Post–Liver Transplant Management

The First 90 Days

Typically, an uncomplicated LT recipient spends up to 3 days in the intensive care unit, and 7 to14 days in the hospital following the operation. Following discharge from the hospital, blood tests are performed once or twice weekly initially, with the interval between blood tests extending as the patient recovers.

The cause of liver dysfunction following transplantation is broad. However, as shown in Table 52-2 , the cause of graft dysfunction also changes as the time from transplantation increases. Rejection of the allograft remains one of the most common causes of this dysfunction across all time spans after LT. Although the immunogenicity of the liver allograft decreases with time, it is greatest during the first 90 days: approximately 60% of episodes of acute cellular rejection (ACR) occur in this period.

All liver allografts are subjected to a period of inadequate vascular perfusion during preservation, followed by reperfusion, which results in an ischemic-reperfusion injury. This is manifested by aminotransferase levels often as high as 1000 U/L in the first postoperative week. Typically, the aminotransferase levels start to recover in 1 to 2 days, along with stabilization of the international normalized ratio and gradual improvement in serum bilirubin level. Primary nonfunction (PNF) of the allograft is an umbrella term describing the failure of the allograft to establish normal function immediately after the LT. PNF is due to the combined effects of ischemia-repulsion and donor factors, especially macrovesicular steatosis. For this reason it is common practice to decline donor organs with greater than 25% macrovesicular fat content on pretransplant assessment. Occlusion or stenosis of the hepatic artery or portal vein may also present as PNF. Biliary strictures may also present in the early period with liver enzyme level abnormalities, typically in a cholestatic pattern.

As the first 90 days after LT is when the highest doses of immunosuppressive medications are used, it is also the time of greatest risk of infection. One must be vigilant for the onset of urinary tract infections, wound infections, pneumonias, infected intravenous cannulae, and septicemia.

As will be discussed later, ACR does not have a characteristic clinical presentation. Frequent monitoring of liver tests is the primary method of early detection of ACR, with a liver biopsy the favored means for definitive diagnosis.

Beyond the First 90 Days

Most LT patients are healthy, albeit at risk of the adverse complications of immunosuppression and the recurrence of the underlying disorders that lead to their LT. Table 52-3 outlines an approach to health maintenance in the LT recipient. Liver blood test results should be monitored intermittently; every 3 months is typical in a healthy uncomplicated LT recipient.

According to the guidelines of the American Association for the Study of Liver Diseases (AASLD), all adult LT recipients should receive “an annual influenza vaccination (grade 1, level B); should avoid live virus vaccines (grade 1, level A); and should receive re-immunization for some vaccines, notably the pneumococcal vaccine (every 3-5 years; no class or level provided).”

Allograft Immune Response

T lymphocytes are the key cellular activators of the allograft immune response ( Fig. 52-2 ). In recent years a contributory role for antibody-mediated immunity has been increasingly recognized in the rejection response. LT recipients differ from recipients of other solid organs in that the immunogenicity of the liver allograft declines as the successful transplant progresses. All LT recipients become partially tolerant of their allograft, by which is meant the host immune system treats the allograft as self while maintaining immune surveillance toward other foreign antigens. Nevertheless, LT recipients typically require lifelong immunosuppression.

Activation of T lymphocytes plays a central role in the immune response to an allogeneic transplanted tissue. Prevention or interruption of T-cell activation is the principal goal of post-LT immunosuppression of costimulatory molecules. The best characterized positive costimulatory signals are shown in Figs. 52-3 and 52-4 . Costimulatory signals differ both in their ability to increase or decrease T-cell activation and in their patterns of expression. Thereafter, soluble factors such as interleukin (IL)-2, derived from the activated T cells, create a milieu to propagate and augment responses (sometimes referred to as signal 3 ). T-lymphocyte activation occurs through a cascade of stimulatory or augmentative signals. The first, referred to as signal 1 , arises when polymorphic proteins from the donor tissue, processed into peptides bound to self major histocompatibility complex (MHC) molecules on the surface of autologous antigen-presenting cells, are presented to the T-cell receptor of naïve T lymphocytes. The second signal, called costimulatory signal 2 , is required for the induction of activation of the naïve T cells, and occurs through the interaction of costimulatory molecules on antigen-presenting cells and specific receptors on T lymphocytes. There are several families.

Immune injury, mediated by donor-specific HLA antibodies (DSAs), has emerged as an area of new understanding in relation to LT immune response. Acute antibody-mediated rejection (AMR) should be understood as a component of the immune response rather than as a distinct entity independent of cell-mediated immune allograft injury. Consequently AMR overlaps clinically with T cell–mediated rejection. The presence of DSAs in pre-LT candidates is indicative of greater immunoreactivity with the liver graft, and greater risk of clinical rejection after transplantation.

Acute Allograft Rejection

Acute cellular rejection (ACR) is a misnomer as ACR may occur even years after transplantation. The word acute in acute cellular rejection (ACR) actually alludes to a process that has not yet caused chronic damage to the graft, and the ductular structure, though inflamed, is still viable. ACR is most common in the first 90 days after LT, after which the immunogenicity of the LT allograft gradually declines.

ACR has no characteristic biochemical presentation, and may present with any of the common patterns of liver injury. Liver biopsy remains the gold standard for diagnosis, with Banff criteria being the internationally accepted common grading system for describing features of allograft rejection. As shown in Fig. 52-5 , characteristic histologic features of ACR include the following triad:

• 1.

  mononuclear polycellular inflammatory infiltrate comprising abundant small lymphocytes, but also including eosinophils

• 2.

  bile duct inflammation and injury

• 3.

  subendothelial inflammation in portal veins and/or hepatic venules

The decision to perform a biopsy is based on clinical judgment and on such factors as prior experience of rejection, adherence by the patient to the immunosuppressive regimen, the severity of biochemical disturbance, and the patient's overall well-being.

ACR arising later in the clinical course suggests either overly rapid reduction in immunosuppression or lack of adherence to the immunosuppressive regimen. As indicated in Table 52-4 , several agents may decrease the effective levels of calcineurin inhibitors or mammalian target of rapamycin (mTOR) inhibitors, and inadvertent administration of a medicine such as rifampin, a cytochrome P-450 inducer, may lead to ineffective immunosuppression and, as a result, ACR.

Initial treatment of ACR consists of high-dose intravenous or oral corticosteroids, which may be started before the final biopsy results are available. There is no widely agreed dosing regimen for corticosteroids to be used in ACR episodes. Maintenance immunosuppressive therapy may be maintained at prior doses or increased while pulse corticosteroids are administered.

ACR that fails to respond to high-dose corticosteroids is called corticosteroid-resistant rejection . T cell–depleting agents are used to treat episodes of corticosteroid-resistant rejection. Although prevention of ACR is the purpose of immunosuppression, mild, easily reversible ACR, especially that occurring in the early postoperative period, is not harmful to the allograft. Contrariwise, over-immunosuppression promotes infection, cancer development, and end-organ injury.

Chronic Ductopenic Rejection

Chronic ductopenic rejection denotes damage and eventual loss of bile ducts in portal tracts. Although called chronic , it can occur in the first few months after LT. Chronic ductopenic rejection occurs as a consequence of corticosteroid-resistant rejection or de novo .

Multiple risk factors for the development of chronic rejection in the liver have been identified in various studies :

• donor/recipient specific: non-Caucasian recipient race, chronic hepatitis virus infection, positive pretransplant lymphocytotoxic crossmatch, cytomegalovirus (CMV) infection, treatment with α-interferon

• organ/transplant specific: a previously failed allograft, multiple and/or poorly controlled ACR episodes, development of anti-MHC antibodies after LT, matching at the class II MHC locus, and mismatching at the MHC class I locus

In some cases, arteriopathy is observed on serial biopsies, and arteriopathic rejection is a synonym of chronic ductopenic rejection . It has been suggested that DSAs, persistenting after LT, contribute to both ACR and allograft injury, leading to ductopenic rejection. Ductopenic rejection is a challenging complication to treat; it may respond to increased doses of tacrolimus, plasmapheresis, and intravenous immune globulin. When all other treatment fails, chronic ductopenic rejection requires retransplantation.

Antibody-Mediated Rejection

The clinical manifestations of AMR are protean, ranging from typical lymphocyte predominant rejection that is poorly responsive to standard therapy to ductopenia, fibrosis, plasma cell–rich hepatitis, and biliary strictures. The condition of AMR is recognized by measurement of circulating DSAs in association with the identification on liver biopsy of diffuse C4d deposition in the portal tracts (DSA positive /diffuse C4d positive) ( Fig. 52-6 ). The use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels are associated with increased risk of de novo DSA formation, whereas a calculated Model for End-Stage Liver Disease score greater than 15 at LT and recipient age greater than 60 years are associated with lower risk. The best methods to prevent the onset of AMR or to treat AMR have not been defined. Antihumoral agents and techniques used in kidney transplant recipients, such as plasmapheresis, intravenous immune globulin, rituximab, bortezomib, and eculizumab, are most commonly used as multimodality regimens but the relative contribution of the component therapies in managing AMR is difficult to ascertain.

Immunosuppression

Immunosuppressive management after LT is the cornerstone of posttransplant care. The goals of immunosuppressive therapy in LT recipients are:

• prevention of allograft rejection

• optimization of graft function

• minimization of side effects of the immunosuppressive regimen

A summary of the immunosuppressive agents used after LT and outlines of the mechanisms of action are provided in Table 52-5 and Figs. 52-2 and 52-3 , respectively.