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Surgical Pathology Criteria

Chronic Rejection of Transplanted Liver


  • Consequence of severe chronic immunologic injury to bile duct epithelium (loss of ducts) and endothelium (obliterated arteries)

Alternate/Historical Names

  • Obliterative arteriopathy
  • Foam cell arteriopathy
  • Vanishing bile duct syndrome
  • Ductopenic rejection

Diagnostic Criteria

  • Two types: bile duct loss and obliterative arteriopathy
    • Usually occur together
    • Only one site affected in about 15% of cases
  • Bile duct loss (ductopenia, vanishing bile duct syndrome)
    • At least 50% of portal tracts lack bile ducts
      • Need at least 4-5 complete portal tracts to evaluate
      • Preferably 20 tracts to evaluate
    • Absence of bile ductular proliferation
    • Cholestasis in zone 3 (pericentral)
    • Pericentral hepatocyte ballooning and dropout
    • Due to chronic injury
      • Acute bile duct loss after acute rejection may be reversible
  • Obliterative arteriopathy
    • Requires hepatectomy for diagnosis
      • Occluded arteries due to concentric intimal thickening and lipid rich macrophages
      • Biliary strictures may occur
    • Centrilobular hepatocyte dropout

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

Original posting : May 9, 2007

Supplemental studies

  • Anti-keratin stain to evaluate ductopenia
    • CK7 and AE1 are useful markers because they have 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

Diseases with a significant incidence of recurrence in transplants

  • Autoimmune hepatitis
  • Hepatocellular carcinoma
  • Primary biliary cirrhosis
    • Can be impossible to distinguish from chronic rejection on histology
  • Primary sclerosing cholangitis
  • Viral hepatitis B
  • Viral hepatitis C


  • Usually presents >6-12 months post-transplant
  • Initial symptoms may mimic acute rejection
  • Late features are cholestatic
    • Elevated alkaline phosphatase, GGT

Grading / Report

  • Early chronic rejection
    • Loss of bile ducts in 20-50% of portal tracts
    • Dystrophic changes in >50% of remaining bile ducts
    • Often reversible
  • Late chronic rejection
    • >50% of portal tracts lack bile ducts


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.
  • Banff Working Group; Demetris AJ, Adeyi O, Bellamy CO, Clouston A, Charlotte F, Czaja A, Daskal I, El-Monayeri MS, Fontes P, Fung J, Gridelli B, Guido M, Haga H, Hart J, Honsova E, Hubscher S, Itoh T, Jhala N, Jungmann P, Khettry U, Lassman C, Ligato S, Lunz JG 3rd, Marcos A, Minervini MI, Molne J, Nalesnik M, Nasser I, Neil D, Ochoa E, Pappo O, Randhawa P, Reinholt FP, Ruiz P, Sebagh M, Spada M, Sonzogni A, Tsamandas AC, Wernerson A, Wu T, Yilmaz F. Liver biopsy interpretation for causes of late liver allograft dysfunction. Hepatology. 2006 Aug;44(2):489-501.
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