Post-Liver Transplantation Management

Overview

Bijan Eghtesad, MD
Charles M. Miller, MD
John J. Fung, MD

Orthotopic liver transplantation (OLT) replaces the diseased liver with a transplanted allograft liver in the anatomically correct position and has become an increasingly used treatment for end-stage liver disease. Since the first successful OLT, done by Thomas Starzl in 1967, the technique of OLT has been refined to a relatively standardized procedure, but the operation remains a formidable surgical challenge. As such, OLT can be associated with a spectrum of technical and medical complications; the recipient’s pretransplantation condition and donor and immunologic factors may all be contributing factors. Preoperative recipient factors such as age older than 60 years, presence of comorbid conditions such as cardiac or pulmonary disease, renal failure, diabetes, and severe malnutrition, and the nature of the liver disease can affect survival. Perioperative factors such as the quality of the donor liver, difficulty of the liver transplantation procedure, development of postoperative infection, and side effects of immunosuppressive agents are important factors influencing outcome.

Patients with end-stage liver disease undergo extensive workups before being listed for liver transplantation. The preoperative condition, nature and severity of the liver disease, and comorbid conditions are assessed during the evaluation process. Patients are presented and discussed in a multidisciplinary committee to be approved for final listing.

The purpose of this chapter is to focus on the perioperative care of OLT patients and delineate potential surgical and medical complications, management of immunosuppressive regimens, and diagnosis and treatment of rejection and other immunologic problems in these patients.

Operative Technique

The technique of OLT has been progressively refined since its introduction in humans in 1963. Several variations are applied selectively, according to the patient’s specific situation, transplantation center’s routine practice, or both. The traditionally described OLT involves resecting the recipient native liver (hepatectomy) together with the retrohepatic inferior vena cava (IVC), a short anhepatic phase, and implanting a whole deceased donor liver graft with the interposed donor IVC. Restoration of venous continuity during the implantation is achieved by an upper subdiaphragmatic and lower end-to-end donor-to-recipient IVC anastomosis; the donor-to-recipient portal vein and hepatic artery anastomoses are also performed in an end-to-end fashion. The biliary connections involve a primary duct-to-duct technique or the performance of a hepaticojejunostomy.

One modification of the standard procedure is to preserve the retrohepatic IVC in the recipient and restore the venous drainage of the liver allograft by anastomosis of the suprahepatic IVC to a common venous channel. This is made from the confluence of three hepatic veins in the recipient and ligation of the infrahepatic allograft IVC, also referred to as the piggyback technique. This technique also allows live donor and segmental liver transplantation, in which venous outflow is connected to the preserved native IVC while the new segment of the liver is revascularized between the corresponding recipient and donor vascular structures, as described for whole-liver transplantation.

Other modifications may be required, depending on the nature of the structures in the recipient. For example, if the portal vein of the recipient is thrombosed, portal vein reconstruction using a conduit from the superior mesenteric vein or portal vein thrombectomy may be required. Similarly, if the hepatic artery is unsuitable for revascularization of the transplanted liver, an arterial conduit from the aorta may be required.

Postoperative Care

General Intensive Care Unit Measures

Immediately following OLT, these patients are returned to the surgical intensive care unit (ICU). In the ICU, they are maintained on a ventilator until fully conscious and able to breathe on their own while being able to protect their airway. During the ICU stay, there is a need for close attention to management of fluid and electrolytes, which could be significantly abnormal as a result of the prolonged operation and massive fluid shifts.

Immunosuppressive agents, based on specific protocols and on the patient’s renal function, are started early after OLT. Doses are adjusted according to blood levels and functional status of the transplanted liver and renal function. Most patients with an uncomplicated postoperative course and good liver function remain in the ICU for 1 or 2 days before being transferred to an inpatient transplantation unit.

Transfer to an Inpatient Transplantation Unit

Following transfer to a designated transplantation inpatient unit, the patient should be closely followed by the surgical and medical team, as well as by pharmacists, nutritionists, and physical therapists. Fluid and electrolyte status and kidney and liver function need to be monitored at least daily. Dosages of immunosuppressive agents are adjusted according to blood levels and organ function during this period. The pattern of liver function test (LFT) results are monitored for early signs of dysfunction, which can require further study or intervention. Any major alteration in liver function should initiate a series of studies, which may include Doppler ultrasound to evaluate vascular patency of the new liver, bile duct studies (e.g., T-tube cholangiography, endoscopic retrograde cholangiopancreatography [ERCP], percutaneous transhepatic cholangiography) to evaluate any abnormality of the biliary system (e.g., stricture, bile leak, obstruction), and liver biopsy to rule out rejection. Necessary treatments are initiated based on these findings. Usually, in an uneventful recovery, the patient is discharged within 10 to 14 days after OLT and followed as an outpatient.

During the transition to an outpatient setting, the patient meets with the post-OLT coordinator and goes through extensive teaching regarding his or her medications and immunosuppressive agents and their potential side effects. The patient receives instructions about the schedule for blood work and follow-up clinic visits. The patient receives a book containing after-discharge instructions, including when and how to notify the transplantation program if he or she feels that there is something wrong, such as abnormal pain, fever, diarrhea, and headaches. The recipient is also instructed about physical activities, diet, and general health maintenance, such as vaccinations, avoidance of sun, and cancer screening.

Discharge Instructions

Medications and Prophylactic Measures

The maintenance medications after discharge include immunosuppressive agents, prophylactic medications for prevention of opportunistic infections, such as for Pneumocystis jiroveci infection (trimethoprim-sulfamethoxazole, or in case of sulfa allergy, dapsone or pentamidine), herpetic infections (acyclovir), Candida esophagitis (nystatin [Mycostatin]), as well as other prophylactic medications, such as acid-reducing agents (proton pump inhibitors, histamine-2 blockers). In addition to these agents, the patient might also require antihypertensive medications, insulin or oral hypoglycemic agents, or mild analgesics. In addition, certain patients require additional medications depending on their original disease; for example, patients who received a transplant for hepatitis B require anti– hepatitis B treatment (hepatitis B immunoglobulin, antivirals), and patients who received a transplant for Budd-Chiari syndrome might require anticoagulation. It is also emphasized that patients call the transplantation program with any new medication started for them by other physicians for assessing compatibility with their immunosuppressive agents.

Blood Work Instructions

Laboratory studies are usually done biweekly for the first 2 weeks, weekly for the next 8 weeks, every other week for 2 months, and then once monthly if laboratory test results are stable. Blood work can be done at the patient’s local laboratory. In any case, a prescription listing the needed blood tests and instructions for mailing blood samples for immunosuppression monitoring will be given to the patient. Outpatient laboratory work is reviewed by the post- transplantation coordinator in conjunction with the transplantation surgeon or physician.

Short-Term and Long-Term Problems During Follow-Up

Fever

Fever higher than 101° F or associated with chills should be taken seriously in immunosuppressed patients. The spectrum of potential infectious organisms is large in the immunosuppressed population and might also point to anatomic complications after OLT. In addition, fever could be the primary sign of rejection. The fever workup includes cultures, blood and radiologic diagnostic tests and, if needed, endoscopies and biopsies. Patients might need to be hospitalized and kept on broad-spectrum antibiotics or antiviral agents until results are available. Identifying the cause of the fever allows targeted appropriate treatment.

Increased Liver Function Test Results

Any dramatic or persistent increase in the results of LFTs mandates a series of diagnostic tests to evaluate for possible causes, such as rejection, ischemic insult to the liver (hepatic artery problems), biliary complications, infections (viral hepatitis, bacterial sepsis), or drug toxicities or hypersensitivities. A thorough workup, including blood tests, computed tomography (CT) scanning and ultrasound of the abdomen, radiologic studies of the biliary system, viral studies, and liver biopsy, may be indicated for appropriate therapeutic response.

Immunosuppression

The nature of immunosuppressive agent use in OLT in the United States has been reported by the Scientific Registry of Transplant Recipients, which analyzed data from the United Network for Organ Sharing database. The use of calcineurin inhibitors (CNIs) was reported in 97% of patients discharged from the hospital after OLT in the United States in 2004. Corticosteroid use was reported in more than 80%, mycophenolate mofetil (MMF) in nearly 54%, and azathioprine (AZA) in approximately 4% of patients at discharge. Sirolimus (SRL) use was noted in nearly 5% of OLT patients at discharge. Induction antibody use was noted in 21%, with most antibody use being anti-interleukin-2 receptor (IL-2r) antibodies and the remainder being antithymocyte globulin. It is clear that the overwhelming majority of programs view the use of CNIs as essential to the success of OLT, in both early and later phases after OLT.

Primary Immunosuppressants

CNIs—tacrolimus (TAC) and cyclosporine (CsA)—remain the cornerstone of immunosuppressive therapy; tacrolimus is used in 90% of primary OLT recipients at the time of discharge. Administration of one of these agents at therapeutic doses is the key to preventing rejection of the liver allograft.

Calcineurin Inhibitors. CsA and TAC are CNIs by virtue of their shared property of binding to their specific immunophilin, which leads to inhibition of calcineurin activity. The routine application of CNIs to OLT has dramatically reduced rejection, morbidity associated with treatment of rejection and graft loss, and death caused by rejection. The dosage of CsA or TAC is based on blood levels and is tailored based on time after OLT, presence or absence of renal dysfunction, or other side effects. The usual acceptable trough levels early after OLT are 8 to 12 ng/mL for TAC and 200 to 300 ng/mL for CsA. The side effects of TAC and CsA overlap and include nephrotoxicity, neurotoxicity, diabetogenicity, increased susceptibility to opportunistic infections, and certain de novo malignancies.

Because CNIs are metabolized in the liver by the cytochrome P-450 system, it is important to recognize when other drugs are being used that can increase blood levels of CNIs by inhibiting or competing for this system. Agents such as fluconazole, erythromycin, diltiazem, verapamil, and protease inhibitors are well recognized as causing increased CNI levels, which can result in increased CNI toxicities. Other drugs that enhance cytochrome P-450 activities, such as barbiturates, phenytoin, rifampin, and carbamazepine, can lead to reduction of CNI blood levels; if left untreated, this can lead to insufficient immunosuppression and resultant rejection. Thus, it is important to readjust CNI dosages when these medications are started or discontinued in transplant patients.

Corticosteroids. The most commonly used non-CNI immunosuppressive agents in OLT are corticosteroids. Corticosteroids have been shown to decrease transplant rejection when combined with other immunosuppressive agents. Whereas most post-transplantation protocols rapidly lower the dosage of corticosteroids to a minimum, some protocols also discontinue them shortly after OLT. These practices recognize that acute and chronic dosing of corticosteroids are associated with side effects that include hypertension, hyperglycemia, delayed wound healing, osteoporosis, glaucoma, suppressed growth, hyperlipidemia, increased risk of gastrointestinal ulceration, risk of fungal infections, and suppression of the pituitary-adrenal axis. Thus, attempts to reduce or eliminate corticosteroid use have encouraged the use of other non-CNI immunosuppressive agents with CNI maintenance therapy.

Adjunctive Agents

Adjunctive medications are usually prescribed in addition to a CNI and include the antiproliferative agents MMF, AZA, and SRL. In addition, induction antibody can help decrease the incidence of early rejection.

Mycophenolate Mofetil. Before the availability of MMF, AZA was used as an adjuvant immunosuppressive agent but was associated with significant myelosuppression and hepatotoxicity and was not useful in treating acute cellular rejection (ACR). MMF acts by a similar mechanism as AZA but is more selective, has fewer myelotoxic and hepatotoxic side effects, and appears to be a more effective immunosuppressive agent. When MMF is used in combination with TAC and steroids, the dose of TAC required is usually lowered. This can improve renal dysfunction that results from higher levels of CNI. MMF, as monotherapy after CNI withdrawal, should be used cautiously, because abrupt transition to MMF monotherapy has been associated with an unacceptably high incidence of ACR, severe ductopenic rejection requiring retransplantation, and severe steroid-resistant ACR. Although MMF is not suitable for all OLT candidates, it does have a role as a CNI-sparing agent, particularly in patients with renal dysfunction and neurotoxicity. It can be safely added to the current immunosuppressive regimen without increasing infectious complications.

Sirolimus. SRL is a macrolide antibiotic structurally related to TAC. It binds to the immunophilin FKBP12, but it does not inhibit cytokine gene transcription in T cells. Rather, SRL blocks signals transduced from various growth factor receptors to the nucleus by acting on phosphatidyl inositol kinases, known as mammalian targets of rapamycin. The pivotal prospective controlled trials in kidney transplantation that led to U.S. Food and Drug Administration (FDA) approval in 1999 delineated the efficacy and side effects of SRL, which included leukopenia, thrombocytopenia, elevated serum cholesterol levels, anemia, gastrointestinal disturbances, lymphocele, wound disruptions and infections, oral ulcerations, and elevated triglyceride levels. An increased incidence of pneumonitis and aseptic pneumonia has been reported, which in most cases is reversible with SRL discontinuation; however, it can be fatal.

Because of some reported cases of early vascular thrombosis after OLT, the FDA has not approved the drug to be used in liver transplantation, especially in the early period after OLT. A combination of SRL and low-dose CNIs has been used to protect renal function after OLT. Because of the antiproliferative activities of SRL, it is being tested for preventing recurrence of hepatocellular carcinoma after OLT.

Antibody Induction. Antibody induction therapy has been limited to the perioperative period as a means to reduce early exposure to CNIs or to obviate the need for large doses of perioperative corticosteroids. Antibody therapy can be depleting, receptor- modulating, or both. With the use of depleting antibody preparations, a phenomenon known as a first-dose effect can occur, related to the intravascular release of cytokines by lymphocytes. The symptoms, including fever, chills, tachycardia, gastrointestinal disturbances, bronchospasm, and fluctuations in blood pressure, can be blocked by pretreatment with corticosteroids, diphenhydramine hydrochloride, and acetaminophen.

More common antibodies used in liver transplantation are IL-2r blockers (daclizumab or basiliximab), antilymphocyte globulins (rabbit thymoglobulin), monoclonal anti–T cell antibodies (muromonab-CD3 or OKT-3), or anti-CD52 monoclonal antibody (alemtuzumab). Each of these antibodies has its own place in induction therapy or treatment of rejection.

Complications and Outcomes

The postoperative course in OLT patients ranges from straightforward to extremely complicated, and the outcome depends on the status of the recipient, donor organ, and technical issues in the operation. Complications after liver transplantation can have a significant impact on outcomes and costs of the procedure. Timely diagnosis of alterations in the normal postoperative course is the critical factor to minimize morbidity and mortality and to improve outcomes.

Primary Nonfunction

Primary nonfunction is characterized by post-transplantation encephalopathy, coagulopathy, minimal bile output, and progressive renal and multisystem failure, with increasing serum lactate and rapidly rising liver enzyme levels and histologic evidence of hepatocyte necrosis in the absence of any vascular compromise. With improved donor selection and management, operative techniques, reducing cold ischemia times, and newer preservative solutions, the risk of primary nonfunction has decreased but remains between 4% and 6% following OLT. Patients with initial dysfunction, also known as primary graft dysfunction, might recover with support, but those who progress to show evidence of extrahepatic complications, such as hemodynamic instability, renal failure, or other organ system dysfunction, can require urgent retransplantation.

Hepatic Artery Stenosis and Thrombosis

Angiographic evidence of more than a 50% reduction in the caliber of the hepatic artery lumen is defined as hepatic artery stenosis. When there is no arterial flow, the hepatic artery is thrombosed, which occurs in about 3% to 4% of the cases after liver transplantation. Usually, hepatic artery pathology is detected by ultrasonography, with the presence of a low resistive index, lower than 0.5, often with an increase in focal peak velocity as the first clue of stenosis. Lack of arterial flow, however, should raise suspicion for thrombosis. Clinically, these patients might show no symptoms (most often with stenosis), but generally there is an increase in abnormal LFT results, or fever and infection caused by infarcts in the liver after the hepatic artery is thrombosed. Hepatic artery stenosis can be treated by surgical intervention, especially soon after liver transplantation, whereas percutaneous angioplasty is generally reserved for stenosis occurring several weeks after the transplantation procedure, with more than a 90% success rate.

Complete hepatic artery thrombosis (HAT) usually occurs in the very early stages after liver transplantation, but it can occur many months after the procedure. Because the liver depends on the hepatic artery for most of its oxygenated blood, HAT can lead to acute massive hepatocyte necrosis, formation of a central biloma secondary to intrahepatic duct necrosis, multiple biliary structures, or intermittent bacteremia. Occasionally, rarely in adults and more often in children, HAT can be asymptomatic. The factors that determine whether a liver fails or survives with complete HAT is unknown, but the presence of collateral circulation (e.g., from the phrenic artery via vascularized adhesions to the liver) is usually associated with a more benign course after HAT. Angiography is the gold standard for diagnosis. In cases of early documentation of the problem (i.e., within 24-48 hours), urgent revascularization can result in arterial patency. However, a significant number of patients treated in this manner still require retransplantation because of biliary complications, persistent biliary sepsis, and intra-abdominal infection.

Portal Vein Stenosis and Thrombosis

Portal vein stricture can manifest shortly after liver transplantation because of the increased production of ascites and liver allograft dysfunction. The incidence of portal vein complications is less than 2% of OLT cases. Ultrasonography and CT angiography are usually diagnostic, whereas superior mesenteric artery angiography with late films is the confirmatory test. Treatment is by surgical intervention in early post-transplantation and by percutaneous transhepatic dilation or stenting of the stricture later after liver transplantation. If left untreated, it can progress to complete thrombosis of the vein or severe graft dysfunction and hemodynamic instability secondary to massive ascites.

Hepatic Outflow Obstruction

Complications associated with vena cava stenosis include a 2.5% to 6% incidence of venous outflow obstruction (iatrogenic Budd-Chiari syndrome), caused by rotation of the liver graft or anastomotic stricture. Stenosis of the suprahepatic cava anastomosis can manifest with hepatic outflow obstruction in the form of liver allograft dysfunction, ascites formation, and impairment of renal function. The problem carries a high risk for morbidity and mortality. Treatment is generally radiologic, using stents to treat the stenosis, but the success rate is between 50% and 60%. In some cases, retransplantation may be necessary.

Biliary Complications

Biliary complications continue to be the most common technical complication after liver transplantation, with an overall incidence of 15% to 20%. These complications range from early anastomotic leak to late stricture and obstruction in the extrahepatic or intrahepatic biliary system. The associated mortality rate with biliary complications is about 10%, which is mainly because of the delay in diagnosis or misdiagnosis of the problem, resulting in secondary infectious complications and graft dysfunction.

The biochemical abnormalities of elevated bilirubin and canalicular enzyme levels (e.g., alkaline phosphatase, γ-glutamyl transferase) associated with biliary complications are not specific; these indicators of biliary obstruction are also seen in ischemic graft injury, rejection, recurrent hepatitis C virus (HCV) infection, and sepsis. Imaging modalities such as ultrasonography to detect biliary dilation and radioisotope studies to evaluate anastomotic or cut surface leaks are considered relatively insensitive. The gold standard for evaluating biliary pathology is cholangiography (transhepatic or endoscopic) which helps make an accurate diagnosis. In addition, endoscopically or radiographically detected strictures, leaks, or obstruction can be treated at the time of diagnosis, often with biliary stenting. In fact, biliary leaks that occur after removal of the T-tube are preferentially treated by endoscopic biliary stent placement.

The most common biliary complication is biliary stenosis. This is the result of imperfect anastomotic technique or ischemia of the bile duct, which appears as a stenotic area in the common bile duct, at or slightly proximal to the biliary anastomosis, with proximal biliary dilation. Recurrent bouts of cholangitis or persistent abnormal LFT results can indicate an obstruction to bile outflow. In these cases, endoscopic or percutaneous balloon dilation of the bile duct stricture and stenting have been successful. In cases with no response, revision of the choledochojejunostomy or conversion of duct-to-duct anastomosis to choledochojejunostomy with a Roux-en-Y loop is the treatment of choice. A number of intrahepatic strictures of the biliary tree can be indistinguishable from simple anastomotic strictures at a clinical level and must be evaluated by cholangiography. The etiology and pathophysiology of these intrahepatic strictures have not been clearly elucidated. Often, the strictures seem to be associated with a hepatic artery thrombosis or stenosis, and ischemia of the biliary tree is probably the cause, especially in livers used from non–heart-beating donors. Preservation damage of the allograft can result in multiple intrahepatic biliary strictures, with or without biliary sludge and casts. In some patients, who originally received transplants for primary sclerosing cholangitis, recurrence of the disease seems a possibility. Although some patients with multiple intrahepatic strictures eventually need retransplant, others can live for years with minimal difficulties, especially if they receive chronic antibiotic prophylaxis.

Bleeding

Poor graft function, coagulopathy, imperfect hemostasis, or slippage of a tie can result in postoperative bleeding that requires re-exploration. Postoperative bleeding is reported in 7% to 15% of patients and requires re-exploration in approximately 50% of them. Even if easily controlled, postoperative bleeding leads to increased cost, morbidity, and mortality.

Ascites and Fluid Retention

A possible problem after OLT is fluid retention and the formation of ascites. This is especially more significant in malnourished patients and patients with preexisting ascites and edema. After ruling out the possibilities of renal dysfunction or vascular problems with the liver, these patients should be managed with diuretics and fluid management. Most patients start mobilizing the extra fluid a week after OLT and then can be treated with diuretic therapy if their kidneys are functioning. Nutritional support and careful management of fluid and electrolyte balance, in addition to diuretic therapy, are essential for treatment.

Infection

Infection is one of the leading causes of morbidity and mortality in liver transplant recipients. More than two thirds of liver transplant recipients have an infection in the first year after transplantation, and infection is the leading cause of death in these patients. In addition, the release of cytokines during the infection can have other indirect and negative effects, including allograft injury, opportunistic superinfection, and malignancy. The risk of infection in liver transplant recipients is determined by the intensity of exposure to infectious agents (hospital or community sources) and the overall immunosuppression level. This net state of immunosuppression is influenced by dose, duration, sequence, and choice of immunosuppressive medications; underlying immune deficiencies; presence of neutropenia or lymphopenia; mucocutaneous barrier integrity: presence of necrotic tissue, ischemia, or fluid collection; metabolic conditions such as diabetes mellitus; and activity of immunomodulating viruses.

After OLT, there are three periods during which infections with specific organisms are likely to occur. The patient’s susceptibility to infection at these times is strongly influenced by surgical factors, level of immunosuppression and environmental exposure, and doses, duration, and types of prophylaxis. During the first period, the first month immediately after transplantation, most infections are related to technical or surgical issues and complications. Exposure to infectious agents through prolonged hospitalization before transplantation or during postoperative care can also result in infection. Bacterial and candidal wound infections, urinary tract infections, catheter-related infections, bacterial pneumonias, and Clostridium difficile colitis predominate during this period; the causative organisms are similar to those for hospital-acquired infections common in other surgical patients. Although its incidence has markedly diminished with prophylaxis, reactivated human herpesvirus (herpes simplex virus) infection can occur in this time frame.

The next period is the second through sixth month after transplantation. During this time, infections from opportunistic organisms predominate as a result of cumulative immunosuppression. Viral infections, predominantly cytomegalovirus, and fungal infections, such as those caused by Aspergillus, Cryptococcus, Histoplasma, and Coccidioides species, can occur. Other herpesviruses, such as varicella-zoster virus, and de novo or recurrent hepatitis B and C viruses can cause infections in this period. Some rare bacterial infections caused by Nocardia and Listeria species, and Mycobacterium tuberculosis infection can also occur.

Approximately 7 to 12 months after transplantation, and beyond, most recipients can develop infections such as influenza, urinary tract infections, and community-acquired pneumonias, similar to those acquired by patients who have not received transplants. Reactivation of human herpesvirus 3 can manifest as herpes zoster, and, although it is uncommon, cytomegalovirus infections can occur. Sinister opportunistic fungal infections can occur as a result of cumulatively high levels of immunosuppression, poor graft function, or heavy environmental exposure.

Three notable scenarios can enhance patient susceptibility to opportunistic infections: acute organ rejection necessitating increased immunosuppression therapy; retransplantation, which restarts the immunosuppression and infection time line; and chronic viral infections, such as human immunodeficiency virus or hepatitis B or C.

Rejection

Acute rejection is an ongoing risk in any solid organ transplant, although it is somewhat less of a risk in OLT compared with more immunogenic organs, such as the kidney. Improvements in immunosuppressive therapy have reduced rejection rates and improved graft survival, but acute (cellular) rejection still develops in 25% to 50% of OLT patients treated with CNI-based immunosuppression. Chronic (ductopenic) rejection is somewhat less frequent and is declining; it occurs in approximately 4% of adult OLT patients. The incidence of rejection varies by type of immunosuppressive agent used and by the patient population.

Increases in bilirubin or liver enzyme levels, or both, after OLT in a stable patient may be the first sign of rejection. Histologic evaluation of the liver allograft (liver biopsy) is essential for making the diagnosis of rejection. Based on the presence and then the severity of rejection, the patient receives additional treatments, which could range from an increase in the baseline immunosuppressive regimen to the administration of steroid boluses and the addition of other drugs to the maintenance therapy, or the administration of antilymphocyte antibodies in case of resistance to the primary line of therapy.

Early acute rejection does not generally affect patient or graft outcomes for patients not infected with hepatitis C virus (HCV), except that multiple acute rejection episodes might be a risk factor for chronic rejection. Many patients with focal or mild histologic signs of rejection on protocol biopsy maintain steady graft function, even without treatment, and many centers no longer treat acute rejection aggressively, particularly in the setting of hepatitis C. Studies have shown a higher relative risk of death for HCV-infected patients with rejection versus that for non–HCV-infected patients with rejection (2.9 vs. 0.5, respectively). Therefore, rejection is to be avoided in HCV-infected patients at all times. Late acute rejection, defined as histologically confirmed acute cellular rejection occurring months after transplantation, can result from a precipitous or marked reduction in immunosuppressive agents or with nonadherence to medication.

Chronic rejection is characterized by the destruction of the portal bile ducts or biliary epithelial atrophy, a decreased number of hepatic arterioles in the portal tract, or obliterative arteriopathy. Chronic rejection was once a major cause of liver graft failure; with the newer immunosuppressive agent tacrolimus, the risk of chronic rejection is markedly reduced when used de novo after OLT. This can even successfully reverse chronic rejection, especially in its early stages (also known as rescue therapy) when the maintenance immunosuppression does not include tacrolimus.

Electrolyte Imbalances and Other Metabolic Abnormalities

Almost any metabolic imbalance can occur after OLT. This is not surprising, considering the magnitude of the physiologic stress of surgery, fluid shifts, multitude of pharmacologic agents administered, and multisystem complications. The most common imbalances, however, are hypokalemia, hyperkalemia, hyperglycemia, and hypomagnesemia.

Hypokalemia can occur as a side effect of potassium-wasting diuretic therapy, intracellular fluid shifts secondary to metabolic alkalosis, hypothermia, insulin therapy, and corticosteroid therapy. Rarely, if the serum potassium level is monitored regularly and supplementation given when indicated, hypokalemia from any cause is significant enough to produce physical signs.

Hyperkalemia is more often seen after transplantation, beginning 1 to 2 weeks after OLT. It is caused by renal tubular acidosis secondary to CNI use. It is easily manageable with a dietary regimen. Rarely, patients need to be placed on mineralocorticoids or potassium- chelating agents.

The main cause of hyperglycemia in liver transplant patients is preexisting diabetes mellitus. Other important causes are corticosteroids and CNIs. Drug-induced hyperglycemia is usually transient and improves after discontinuation of steroids and reduction in dosage of CNIs. Less than 5% of these patients require long-term treatment.

Hypomagnesemia is another phenomenon after OLT. Many patients are hypomagnesemic from malnutrition before transplantation, and the condition is exacerbated during the postoperative period. The exact nature of this problem is not completely understood. However, contributing postoperative factors are believed to include diuretic therapy and the renal effects of CNIs. Routine monitoring of the serum magnesium level and supplementation with IV or oral magnesium may be indicated.

Patients after transplantation and immunosuppression are prone to develop osteoporosis and other metabolic bone abnormalities. These patients should be monitored regularly by bone densitometry and other metabolic tests and receive appropriate replacement therapies with oral calcium and bisphosphonates.

Renal Dysfunction

Renal dysfunction (acute or chronic) occurs in 17% to 95% of patients after OLT. The wide range of incidence reported could result from the wide disparity in the criteria used to define renal failure and differences in the duration of follow-up. The most common causative factors include acute tubular necrosis secondary to ischemic or toxic insult to the kidneys, preexisting hepatorenal syndrome (HRS) or renal insufficiency, diabetes mellitus, drug-induced interstitial nephritis, and CNI nephrotoxicity. Dialysis requirements in the pre- or post-transplantation period, hepatitis C infection, and age have also been variably shown to be associated with an increased risk for the development of chronic kidney disease.

CNIs are generally considered to be the main cause of post-transplantation nephropathy in liver transplant patients, estimated to be responsible for 70% of progressive end-stage renal failure after OLT. In the presence of renal dysfunction after OLT, as the first line of therapy, these agents are withdrawn from the immunosuppressive regimen or the dose is reduced to minimize their nephrotoxic effect. Many recent immunosuppressive protocols contain fewer CNIs and instead have more of other agents, such as MMF or SRL, as the baseline immunosuppressant. Many patients with end-stage liver disease can have preexisting renal problems, and in the post-OLT period, CNIs should not be considered as the main cause of renal dysfunction. Careful assessment of patients and the cause of their renal dysfunction (possibly performing a renal biopsy) is helpful for decision making and for assessing the recoverability of kidney in order to offer appropriate treatment to these patients. In patients in whom significant and prolonged renal dysfunction occurs before OLT, combined liver and kidney transplantation should be considered.

Neurologic Complications

Natients occasionally experience various neurologic problems after OLT. These are more common in adults than in children. Most neurologic complications are related to the degree of pretransplantation encephalopathy caused by hepatic encephalopathy or electrolyte disturbances, in particular hyponatremia, as well as the idiosyncratic central nervous system effects of metabolic abnormalities caused by immunosuppressive agents, most notably the CNIs. These drugs can produce a wide clinical spectrum of signs and symptoms, from mild tremor and acute confusion to status epilepticus. CNI-related neurotoxicity occurs in approximately 25% of liver transplant recipients. These could be dose-related and include impaired mentation or confusion, psychosis, dysphasia, mutism, cortical blindness, extrapyramidal syndromes, quadriplegia, encephalopathy, seizures, and coma. Treatment includes reducing or completely discontinuing the suspected offending agent. In some cases of suspected CNI toxicity, substitution of one CNI by another is all that is needed. It is also important to identify other drugs on the patient’s list that might increase immunosuppressive levels and thereby trigger neurotoxicity.

Malignancy

Solid organ graft survival rates have improved remarkably since the 1990s because of improved immunosuppression, innovative technical procedures, and assiduous post-transplantation monitoring. However, recipient mortality caused by de novo post-transplantation malignancies remains a serious impediment to long-term survival. The increasing prevalence of post-transplantation malignancies has been evidenced by data collected by transplant registries in the United States, Europe, Australia, and New Zealand, as well as a large single-center analysis. In liver transplantation, estimates of cancers approach 15% by 10 years after OLT, with the rate for solid organ tumors being markedly higher in adults than in children and in patients with risk factors, such as colon cancer in OLT patients with ulcerative colitis and aerodigestive cancers in smokers.

Various factors have been proposed to explain the increased cancer risk in transplant recipients. Among the earliest was the concept of impaired immune surveillance resulting from systemic immunosuppression. Long-term antigenic stimulation and environmental influences, such as UV irradiation, genetic predisposition, uremia preceding transplantation, donor-and-host interactions, and mutagenic activity of immunosuppressive agents, have also been implicated as potential causative factors. Many of the cancers with a significantly increased incidence are considered to be associated with viral infections, such as skin cancers, possibly from human papillomavirus (HPV), Kaposi’s sarcoma, cervical cancer (from HPV), and lymphomas. As might be expected, post-transplantation malignancies are associated with higher mortality rates, and many of the deaths occur in patients with a fully functioning allograft.

Post-transplantation lymphoproliferative disorders (PTLDs) are a heterogeneous group of hyperplasias and lymphomas that are serious post-transplantation complications for all organ recipients. Most cases of PTLD are believed to arise from Epstein-Barr virus (EBV)-infected B cells. The clinical signs and symptoms of PTLD are diverse and are similar to those seen during primary EBV infection, such as fever, sweats, malaise, and lymphadenopathy. The incidence of PTLD varies with the transplanted organ, with the highest prevalence in the small bowel (approximately 20%) and a lower prevalence in other solid organs (1% to 10%). However, despite identification of EBV as the causative factor in 90% of patients with PTLD, the immunosuppressive drugs used to prevent graft rejection are largely responsible for the deficient immune response to EBV infection or reactivation. In contrast to solid organ cancers after OLT, the preponderant risk is in the pediatric population.

In any case, it is critical that the local physician and transplantation team search diligently for de novo cancers in OLT patients and, most importantly, educate patients about reducing the risk of cancers by routine use of sunscreens, early testing, and vaccinations.

Disease Recurrence

Hepatitis B

A total of 5% to 10% of patients undergoing OLT have HBV- associated chronic or fulminant liver disease. Long-term survival depends on preventing allograft reinfection or slowing disease progression in those who have recurrent disease. In the absence of prophylactic measures, the risk of HBV reinfection after OLT is approximately 80%; it is related mainly to the level of HBV replication at the time of transplantation. Recurrent infection in the graft can lead to graft failure, retransplantation, or death, and in the past this was the most common cause of reduced patient and graft survival.

Significant improvements in patient and graft survival in HBV liver transplant recipients have been made during the past 15 years. The first major therapeutic advance was the use of long-term hepatitis B immune globulin (HBIG) to prevent reinfection. The second major advance came with the availability of highly effective and well-tolerated antiviral agents against HBV, such as lamivudine, adefovir dipivoxil, and more recently, entecavir and tenafovir, which improved the outcomes of patients with decompensated cirrhosis awaiting transplantation as well as transplant recipients who had recurrent HBV disease. Finally, with the use of HBIG in combination with antivirals, the risk of reinfection has been reduced to 10% or lower during the first 2 years following transplantation. As a result of these therapies, the outcomes of patients with acute and chronic HBV-related liver disease undergoing liver transplantation are now similar to or better than those of patients undergoing transplantation for non-HBV indications. Because of the increase in development of resistance to lamivudine, the American Association for the Study of Liver Diseases has recommended entecavir for preventing disease recurrence after OLT.

Hepatitis C

Post-transplantation recurrence of HCV infection is a universal phenomenon, with a highly variable natural history. The histologic progression of chronic hepatitis C is more aggressive and is associated with lower patient and graft survival when compared with that of non-HCV liver recipients. Approximately 40% of the liver recipients develop hepatic decompensation in 1 year, and 10% to 25% develop cirrhosis within 5 years after transplantation. Factors associated with recurrence include donor and recipient age, recipient gender and race, presence of genotype 1, level of viremia at the time of transplantation, the use of strong antilymphocyte induction therapy, and high doses of corticosteroids. No single factor has been uniformly shown to be the strongest predictor of outcome.

Results of antiviral therapy in recurrent HCV after OLT have also not been totally convincing. A number of reports have shown no response to histologic improvement. Unfortunately, there are no standard time courses for treatment, dosages, and modes of follow-up. It seems that only prolonged treatment and histologic follow-up can evaluate whether progression of fibrosis is halted following post-OLT treatment for recurrent HCV infection. The current sustained virologic response after a combination of pegylated interferon and ribavirin in the OLT population is approximately 10% to 25%. Recently, trials with protease inhibitors, alone or in combination with interferon and ribavirin, have shown promising results. Most centers, including our program, start antiviral therapy with interferon and ribavirin in the presence of stage II or III fibrosis in the liver allograft or signs of aggressive recurrence of HCV. During the treatment course, monitoring of platelets, white cell count, hemoglobin, and renal function, in addition to LFTs, is essential. Abnormalities in these tests mandate the dose adjustment of growth factors, such as filgastrim (Neupogen) and epoetin alfa (Epogen). Biochemical, histologic, and virologic responses are followed by LFTs, liver biopsy, and quantitative measurement of HCV RNA.

Cholestatic Diseases

There is approximately a 10% to 20% long-term risk of recurrence for cholestatic liver disorders, such as primary sclerosing cholangitis and primary biliary cirrhosis. Recurrence can occur within months after OLT but generally it takes years for the recurrence to occur. It can mimic rejection or bile duct complications. Diagnosis is made by appropriate histologic, biochemical, and radiologic tests. The impact of recurrent cholestatic disease is minimal in terms of patient and graft survival, with rates of retransplantation in primary biliary cirrhosis lower than 2% and, for primary sclerosing cholangitis, approximately 15% at 10 years.

Graft and Patient Survival

With improvements in immunosuppressive agents and increased knowledge about the care of post-OLT patients since the 1990s, 1- and 2-year patient survival rates have increased from 76% and 72% to 86% and 84% respectively, with a 5-year survival of 72%. During the same period, with increased understanding of organ donor management and better preservation solutions, graft survival at 1 year has increased from 72% to 82% and the 5-year survival has increased to 67%.

Conclusions

Liver transplantation has progressed to become an acceptable means for treating end-stage liver disease, with excellent long-term outcomes. This was not achievable without multidisciplinary teamwork among transplantation center teams and outside primary physicians and caregivers. Increased understanding of the care of these highly complicated patients and effective communication among team members has benefited these patients, with consequently better long-term functional recovery.

Summary

• Liver transplantation has progressed to become an acceptable means for the treatment of end-stage liver disease, with excellent long-term outcomes. Survival outcomes have dramatically improved over the years; the longest living patient has survived more than 35 years after liver transplantation.
• Orthotopic liver transplantation involves the resection of the recipient native liver followed by the implantation of a whole or partial liver graft from a deceased or living donor.
• Immunosuppressive agents are the mainstay of rejection prevention in liver transplantation. To prevent their long-term toxicity, the patient must adhere to the prescribed regimen and compliance with close follow-up for medication adjustments.
• Complications (e.g., infection, rejection, disease recurrence) are common after liver transplantation and, if untreated, can lead to graft failure and increased morbidity and mortality. Close follow-up of the patients by the transplantation team is essential for prevention, early diagnosis, and treatment of these issues.
• Liver failure secondary to viral hepatitis (especially hepatitis B and C) is a common indication for liver transplantation. Hepatitis B recurrence is manageable with new antiviral drugs. Hepatitis C recurrence is universal, with a highly variable natural history and potentially lower patient and graft survival.
• New treatments for the prevention of recurrent diseases and rejection are being tested and are likely to improve long-term outcomes.

Suggested Reading

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