Overall Bottom Line
- From a clinical perspective it is very important to distinguish between “histological” and “clinically relevant” AR.
- The majority of AR episodes occur in the first 6 weeks after LT.
- The diagnosis of AR needs confirmation on liver biopsy.
- The differential diagnosis includes conditions that cause elevation of liver injury tests, jaundice and even fever in the first 3 months after LT.
- The severity of rejection dictates the treatment strategy, particularly in the presence of HCV infection.
Section 1: Background
Definition of disease
- Allograft rejection can be defined as an immunological reaction to the presence of foreign tissue or organ, which has the potential to result in graft dysfunction and failure.
- AR is defined as an inflammation of the allograft, elicited by genetic disparity between the donor and recipient, primarily affecting interlobular bile ducts and vascular endothelium, including portal veins, hepatic venules and occasionally the hepatic artery and its branches.
Disease classification
- Several methods for classifying acute rejection exist:
- Based on the timing of onset after LT:
- early AR in the first 3–6 months after LT.
- late AR after 3–6 months from LT.
- early AR in the first 3–6 months after LT.
- Based on the presence of abnormal liver chemistry tests:
- histological (only histological signs of AR).
- clinically relevant AR (abnormal liver chemistry tests with histological proved AR).
- histological (only histological signs of AR).
- Based on the histological severity of AR (Banff classification).
- Based on steroid treatment response:
- steroid-responsive.
- steroid-resistant.
- steroid-responsive.
- Based on the timing of onset after LT:
Incidence/prevalence
- The cumulative incidence of AR was reported to be as high as 65% by 1 year post-transplantation in the earlier studies after the introduction of CNI.
- The incidence at 3 months has decreased to less than 10% after introduction of interleukin-2 receptor alpha (IL-2Rα) blockers.
- The majority of AR episodes occur in the first 6 weeks post-transplantation.
Etiology
- Acute rejection is the end result of the acute immune response directed against the presence of alloantigens in the transplanted liver, which has the potential to result in endothelial and bile duct damage that may progress to chronic rejection and allograft failure.
Pathology/pathogenesis
- Allograft injury is the result of complex interaction between:
- Hepatic antigen-presenting cells (donor/recipient).
- Recipient helper, effector and regulatory T cells.
- Immune-induced activation of TNF-α superfamily receptors on target cells (mainly cholangiocytes and endothelial cells) that results in bile duct inflammation, endothelial damage and presence of mixed inflammatory infiltrate in the portal areas.
- Hepatic antigen-presenting cells (donor/recipient).
- Direct presentation of alloantigens by donor dendritic cells from the transplanted liver is thought to be the main mechanism responsible for AR.
Predictive/risk factors for early AR
| Risk factor | Relative risk |
|---|---|
| Recipient age (>60 years) | 0.81 (0.73–0.90, CI 95%) |
| Creatinine >2 mg/dL without dialysis | 0.48 (0.29–0.80, CI 95%) |
| Pre-operative AST <40 IU/L vs >200 | 0.52 (0.30–0.90, CI 95%) |
| Pre-operative AST 40–199 IU/L vs >200 | 0.66 (0.48–0.90, CI 95%) |
| Presence of edema immediately pre-transplantation | 0.71 (0.56–0.91, CI 95%) |
| Cold ischemic time ≥15 hours | 1.61 (CI 1.19–2.20, CI 95%) |
| Donor age ≥30 years | 1.27 (1.0002–1.61, CI 95%) |
Section 2: Prevention
- Improved immunosuppressive strategies and the use of IL-2Rα blockers decreases the risk of AR
Screening
- There are no screening strategies for AR although periodic liver injury tests and measurement of immunosuppressive medication levels are performed in order to detect abnormalities at an early stage and avoid low levels of immunosuppression.
Primary prevention
- Maintain corticosteroid treatment during the first 3–6 months after LT.
- For corticosteroid-free regimens use IL-2Rα or alemtuzumab for induction.
- Close monitoring of tacrolimus, cyclosporine or sirolimus levels as dictated by the timing from transplantation.
- Monitor and adjusting the dose of tacrolimus/cyclosporine in correlation with newly introduced medications that may affect pharmacokinetics of immunosuppressive medications.
Secondary prevention
- Maintain higher level of maintenance immunosuppression after an episode of AR.
- If patient only on tacrolimus maintenance consider adding mycophenolate mofetil.
Section 3: Diagnosis (Algorithm 44.1)
- The diagnosis is suggested by elevated liver enzymes, followed by the appearance of jaundice and sometimes fever in LT recipients.
- MRI/MRCP, CT scan or US of the liver are required in order to rule out other conditions that can cause abnormal liver injury tests in the first 3–6 months after LT such as vascular insufficiency, biliary complications and recurrent disease (particularly in the case of hepatitis C).
- The diagnosis of AR needs to be confirmed by core liver biopsy.
- At least two of the following three features are required for a histopathological diagnosis of AR:
1. Mixed but predominantly mononuclear portal inflammation, containing blastic (activated) lymphocytes, neutrophils and frequently eosinophils;
2. Bile duct inflammation/damage;
3. Subendothelial inflammation of portal veins, terminal hepatic venules or hepatic arteries (Figure 44.1).
Differential diagnosis
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