The introduction in 1980 of cyclosporine as an immunosuppressive agent contributed substantially to the improvement in survival after liver transplantation. Cyclosporine, a calcineurin inhibitor, blocks early activation of T cells and is specific for T cell functions that result from the interaction of the T cell with its receptor and that involve the calcium-dependent signal transduction pathway. As a result, the activity of cyclosporine leads to inhibition of lymphokine gene activation, blocking interleukins 2, 3, and 4, tumor necrosis factor a, and other lymphokines. Cyclosporine also inhibits B cell functions. This process occurs without affecting rapidly dividing cells in the bone marrow, which may account for the reduced frequency of posttransplantation systemic infections. The most common and important side effect of cyclosporine therapy is nephrotoxicity. Cyclosporine causes dose-dependent renal tubular injury and direct renal artery vasospasm. Following renal function is therefore important in monitoring cyclosporine therapy, perhaps even a more reliable indicator than blood levels of the drug. Nephrotoxicity is reversible and can be managed by dose reduction. Other adverse effects of cyclosporine therapy include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance, and gingival hyperplasia.
Tacrolimus, a macrolide lactone antibiotic isolated from a Japanese soil fungus, Streptomyces tsukubaensis, has the same mechanism of action as cyclosporine but is 10–100 times more potent. Initially applied as “rescue” therapy for patients in whom rejection occurred despite the use of cyclosporine, tacrolimus was shown to be associated with a reduced frequency of acute, refractory, and chronic rejection. Although patient and graft survival are the same with these two drugs, the advantage of tacrolimus in minimizing episodes of rejection, reducing the need for additional glucocorticoid doses, and reducing the likelihood of bacterial and cytomegalovirus (CMV) infection has simplified the management of patients undergoing liver transplantation. In addition, the oral absorption of tacrolimus is more predictable than that of cyclosporine, especially during the early postoperative period when T-tube drainage interferes with the enterohepatic circulation of cyclosporine. As a result, in most transplantation centers, tacrolimus has now supplanted cyclosporine for primary immunosuppression, and many centers rely on oral rather than IV administration from the outset. For transplantation centers that prefer cyclosporine, a better-absorbed microemulsion preparation is available.
Although more potent than cyclosporine, tacrolimus is also more toxic and more likely to be discontinued for adverse events. The toxicity of tacrolimus is similar to that of cyclosporine; nephrotoxicity and neurotoxicity are the most commonly encountered adverse effects, and neurotoxicity (tremor, seizures, hallucinations, psychoses, coma) is more likely and more severe in tacrolimus-treated patients. Both drugs can cause diabetes mellitus, but tacrolimus does not cause hirsutism or gingival hyperplasia. Because of overlapping toxicity between cyclosporine and tacrolimus, especially nephrotoxicity, and because tacrolimus reduces cyclosporine clearance, these two drugs should not be used together. Because 99% of tacrolimus is metabolized by the liver, hepatic dysfunction reduces its clearance; in primary graft nonfunction (when, for technical reasons or because of ischemic damage prior to its insertion, the allograft is defective and does not function normally from the outset), tacrolimus doses have to be reduced substantially, especially in children. Both cyclosporine and tacrolimus are metabolized by the cytochrome P450 IIIA system, and, therefore, drugs that induce cytochrome P450 (e.g., phenytoin, phenobarbital, carbamazepine, rifampin) reduce available levels of cyclosporine and tacrolimus; and drugs that inhibit cytochrome P450 (e.g., erythromycin, fluconazole, ketoconazole, clotrimazole, itraconazole, verapamil, diltiazem, danazol, metoclopramide, the HIV protease inhibitor ritonavir, and the HCV protease inhibitor paritaprevir) increase cyclosporine and tacrolimus blood levels. Indeed, itraconazole is used occasionally to help boost tacrolimus levels. Like azathioprine, cyclosporine and tacrolimus appear to be associated with a risk of lymphoproliferative malignancies (see below), which may occur earlier after cyclosporine or tacrolimus than after azathioprine therapy. Because of these side effects, combinations of cyclosporine or tacrolimus with prednisone and an antimetabolite (azathioprine or mycophenolic acid, see below)—all at reduced doses—are preferable regimens for immunosuppressive therapy.
Mycophenolic acid, a nonnucleoside purine metabolism inhibitor derived as a fermentation product from several Penicillium species, is another immunosuppressive drug being used for patients undergoing liver transplantation. Mycophenolate has been shown to be better than azathioprine, when used with other standard immunosuppressive drugs, in preventing rejection after renal transplantation and has been adopted widely as well for use in liver transplantation. The most common adverse effects of mycophenolate are bone marrow suppression and gastrointestinal complaints.
In patients with pretransplantation renal dysfunction or renal deterioration that occurs intraoperatively or immediately postoperatively, tacrolimus or cyclosporine therapy may not be practical; under these circumstances, induction or maintenance of immunosuppression with antithymocyte globulin (ATG, thymoglobulin) or monoclonal antibodies to T cells, OKT3, may be appropriate. Therapy with these agents has been especially effective in reversing acute rejection in the posttransplantation period and is the standard treatment for acute rejection that fails to respond to methylprednisolone boluses. Available data support the use of thymoglobulin induction to delay calcineurin inhibitor use and its attendant nephrotoxicity. IV infusions of thymoglobulin may be complicated by fever and chills, which can be ameliorated by premedication with antipyretics and a low dose of glucocorticoids. Infusions of OKT3 may be complicated by fever, chills, and diarrhea, or by pulmonary edema, which can be fatal. Because OKT3 is such a potent immunosuppressive agent, its use is also more likely to be complicated by opportunistic infection or lymphoproliferative disorders; therefore, because of the availability of alternative immunosuppressive drugs, OKT3 is now used sparingly.
Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), blocks later events in T cell activation, is approved for use in kidney transplantation, but is not formally approved for use in liver transplant recipients because of the reported association with an increased frequency of hepatic artery thrombosis in the first month posttransplantation. In patients with calcineurin inhibitor–related nephrotoxicity, conversion to sirolimus has been demonstrated to be effective in preventing rejection with accompanying improvements in renal function. Because of its profound antiproliferative effects, sirolimus has also been suggested to be a useful immunosuppressive agent in patients with a prior or current history of malignancy, such as HCC. Side effects include hyperlipidemia, peripheral edema, oral ulcers, and interstitial pneumonitis. Everolimus is a hydroxyethyl derivative of sirolimus that, when used in conjunction with low-dose tacrolimus, also provides successful protection against acute rejection, with decreased renal impairment compared to that associated with standard tacrolimus dosing. Everolimus and sirolimus share a similar adverse events profile. The most important principle of immunosuppression is that the ideal approach strikes a balance between immunosuppression and immunologic competence. In general, given sufficient immunosuppression, acute liver allograft rejection is nearly always reversible. On one hand, incompletely treated acute rejection predisposes to the development of chronic rejection, which can threaten graft survival. On the other hand, if the cumulative dose of immunosuppressive therapy is too large, the patient may succumb to opportunistic infection. In hepatitis C, pulse glucocorticoids or OKT3 use accelerate recurrent allograft hepatitis, although the routine use of DAA therapy to clear the allograft of HCV should remove or greatly diminish this concern. Further complicating matters, acute rejection can be difficult to distinguish histologically from recurrent hepatitis C. Therefore, immunosuppressive drugs must be used judiciously, with strict attention to the infectious consequences of such therapy and careful confirmation of the diagnosis of acute rejection. In this vein, efforts have been made to minimize the use of glucocorticoids, a mainstay of immunosuppressive regimens, and steroid-free immunosuppression can be achieved in some instances. Patients who undergo liver transplantation for autoimmune diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis are less likely to achieve freedom from glucocorticoids.
Complications of liver transplantation can be divided into nonhepatic and hepatic categories (Tables 338-4 and 338-5). In addition, both immediate postoperative and late complications are encountered. As a rule, patients who undergo liver transplantation have been chronically ill for protracted periods and may be malnourished and wasted. The impact of such chronic illness and the multisystem failure that accompanies liver failure continue to require attention in the postoperative period. Because of the massive fluid losses and fluid shifts that occur during the operation, patients may remain fluid-overloaded during the immediate postoperative period, straining cardiovascular reserve; this effect can be amplified in the face of transient renal dysfunction and pulmonary capillary vascular permeability. Continuous monitoring of cardiovascular and pulmonary function, measures to maintain the integrity of the intravascular compartment and to treat extravascular volume overload, and scrupulous attention to potential sources and sites of infection are of paramount importance. Cardiovascular instability may also result from the electrolyte imbalance that may accompany reperfusion of the donor liver as well as from restoration of systemic vascular resistance following implantation. Pulmonary function may be compromised further by paralysis of the right hemidiaphragm associated with phrenic nerve injury. The hyperdynamic state with increased cardiac output that is characteristic of patients with liver failure reverses rapidly after successful liver transplantation.
TABLE 338-4Nonhepatic Complications of Liver Transplantation ||Download (.pdf) TABLE 338-4 Nonhepatic Complications of Liver Transplantation
|Category ||Complication |
|Cardiovascular instability ||Arrhythmias |
|Congestive heart failure |
|Pulmonary compromise ||Pneumonia |
|Pulmonary capillary vascular permeability |
|Fluid overload |
|Renal dysfunction ||Prerenal azotemia |
|Hypoperfusion injury (acute tubular necrosis) |
|Drug nephrotoxicity |
|↓ Renal blood flow secondary to ↑ intraabdominal pressure |
|Hematologic ||Anemia secondary to gastrointestinal and/or intraabdominal bleeding |
|Hemolytic anemia, aplastic anemia |
|Infection ||Bacterial: early, common postoperative infections |
|Fungal/parasitic: late, opportunistic infections |
|Viral: late, opportunistic infections, recurrent hepatitis |
|Neuropsychiatric ||Seizures |
|Metabolic encephalopathy |
|Difficult psychosocial adjustment |
|Diseases of donor ||Infectious |
|Malignancy ||B cell lymphoma (posttransplantation lymphoproliferative disorders) |
|De novo neoplasms (particularly squamous cell skin carcinoma) |
TABLE 338-5Hepatic Complications of Liver Transplantation ||Download (.pdf) TABLE 338-5 Hepatic Complications of Liver Transplantation
|Hepatic Dysfunction Common after Major Surgery |
|Prehepatic ||Pigment load |
|Blood collections (hematomas, abdominal collections) |
|Intrahepatic || |
| Early ||Hepatotoxic drugs and anesthesia |
|Hypoperfusion (hypotension, shock, sepsis) |
|Benign postoperative cholestasis |
| Late ||Transfusion-associated hepatitis |
|Exacerbation of primary hepatic disease |
| Posthepatic ||Biliary obstruction |
|↓ Renal clearance of conjugated bilirubin (renal dysfunction) |
|Hepatic Dysfunction Unique to Liver Transplantation |
|Primary graft nonfunction || |
|Vascular compromise ||Portal vein obstruction |
|Hepatic artery thrombosis |
|Anastomotic leak with intraabdominal bleeding |
|Bile duct disorder ||Stenosis, obstruction, leak |
|Recurrent primary hepatic disease |
Other immediate management issues include renal dysfunction. Prerenal azotemia, acute kidney injury associated with hypoperfusion (acute tubular necrosis), and renal toxicity caused by antibiotics, tacrolimus, or cyclosporine are encountered frequently in the postoperative period, sometimes necessitating dialysis. Hemolytic-uremic syndrome can be associated with cyclosporine, tacrolimus, or OKT3. Occasionally, postoperative intraperitoneal bleeding may be sufficient to increase intraabdominal pressure, which, in turn, may reduce renal blood flow; this effect is rapidly reversible when abdominal distention is relieved by exploratory laparotomy to identify and ligate the bleeding site and to remove intraperitoneal clot.
Anemia may also result from acute upper gastrointestinal bleeding or from transient hemolytic anemia, which may be autoimmune, especially when blood group O livers are transplanted into blood group A or B recipients. This autoimmune hemolytic anemia is mediated by donor intrahepatic lymphocytes that recognize red blood cell A or B antigens on recipient erythrocytes. Transient in nature, this process resolves once the donor liver is repopulated by recipient bone marrow–derived lymphocytes; the hemolysis can be treated by transfusing blood group O red blood cells and/or by administering higher doses of glucocorticoids. Transient thrombocytopenia is also commonly encountered. Aplastic anemia, a late occurrence, is rare but has been reported in almost 30% of patients who underwent liver transplantation for acute, severe hepatitis of unknown cause.
Bacterial, fungal, or viral infections are common and may be life-threatening postoperatively. Early after transplant surgery, common postoperative infections predominate—pneumonia, wound infections, infected intraabdominal collections, urinary tract infections, and IV line infections—rather than opportunistic infections; these infections may involve the biliary tree and liver as well. Beyond the first postoperative month, the toll of immunosuppression becomes evident, and opportunistic infections—CMV, herpes viruses, fungal infections (Aspergillus, Candida, cryptococcal disease), mycobacterial infections, parasitic infections (Pneumocystis, Toxoplasma), bacterial infections (Nocardia, Legionella, Listeria)—predominate. Rarely, early infections represent those transmitted with the donor liver, either infections present in the donor or infections acquired during procurement processing. De novo viral hepatitis infections acquired from the donor organ or, almost unheard of now, from transfused blood products occur after typical incubation periods for these agents (well beyond the first month). Obviously, infections in an immunosuppressed host demand early recognition and prompt management; prophylactic antibiotic therapy is administered routinely in the immediate postoperative period. Use of sulfamethoxazole with trimethoprim reduces the incidence of postoperative Pneumocystis carinii pneumonia. Antiviral prophylaxis for CMV with ganciclovir should be administered in patients at high risk (e.g., when a CMV-seropositive donor organ is implanted into a CMV-seronegative recipient).
Neuropsychiatric complications include seizures (commonly associated with cyclosporine and tacrolimus toxicity), metabolic encephalopathy, depression, and difficult psychosocial adjustment. Rarely, diseases are transmitted by the allograft from the donor to the recipient. In addition to viral and bacterial infections, malignancies of donor origin have occurred. Posttransplantation lymphoproliferative disorders, especially B cell lymphoma, are a recognized complication associated with immunosuppressive drugs such as azathioprine, tacrolimus, and cyclosporine (see above). Epstein-Barr virus has been shown to play a contributory role in some of these tumors, which may regress when immunosuppressive therapy is reduced. De novo neoplasms appear at increased frequency after liver transplantation, particularly squamous cell carcinomas of the skin. Routine screening should be performed.
Long-term complications after liver transplantation attributable primarily to immunosuppressive medications include diabetes mellitus and osteoporosis (associated with glucocorticoids and calcineurin inhibitors) as well as hypertension, hyperlipidemia, and chronic renal insufficiency (associated with cyclosporine and tacrolimus). Monitoring and treating these disorders are routine components of posttransplantation care; in some cases, they respond to changes in immunosuppressive regimen, while in others, specific treatment of the disorder is introduced. Data from a large U.S. database showed that the prevalence of renal failure was 18% at year 5 and 25% at year 10 after liver transplantation. Similarly, the high frequency of diabetes, hypertension, hyperlipidemia, obesity, and the metabolic syndrome renders patients susceptible to cardiovascular disease after liver transplantation; although hepatic complications account for most of the mortality after liver transplantation, renal failure and cardiovascular disease are the other leading causes of late mortality after liver transplantation.
Hepatic dysfunction after liver transplantation is similar to the hepatic complications encountered after major abdominal and cardiothoracic surgery; however, in addition, hepatic complications include primary graft failure, vascular compromise, failure or stricture of the biliary anastomoses, and rejection. As in nontransplantation surgery, postoperative jaundice may result from prehepatic, intrahepatic, and posthepatic sources. Prehepatic sources represent the massive hemoglobin pigment load from transfusions, hemolysis, hematomas, ecchymoses, and other collections of blood. Early intrahepatic liver injury includes effects of hepatotoxic drugs and anesthesia; hypoperfusion injury associated with hypotension, sepsis, and shock; and benign postoperative cholestasis. Late intrahepatic sources of liver injury include exacerbation of primary disease. Posthepatic sources of hepatic dysfunction include biliary obstruction and reduced renal clearance of conjugated bilirubin. Hepatic complications unique to liver transplantation include primary graft failure associated with ischemic injury to the organ during harvesting; vascular compromise associated with thrombosis or stenosis of the portal vein or hepatic artery anastomoses; vascular anastomotic leak; stenosis, obstruction, or leakage of the anastomosed common bile duct; recurrence of primary hepatic disorder (see below); and rejection.
Despite the use of immunosuppressive drugs, rejection of the transplanted liver still occurs in a proportion of patients, beginning 1–2 weeks after surgery. Clinical signs suggesting rejection are fever, right upper quadrant pain, and reduced bile pigment and volume. Leukocytosis may occur, but the most reliable indicators are increases in serum bilirubin and aminotransferase levels. Because these tests lack specificity, distinguishing among rejection, biliary obstruction, primary graft nonfunction, vascular compromise, viral hepatitis, CMV infection, drug hepatotoxicity, and recurrent primary disease may be difficult. Radiographic visualization of the biliary tree and/or percutaneous liver biopsy often help to establish the correct diagnosis. Morphologic features of acute rejection include a mixed portal cellular infiltrate, bile duct injury, and/or endothelial inflammation (“endothelialitis”); some of these findings are reminiscent of graft-versus-host disease, primary biliary cirrhosis, or recurrent allograft hepatitis C. As soon as transplant rejection is suspected, treatment consists of IV methylprednisolone in repeated boluses; if this fails to abort rejection, many centers use thymoglobulin or OKT3. Caution should be exercised when managing acute rejection with pulse glucocorticoids or OKT3 in patients with HCV infection, because of the high risk of triggering recurrent allograft hepatitis C. The availability of DAAs for HCV should greatly alleviate this concern.
Chronic rejection is a relatively rare outcome that can follow repeated bouts of acute rejection or that occurs unrelated to preceding rejection episodes. Morphologically, chronic rejection is characterized by progressive cholestasis, focal parenchymal necrosis, mononuclear infiltration, vascular lesions (intimal fibrosis, subintimal foam cells, fibrinoid necrosis), and fibrosis. This process may be reflected as ductopenia—the vanishing bile duct syndrome, which is more common in patients undergoing liver transplantation for autoimmune liver disease. Reversibility of chronic rejection is limited; in patients with therapy-resistant chronic rejection, retransplantation has yielded encouraging results.