Acute Rejection of Transplanted Liver
Definition
- Immunological reaction to foreign (donor) tissue components, especially bile duct epithelium and endothelium
Alternate/Historical Names
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 LiverDefinition
- 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
- 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
- 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 |
Clinical
- 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
Lists
Pathologic Processes Associated with Transplanted Liver
Bibliography
- 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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