosis.

Late T-cell–mediated rejection (late TCMR)

  • Typical timing: Defined in the current guideline as >6 months after transplant, though older literature has used other cutoffs. [Te et al. 2026]
  • Pathophysiology: Persistent or renewed cellular alloimmunity, commonly associated with reduced immunosuppression or nonadherence. [Te et al. 2026]
  • Biopsy pattern compared with acute TCMR:
    • Fewer blastic lymphocytes
    • Greater interface and perivenular necroinflammation
    • Less venous endotheliitis
    • Slightly more lobular activity. [Te et al. 2026]
  • How RAI fits:
    • The guideline does not define a distinct late-specific RAI system.
    • Instead, it treats late TCMR using the same severity-based approach as acute TCMR.
    • That means, in practice:
      • lower-grade disease can often be managed with augmentation of baseline immunosuppression
      • more severe disease is treated with high-dose corticosteroids plus augmented immunosuppression. [Te et al. 2026]
  • Clinical course:
    • Response can be less robust than with early acute TCMR
    • Associated with lower graft survival and risk of progression to ductopenic rejection if poorly responsive. [Te et al. 2026]

Plasma cell-rich rejection (PCR)

  • Typical timing: A late rejection phenotype. [Te et al. 2026]
  • Pathophysiology: Plasma cell-predominant alloimmune injury; historically called de novo autoimmune hepatitis, but current guidance classifies it as rejection. [Te et al. 2026]
  • Biopsy pattern:
    • Prominent plasma cells (>30%) in portal or perivenular infiltrates
    • Readily recognizable periportal/interface and/or perivenular necroinflammatory activity
    • Usually involves a majority of portal tracts and/or central veins
    • IgG4-positive plasma cell enrichment in some cases
    • Prevalent central perivenulitis
    • More frequent DSA and portal microvascular endothelial C4d deposition than routine TCMR. [Te et al. 2026]
  • Workup:
    • Biopsy to confirm the plasma cell-rich pattern
    • Consider DSA testing and C4d staining to assess for a coexistent AMR component
    • Evaluate for concomitant TCMR or CDR. [Te et al. 2026]
  • Management:
    • Corticosteroids
    • Augment existing immunosuppression
    • Consider low-dose maintenance prednisone
    • Consider adding an antimetabolite
    • Retransplantation if graft failure develops. [Te et al. 2026]
  • PCR was historically labeled de novo autoimmune hepatitis, but the current guideline classifies it as rejection.
  • Because DSA and C4d are more common in PCR than in routine TCMR, always think about a mixed AMR component.
  • PCR can coexist with TCMR or CDR, so pathology review should explicitly comment on overlap.

Chronic ductopenic rejection (CDR)

  • Typical timing: Usually develops months to years after transplant, often after severe or recurrent rejection. The guideline emphasizes that early vs late CDR is a pathologic distinction, not simply a calendar-based one. [Te et al. 2026]
  • Pathophysiology: Progressive chronic alloimmune injury damages small bile ducts, arteries, and veins, leading to duct loss, arteriopathy, fibrosis, and chronic cholestatic graft dysfunction. [Te et al. 2026]
  • Biopsy pattern:
    • Bile duct atrophy/pyknosis affecting the majority of bile ducts, with or without bile duct loss
    • Foam cell obliterative arteriopathy or bile duct loss in >50% of portal tracts
    • Perivenular fibrosis
    • Features associated with progression include:
      • Centrilobular necroinflammation
      • Hepatocyte necrosis/apoptosis
      • Loss of hepatic artery branches from portal tracts
    • Reversibility is more likely when bile duct loss is <50%. [Te et al. 2026]
  • Workup:
    • Biopsy to quantify duct loss and fibrosis
    • Review prior rejection history and immunosuppression exposure
    • Reassess adherence
    • Determine whether pathology still suggests a potentially reversible early phenotype. [Te et al. 2026]
  • Management:
    • Prevent and treat earlier rejection effectively
    • Augment existing immunosuppression
    • If on cyclosporine, switch to tacrolimus
    • If on tacrolimus, consider MMF or an mTOR inhibitor
    • Steroids and anti-thymocyte globulin are not effective
    • Retransplant evaluation if graft failure progresses. [Te et al. 2026]
  • <50% bile duct loss
  • Less advanced perivenular fibrosis
  • Potentially correctable under-immunosuppression
  • Earlier-stage pathologic changes rather than established advanced ductopenia/arteriopathy

Acute antibody-mediated rejection (acute AMR)

  • Typical timing: Usually an early complication, especially in highly sensitized recipients or ABO-incompatible transplantation, though it can also occur in ABO-compatible grafts. [Te et al. 2026] [Demetris et al. 2016]
  • Pathophysiology: DSA bind graft microvascular endothelium, activate complement, and produce microvascular injury. [Te et al. 2026] [Demetris et al. 2016]
  • When to suspect it: Unexplained graft dysfunction, especially with thrombocytopenia and hypocomplementemia. [Te et al. 2026]
  • Biopsy / pathology:
    • Endothelial hypertrophy
    • Portal capillary dilatation
    • Microvasculitis
    • Periportal edema
    • C4d staining of portal microvascular and/or sinusoidal endothelium
    • DSA are a key part of the overall clinicopathologic assessment. [Te et al. 2026] [Demetris et al. 2016]
  • Workup:
    • Send DSA testing
    • Obtain liver biopsy with C4d staining
    • Review sensitization context
    • Exclude competing causes of graft dysfunction
    • Think of AMR when presumed TCMR is steroid-refractory. [Te et al. 2026] [Cicalese et al. 2024]
  • Management:
    • High-dose corticosteroids
    • Augment existing immunosuppression
    • If appropriate, switch cyclosporine to tacrolimus
    • Consider adding MMF or an mTOR inhibitor
    • Refractory disease: plasmapheresis + IVIG ± anti-CD20 therapy
    • Retransplantation for graft failure. [Te et al. 2026]

Chronic antibody-mediated rejection (chronic AMR)

  • Typical timing: Usually months to years after transplant; often associated with de novo class II DSA, especially HLA-DQ. [Te et al. 2026]
  • Pathophysiology: Persistent antibody-driven endothelial injury results in chronic portal/perivenular inflammation and fibrosis, often in overlap with TCMR or other chronic graft injuries. [Te et al. 2026]
  • Biopsy pattern:
    • Unexplained mononuclear and/or perivenular inflammation
    • Low-grade interface and/or perivenular necroinflammatory activity
    • Moderate portal/periportal sinusoidal and/or perivenular fibrosis
    • Focal C4d staining in >10% of portal tract endothelia
    • Nodular regenerative hyperplasia and obliterative arteriopathy in some cases
    • DSA support the diagnosis, but the diagnosis remains clinicopathologic and requires exclusion of competing liver diseases. [Te et al. 2026]
  • Workup:
    • DSA testing
    • Biopsy with attention to chronic AMR features and C4d
    • Exclude competing etiologies and overlapping chronic rejection phenotypes. [Te et al. 2026]
  • Management:
    • Augment existing immunosuppression
    • Optimize tacrolimus exposure
    • Consider adding a second immunosuppressive class
    • Current guideline states there are insufficient data to recommend anti-CD20 therapy, proteasome-directed therapy, plasma exchange, or IVIG for chronic AMR
    • Retransplantation for graft failure. [Te et al. 2026]

High-yield comparison and clinical pearls

  • RAI is explicit for acute TCMR, but the guideline applies the same severity-based treatment framework to late TCMR. [Te et al. 2026] [Höroldt et al. 2006]
  • Acute TCMR: early, common, classic triad of portal inflammation + bile duct injury + endotheliitis. [Te et al. 2026] [AASLD Pathology Pearls 2022]
  • Late TCMR: more interface/perivenular necroinflammation, less classic endotheliitis, often harder to treat. [Te et al. 2026]
  • PCR: think plasma cells >30%, and actively assess for DSA/C4d because mixed AMR biology is common. [Te et al. 2026]
  • CDR: chronic duct injury and arteriopathy; disease is more reversible when duct loss is <50%. [Te et al. 2026]
  • Acute AMR: think unexplained dysfunction + thrombocytopenia + hypocomplementemia + DSA/C4d. [Te et al. 2026]
  • Chronic AMR: chronic inflammatory-fibrotic injury with DSA-associated clinicopathologic features; evidence for advanced antibody-directed therapy remains limited. [Te et al. 2026]
  • If asked which rejection type has explicit RAI cutoffs in the guideline, the answer is acute TCMR.
  • If asked whether late TCMR is managed using the same severity-based framework, the answer is yes.
  • If the biopsy shows plasma cells >30%, think PCR.
  • If the biopsy shows duct loss and arteriopathy, think CDR.
  • If graft dysfunction is paired with thrombocytopenia, hypocomplementemia, DSA, and C4d, think acute AMR.
  • If chronic inflammatory-fibrotic injury is paired with class II DSA and C4d, think chronic AMR.

References

  • Te et al. 2026 — AASLD/AST Practice Guideline on adult liver transplantation: diagnosis and management of graft-related complications.
  • Demetris et al. 2016 — 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.
  • Höroldt et al. 2006 — Does the Banff rejection activity index predict outcome in patients with early acute cellular rejection following liver transplantation?
  • AASLD Pathology Pearls 2022 — Pathology Pearls: Acute Cellular Rejection.
  • Cicalese et al. 2024 — Antibody-Mediated Rejection in Liver Transplantation: Immuno-Pathological Characteristics and Long-Term Follow-Up.

Last Edited 03/22/2026