Liver & intrahepatic bile ducts
Liver transplantation
Late onset graft injury
Chronic rejection
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PubMed Search: Liver chronic rejection
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Electron microscopy description | Electron microscopy images | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1Cite this page: Bomfim I, Saxena R. Chronic rejection. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverchronicrejection.html. Accessed July 15th, 2024.
Definition / general
- Immunologic injury to the allograft, which usually evolves from severe or refractory acute rejection, leading to irreversible damage to bile ducts and hepatic parenchyma, resulting in graft failure (Hepatology 2000;31:792)
Essential features
- Rare, 2 - 3% percent of liver transplants
- Risk factors: prior episodes of acute / intractable rejection, transplantation for autoimmune diseases
- Poor response to antirejection therapy
- Microscopic features on liver biopsy: senescent changes of biliary epithelium, severe cholestasis, perivenular necrosis, with or without clusters of foamy macrophages
Terminology
- Vanishing bile duct syndrome
- Ductopenic rejection
- Arteriopathic rejection
- Foam cell arteriopathy
ICD coding
- ICD-10: T86.91 - unspecified transplanted organ and tissue rejection
Epidemiology
- Rare; 2 - 3% percent of liver transplants
- Risk factors: prior episodes of acute rejection, intractable acute rejection, donor age > 40 years old, inadequate immunosuppression, cytomegalovirus (CMV) infection (Transplantation 2000;69:2330)
- Transplantation for autoimmune diseases
Pathophysiology
- Exact pathophysiology is not entirely clear but involves both T cell mediated and antibody mediated immune reactions against graft
- Antibody mediated chronic rejection is increasingly recognized
- Inadequate immunosuppression is recognized as a major factor
- Reference: Transplant Proc 1995;27:67
Etiology
- Inadequate immunosuppression
- T cell and antibody mediated immune reactions against graft
Diagrams / tables
Images hosted on other servers:
Algorithm for management of posttransplant complications
Clinical features
- Peak incidence is between 2 and 6 months after liver transplantation
- Nonspecific symptoms: fatigue, abdominal pain, fever
- History of prior episodes of acute / intractable rejection with progressively worsening cholestasis
- Poor response to antirejection therapy
- References: Transpl Int 2010;23:971, Hepatology 2000;31:792
Diagnosis
- Combination of clinical, radiologic, laboratory and histopathologic findings
Laboratory
- Cholestatic biochemistry profile: persistent elevation of gamma glutamyl transferase (GGT) and alkaline phosphatase
- Increased total bilirubin
- Followed by persistently elevated transaminases and eventually by coagulopathy and failure of synthetic function
- Reference: Hepatology 2002;35:639
Radiology description
- Absence of other causes of vascular and biliary obstruction
- Ultrasound (US) grayscale and color Doppler to rule out hepatic artery thrombosis and hepatic artery stenosis (World J Gastroenterol 2014;20:6180)
- Magnetic resonance (MR) cholangiography to better assess biliary tree
Radiology images
Images hosted on other servers:
Hepatic artery stenosis, MCTA
Biliary strictures MR
Prognostic factors
- Early chronic rejection is reversible with prompt and adequate therapy
- Late chronic rejection proceeds to rapid deterioration and allograft failure, often within a year
- 15 - 20% of patients ultimately require retransplantation (World J Gastroenterol 2021;27:7771)
Case reports
- 16 year old girl and 19 year old woman with liver transplants for biliary atresia (Transplant Proc 2023;55:530)
- 40 year old man with liver transplant for hepatitis C virus (Liver Transpl Surg 1996;2:299)
- 55 year old woman with polycystic liver and kidney disease who received a combined liver - kidney transplant (Transplant Proc 2022;54:2784)
Treatment
- Optimization of baseline immunosuppression depends on several variables including recipient renal function, cardiovascular disease, risk of infections and tumors, recurrence of underlying liver disease
- Tacrolimus based regimens
- Conversion from cyclosporine to tacrolimus associated with 70% response rate and graft survival (World J Gastroenterol 2021;27:7771)
- mTOR inhibitor additional options
Gross description
- Allograft appears green and shrunken due to bile stasis and atrophy (Liver Transpl 2006;12:S68)
- Not cirrhotic but firm, as some fibrosis is inevitably present
- Subtle yellow plaques may be seen in large hepatic arteries in some cases on careful observation
- Biliary stricture due to obliterative foam cell arteriopathy and subsequent ischemic cholangiopathy
Microscopic (histologic) description
- Biliary and hepatic arterial changes may or may not coexist (Hepatology 2000;31:792)
- Biliary changes: preferentially involve small bile ducts
- Early changes
- Epithelial damage is seen as senescent, atrophic changes (cytoplasmic eosinophilic transformation, nuclear hyperchromasia, loss of polarity and attenuation or disruption of biliary epithelium) and cholestasis with or without mild lymphocytic inflammation
- Late changes
- Loss of bile ducts
- Ductopenia is a term that requires loss of bile ducts in ≥ 50% portal tracts in a biopsy containing at least 10 portal tracts
- Severe cellular and canalicular cholestasis with no / minimal accompanying ductular reaction
- Loss of bile ducts
- Early changes
- Arterial changes: preferentially involves the larger branches of the hepatic artery, changes not often seen in biopsy
- Foamy macrophages within the lumen of the hepatic artery
- With or without obliteration of vascular lumen by subintimal foam cells and fibrointimal proliferation
- Clusters of foamy macrophages within sinusoids
- Perivenular ischemic necrosis with or without perivenular fibrosis
Microscopic (histologic) images
Contributed by Romil Saxena, M.B.B.S., M.D.
Feathery hepatocytes
Bile duct senescent changes
Obliterative artery lumen
Positive stains
- p21: senescence marker in biliary epithelial cells and periportal and perivenular hepatocytes (Am J Pathol 2001;158:1379)
- CK7 and CK19 to characterize bile duct loss and diagnose ductopenia
Electron microscopy description
- Biliary epithelial cells: degenerative changes in mitochondria and nuclei, cellular disintegration, thickened basement membrane, dense bundles of filaments (Hepatology 1985;5:1083)
Electron microscopy images
Images hosted on other servers:
Thickened membrane basement
Disintegrating mitochondria
Prominent bundles of filaments
Sample pathology report
- Liver, allograft, biopsy:
- Severe cholestasis with marked biliary epithelial damage, suggestive of evolving chronic rejection
- Liver, allograft, biopsy:
- Severe cholestasis with ductopenia, consistent with chronic ductopenic rejection (see comment)
- Comment: Microscopic examination reveals severe cellular and canalicular cholestasis. There is extensive biliary epithelial damage with senescent and atrophic changes. Lymphocytic inflammation and ductular reaction are minimal / not seen.
Differential diagnosis
- Recurrent primary biliary cholangitis:
- Presence of granulomatous cholangitis
- Absence of senescent epithelial changes
- Recurrent primary sclerosing cholangitis:
- Presence of fibro-obliterative lesions, bile duct scars
- Absence of senescent changes
- Ischemic cholangiopathy:
- Portal edema, fibrosis, bile ductular reaction
- Absence of senescent changes
- Biliary tract obstruction:
- Portal edema, fibrosis, bile ductular reaction
- Absence of senescent changes
Board review style question #1
A 44 year old patient with a history of orthotopic liver transplant 6 months ago due to primary sclerosing cholangitis as well as several previous episodes of acute cellular rejection developed jaundice and presented with rising transaminases and canalicular enzymes. Liver biopsy was performed to rule out biliary obstruction. What finding on a liver biopsy would be most supportive of ductopenic chronic rejection?
- Activated lymphocytes in portal tracts
- Hemorrhagic necrosis and vascular thrombi
- Necrosis of hepatocytes with associated neutrophilic infiltration
- Senescent and atrophic changes in biliary epithelium and portal tracts lacking bile duct
Board review style answer #1
D. Senescent and atrophic changes in biliary epithelium and portal tracts lacking bile duct. Biliary damage characterized by senescent epithelial changes and loss of bile ducts in > 50% of portal tracts are hallmarks of chronic ductopenic rejection. Answer C is incorrect because necrosis of hepatocytes and associated neutrophilic infiltrate are not features of chronic rejection. These findings are often associated with reperfusion injury.
Answer B is incorrect because hemorrhagic necrosis and vascular thrombi are not features of chronic rejection; these have been associated with antibody mediated rejection. Answer A is incorrect because activated lymphocytes in portal tracts are not features of chronic rejection. Activated lymphocytes in portal tracts are most often associated with acute T cell mediated rejection.
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Reference: Chronic rejection
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Reference: Chronic rejection
