Overall Bottom Line
- The most frequent CR is preceded by one or more episodes of AR that are often resistant to corticosteroid therapy and require anti-lymphocyte or other rescue therapy.
- The early phases of CR are potentially reversible, so it is critical to develop a multidisciplinary management plan with active involvement of an expert liver pathologist.
- There are limited therapeutic options for established CR and none of the options have been compared in a RCT.
- The main challenge in the management of CR is to establish the need for increasing the immunosuppressive regimen versus the option of re-transplantation.
- Signs of allograft failure suggest the need of re-transplantation.
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.
- Chronic allograft rejection is defined as an immunologic injury to the allograft, which usually evolves from severe or persistent AR and results in potential irreversible damage to the bile duct, arteries and veins that evolves into graft failure.
Disease classification
- The classification of CR is based on the histological findings of early versus late findings of CR.
- This classification provides information regarding the likelihood of reversal and does not absolutely define a point of no return.
Incidence/prevalence
- Historically, CR accounted for up to 20% of all cases of liver allograft failure but this has decreased significantly over the last 20 years due to improvement in immunosuppressive medications and monitoring.
- Currently, CR has an incidence of less than 3–4% of all causes of liver allograft failure.
Etiology
- CR is the end result of the persistent immune response directed against the presence of alloantigens in the transplanted liver, which has the potential to result in graft dysfunction and failure.
Pathology/pathogenesis
- Graft injury is the result of a 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 ductopenia and obstructive arteriopathy.
- Hepatic antigen presenting cells (donor/recipient).
- Indirect presentation of donor alloantigens from the transplanted liver by recipient antigen presenting cells which is thought to be the main mechanism responsible for late allograft rejection.
- Direct presentation of alloantigens by donor dendritic cells from the transplanted liver possibly involved in the CR that develops soon after liver transplantation in the setting of multiple episodes of AR and/or in steroid resistant AR.
Predictive/risk factors
| Risk factor | Odds ratio |
|---|---|
| Any episode of AR | 3.6 |
| More than one episode of acute rejection | 7.86 |
| Moderate or severe acute rejection | 4.77 |
| Donor age more than 40 | 2.14 |
| LT for PBC | 10.6 |
| LT for AIH | 6.7 |
| Male donor to female recipient | 5.83 (in cyclosporine-based regimen) |
| Recipient age less than 30 years old | 3.8 |
| CMV IgG positive donor into negative recipient | 3.5 |
| Treatment with IFN for HCV | Unknown |
| CMV infection | Unknown |
Section 2: Prevention
- Improvement of immunosuppressive strategies has decreased the risk of CR from 20% to <4% of all causes of liver allograft failure.
- Continuous patient education regarding the importance of compliance with immunosuppressive medication and monitoring.
Screening
- There are no screening strategies for CR although periodic liver chemistry tests and measurement of immunosuppressive medication levels is performed in order to detect early AR and avoid low levels of immunosuppression.
Primary prevention
- Close monitoring of tacrolimus, cyclosporine or sirolimus as dictated by the timing from transplantation.
- Monitor and adjust the dose of tacrolimus/cyclosporine in correlation with newly introduced medications that may interfere with immunosuppressive medication pharmacokinetics.
- Maintain a higher level of tacrolimus or add mycophenolate mofetil after episodes of AR.
- Start tacrolimus if patient develops AR while on a cyclosporine immunosuppression regimen.
Section 3: Diagnosis (Algorithm 45.1)
- Clinical symptoms are non-specific and present only in the late stages. The onset of jaundice indicates usually severe allograft dysfunction.
- Standard liver injury abnormalities in a patient with CR show a progressive cholestatic pattern that can eventually lead to jaundice.
- MRI/MRCP, CT scan or US of the liver are required in order to rule out other conditions that can cause cholestasis.
- To establish the diagnosis of CR a core liver biopsy is necessary.
- Minimal pathological criteria for CR include:
- Bile duct atrophy/pyknosis affecting the majority of the bile ducts, with or without bile duct loss.
- Foam cell obliterative arteriopathy.
- Bile duct loss greater than 50% of the portal tracts (Figure 45.1).
- Bile duct atrophy/pyknosis affecting the majority of the bile ducts, with or without bile duct loss.
Differential diagnosis
| Differential diagnosis | Features |
|---|---|
| Obstructive cholangiopathy | History of difficult surgical biliary tract reconstruction; presentation with clinical findings suggestive of cholangitis: fever, RUQ pain; imaging studies with intrahepatic biliary duct dilatation |
| Hepatic artery stenosis/thrombosis | History of surgically difficult hepatic artery reconstruction; imaging studies with absence of blood flow in the hepatic artery |
| Drug-induced liver injury | History of recent introduction medications with potential to induce cholestasis |
| Recurrent disease | History of HCV, PSC, PBC, AIH:
|
| De novo AIH | History of recent IFN treatment; new presence of SMA, ANA and high IgG; confirmed by biopsy |
| Infiltrative process (sarcoidosis, amyloidosis, infiltrative neoplasm) | History of sarcoidosis, paraproteinemia and neoplasm; imaging, biochemistry and critical in differential diagnosis |
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
