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Surgical Pathology Criteria

Acute Rejection of Transplanted Liver


  • Immunological reaction to foreign (donor) tissue components, especially bile duct epithelium and endothelium

Alternate/Historical Names

  • Allograft rejection

Diagnostic Criteria

  • Usually occurs within first year post-transplant
    • Most cases during first six months
  • Mixed portal inflammatory infiltrate
    • Eosinophils frequent and relatively specific
  • Intraepithelial lymphocytic bile duct infiltrate
    • Involves interlobular ducts
    • May damage ducts
  • Venous lymphocytic endotheliitis
    • May involve portal or central vein
  • Lobular inflammation and spotty hepatocyte necrosis uncommon
  • Central rejection associated with poorer prognosis
    • Pericentral inflammation and endotheliitis
    • Associated with steroid resistance and evolution to chronic rejection
    • Can evolve to veno-occlusive disease
    • Called parenchymal rejection by some
  • Usually considered to be T cell mediated

Neeraja Kambham MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting : May 9, 2007

Variant: Hyperacute Rejection of Transplanted Liver


  • Rejection associated with pre-formed anti-donor cytotoxic antibodies

Diagnostic Criteria for Hyperacute Rejection:

  • Takes days to develop
  • Confirmed by donor specific antibody titers in recipient's serum
  • Frequently anti-ABO or MHC-I antibodies
  • Graft necrosis
    • Includes parenchyma and portal tracts
  • Fibrin thrombi in vessels
  • Role of C4D staining of liver is unclear
  • Less common than in other solid organ transplants

Supplemental studies

Studies are mostly of use to rule out other processes

  • Viral infection
    • CMV
      • Characteristic nuclear and cytoplasmic inclusions
      • May be in any cell type
    • Adenovirus
      • Smudgy nuclei with inclusions
      • Present in hepatocytes
    • Herpes simplex
      • Intranuclear inclusions in hepatocytes
  • Fungus
    • GMS stain
    • Culture
  • Post-transplant lymphoproliferative disorder (PTLD)
    • CD20 to identify increased large B cells
    • EBV in situ hybridization
  • Chronic rejection
    • Anti-keratin stain to evaluate ductopenia
      • CK7 is best, AE1 also useful, because of low background activity against hepatocytes

Differential Diagnosis

Acute Rejection of Liver Chronic Rejection of Liver
1 week to 1 year post-transplant Presents > 6-12 months post-transplant
Bile duct lymphocytic infiltrate Bile duct loss in at least 50% of portal tracts
No cholestasis unless extensive bile duct damage Centrilobular cholestasis
No hepatocyte swelling Centrilobular hepatocyte swelling
No apoptotic bodies in lobules Scattered apoptotic bodies may be present

Acute Rejection of Liver Preservation / Reperfusion Injury of Transplanted Liver
Mixed portal and/or perivenular infiltrate Lacks perivenular infiltrate
Bile duct lymphocytic infiltrate Neutrophilic pericholangitis and bile ductular proliferation
Endotheliitis Lacks endotheliitis
1 week to 1 year post-transplant Less than 3 weeks post-transplant
Cholestasis absent to mild Centrilobular cholestasis

Acute Rejection

Acute Rejection and

Hepatitis C
Hepatitis C
Endotheliitis prominent Endotheliitis prominent Endotheliitis infrequent
Bile duct damage frequent Bile duct damage frequent Bile duct damage infrequent
Eosinophils frequent Eosinophils frequent Eosinophils few or rare
Steatosis infrequent Steatosis occasional Steatosis occasional
Acidophil bodies absent Acidophil bodies frequent Acidophil bodies frequent
Serum HCV RNA absent Serum HCV RNA present Serum HCV RNA present
Both may show a lymphocytic portal infiltrate, but acute rejection has a mixed infiltrate

Infectious processes in transplanted liver may present clinically or histologically in the differential diagnosis of acute rejection

  • Cytomegalovirus (CMV)
    • Variable features
      • Microabscesses, microgranulomas
      • Lymphocytic portal and sinusoidal infiltrate
      • Hepatocyte ballooning
      • Viral inclusions may be small and/or rare
    • We perform immunoperoxidase stain for CMV when there are microabcesses or prominent hepatocyte necrosis or possible inclusions
      • Even on immunoperoxidase stain inclusions may be small and/or rare
  • Herpes simplex virus
    • Features
      • Nuclear inclusions with ground glass appearance
      • Nuclear chromatin margination
    • We perform immunoperoxidase stain for Herpes when there is prominent hepatocyte apoptosis or possible inclusions
  • Adenovirus
    • Scattered individual or clustered necrotic hepatocytes with smudgy nuclei
      • May be rare and nuclear features may be subtle
    • More common in pediatric patients
    • We perform immunoperoxidase stain for adenovirus when there is prominent hepatocyte apoptosis or possible inclusions
  • Epstein-Barr virus (EBV)
    • Often a reactivation of latent virus
    • Two presentations
      • Systemic viral syndrome with EBV hepatitis
        • Portal tracts and lobules infiltrated by monotonous immunoblasts
      • Post-transplant lymphoproliferative disorder (PTLD)
    • In situ hybridization for EBV is useful for the diagnosis
  • Fungal infections
    • Most often Candida
  • Ascending cholangitis
    • Neutrophils in lumens of interlobular bile ducts
      • Involvement of bile ductules or cholangioles is not sufficient
  • Sepsis
    • Bile ductular proliferation with neutrophilic infiltrate
    • Bile plugs in portal areas


Acute rejection of liver versus recurrence of original disease

  • Recurrences usually seen more than 6-12 months post-transplant
  • Diseases with a significant incidence of recurrence in transplants
    • Autoimmune hepatitis
    • Hepatocellular carcinoma
    • Primary biliary cirrhosis
    • Primary sclerosing cholangitis
    • Viral hepatitis B
    • Viral hepatitis C

Acute Rejection of Liver Bile Duct Obstruction
Mixed infiltrate frequently with eosinophils Eosinophils infrequent
Bile duct lymphocytic infiltrate Bile ductular proliferation with cholestasis and bile plugs, neutrophilic pericholangitis
Endotheliitis Lacks endotheliitis

Acute Rejection of Liver Acute Vascular Anastomotic Problems
Mixed infiltrate frequently with eosinophils No significant inflammation even in preserved parenchyma
No hepatocyte necrosis or infarction Extensive areas of infarction, with or without congestion
Endotheliitis Lacks endotheliitis


  • Lab studies may show hepatocyte damage (AST/ALT) or cholestatic picture (Alkaline Phosphatase, GGR or bilirubin) or both
  • Fever and systemic symptoms may suggest infection
  • Ultrasound doppler study may address vascular anastomosis or bile duct problems
  • Cholangiogram may address bile duct problems

Grading / Staging / Report

Banff Global Assessment

    • Mild
      • Rejection in some portal triads
    • Moderate
      • Rejection in most or all triads
    • Severe (any of the following findings)
      • Centrilobular inflammation and endotheliitis


Pathologic Processes Associated with Transplanted Liver


  • Portmann B, Koukoulis G. Pathology of the liver allograft. Curr Top Pathol. 1999;92:61-105.
  • Jones KD, Ferrell LD. Interpretation of biopsy findings in the transplant liver. Semin Diagn Pathol. 1998 Nov;15(4):306-17.
  • --- Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997 Mar;25(3):658-63.
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