INDICATIONS

The major indications for liver transplantation in adults reflect the most frequent causes of adult liver disease, notably chronic hepatitis C, alcoholic liver disease, and, to a lesser extent, chronic hepatitis B, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis, and hemochromatosis (Fig. 95-1). Many liver transplantation candidates previously diagnosed as having “cryptogenic” cirrhosis are now considered to have underlying nonalcoholic fatty liver disease (NAFLD). An uncommon but important indication for liver transplantation is acute liver failure, which has a high mortality rate in the absence of liver transplantation. The role of liver transplantation in primary hepatic malignancy has become better defined; a subset of patients with primary hepatocellular carcinoma (HCC) have a high likelihood of cure with transplantation, although the roles of adjunctive therapies such as transarterial chemoembolization (TACE), radiofrequency ablation, and the oral chemotherapy agent sorafenib need to be defined (see Chapter 94).¹⁷ The other major primary adult hepatic malignancy, cholangiocarcinoma, had been regarded as a contraindication to liver transplantation because of its rapid and almost invariable recurrence post–liver transplantation, although acceptable outcomes have been reported in a subset of patients with hilar tumors who receive adjuvant external beam radiation and chemosensitization (see Chapter 69).¹⁸ The major indication for pediatric liver transplantation is biliary atresia following a failed Kasai procedure (portoenterostomy) or delayed recognition of the diagnosis (see Chapter 62). Other major pediatric indications include α₁-antitrypsin deficiency and other metabolic disorders (see Chapter 76).

Figure 95-1. Proportion of liver transplants performed for specific indications, 1992 to 2007.

(From O’Leary JG, Lepe R, Davis GL. Indications for liver transplantation. Gastroenterology 2008; 134:1764-76, with permission.)

Recognition of cirrhosis per se is not an indication for liver transplantation, although a key issue in managing a cirrhotic patient is deciding whether transplantation will be needed in the future and when referral for evaluation is appropriate (Table 95-1). Another important aspect of the management of a compensated cirrhotic patient is the anticipation of complications. Endoscopic surveillance of patients with cirrhosis for gastroesophageal varices, for instance, to offer prophylaxis, either pharmacologic or endoscopic, to prevent initial or recurrent gastrointestinal bleeding is now routine practice (see Chapter 90).¹⁴ Surveillance for HCC is also regarded as the standard of care in a cirrhotic patient (see Chapter 94). Discovery of a hepatic mass suggestive of HCC in a cirrhotic patient should prompt evaluation to determine whether hepatic resection or liver transplantation is the most appropriate curative approach. Otherwise, liver transplantation should normally be a consideration only when the limits of medical therapy for complications of cirrhosis have been reached, particularly if LDLT is an option. The risk of surgery must always be weighed against a realistic assessment of the potential recipient’s prognosis in the absence of liver transplantation. For example, in a patient with decompensated cirrhosis caused by HBV infection, effective suppression of viral replication by an effective antiviral agent may result in impressive clinical improvement, thereby delaying or even obviating the need for liver transplantation (see Chapter 78). Similarly, abstinence from alcohol can result in resolution of signs of hepatic decompensation in a patient with alcoholic liver disease (see Chapter 84). The course of chronic liver disease remains unpredictable, however, and observing an apparently well-compensated patient deteriorate dramatically because of an intercurrent complication such as variceal bleeding is sobering. Although recognition of cirrhosis implies a risk of major complications and diminished life expectancy, a cirrhotic patient can remain stable for a protracted period of time. For example, Fattovich and colleagues¹⁹ observed that in patients with well-compensated cirrhosis caused by HCV infection, major complications of portal hypertension such as ascites and variceal hemorrhage occurred in less than 30% at 10 years; in the absence of an index complication, survival was excellent (Fig. 95-2). Once a complication supervenes, however, survival diminishes rapidly. For example, after the development of ascites refractory to diuretics, only 25% of patients survive beyond 1 year.²⁰ A prospective study of more than 200 Italian patients with HCV-related compensated cirrhosis followed for up to 17 years found that HCC was the most common complication of cirrhosis detected, occurring in 32%, followed by ascites. These findings imply that HCC, rather than complications of portal hypertension, is the most frequent reason for a worsening prognosis in a patient with cirrhosis.²¹

Table 95-1 Indications for Liver Transplantation

Figure 95-2. Probability of development of major complications (decompensation) in patients with well-compensated cirrhosis due to hepatitis C.

(From Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology 1999; 112:463-72, with permission.)

The development of predictive models based on the natural history of PBC (see Chapter 89) and PSC (see Chapter 68)²² has helped clinical decision making for patients with these cholestatic disorders, which tend to progress in a fairly stereotypical fashion. Before the introduction of the MELD score, analogous models had not been available for the noncholestatic forms of cirrhosis, and the decision to refer a patient for liver transplantation generally was based on an estimate of disease severity using objective parameters such as the serum albumin level as well as more subjective factors such as the presence of hepatic encephalopathy, as in the Child-Turcotte-Pugh score (see Chapter 90).

On clinical rather than biochemical grounds, important indications for liver transplantation remain disease severity reflective of hepatocellular failure, reflected by coagulopathy and jaundice; complications of portal hypertension, such as refractory ascites and recurrent variceal bleeding; or the combination of portosystemic shunting and diminished hepatocellular function, as in hepatic encephalopathy (see Table 95-1). Following validation of predictive models for the natural history of PBC and PSC, prediction of an individual patient’s course has been possible on the basis of simple clinical and laboratory parameters, the most ominous of which is a rising serum bilirubin level. Although deterioration in a patient’s quality of life typically may not be reflected adequately in predictive models, including MELD, the presence of potentially disabling symptoms such as pruritus and osteopenia in patients with cholestatic and other forms of cirrhosis, as well as recurrent bacterial cholangitis in those with PSC, are important considerations in deciding when to refer a patient for liver transplantation. MELD exceptions, such as adding points to the so-called biological MELD score in order to increase the likelihood of liver transplantation, require approval by a local regional review board, which includes representatives from local transplantation programs. The awarding of extra MELD points recognizes that although this system is a major advance in organ allocation, at least some patients may be disadvantaged by its use of purely objective parameters and exclusion of factors such as intractable ascites or encephalopathy that were incorporated into older allocation schemes. Ideally, liver transplantation should occur before a protracted period of disability reduces the likelihood that post-transplantation rehabilitation will lead to full employment and normal social functioning.

LISTING CRITERIA AND POLICIES OF THE UNITED NETWORK FOR ORGAN SHARING

Organ allocation within the United States is administered by the United Network for Organ Sharing (UNOS), which now considers only disease severity (and not waiting time, as in the past) to determine a patient’s priority for liver transplantation. A variety of organ allocation systems have been used since the 1980s to allocate the limited number of deceased-donor organs in an equitable manner. Older systems were based on a combination of clinical and biochemical parameters such as the Child-Turcotte-Pugh score. The MELD score is a mathematical formula (available at www.unos.org) that incorporates the serum bilirubin level, creatinine level, and international normalized ratio (INR) and provides a more objective and accurate way to stratify liver transplantation candidates for organ allocation and to eliminate time waiting for a donor organ as a determining factor.²³ The MELD score overcomes some of the inherent limitations of the Child-Turcotte-Pugh score, including limited discriminatory ability, subjective interpretation of parameters such as presence or absence of ascites on the basis of the physical examination, and the “ceiling effect” of the Child-Turcotte-Pugh score (e.g., no greater weight is given to a serum bilirubin level of 35 mg/dL than to a level of 3.5 mg/dL, even though a patient with the markedly higher bilirubin level clearly has more advanced liver disease). Inclusion of the serum creatinine level reflects the major prognostic importance of renal dysfunction in patients with advanced liver disease. Adoption of the MELD score has been a major step in achieving an equitable organ allocation system in the United States, although it will undoubtedly continue to undergo refinement.

ABSOLUTE AND RELATIVE CONTRAINDICATIONS

Contraindications to liver transplantation have also evolved, reflecting innovations in surgical technique and postoperative care. As an example of the latter, effective prophylaxis against HBV recurrence now allows excellent graft and patient survival rates in patients with chronic hepatitis B.²⁴ On the other hand, greater experience has highlighted the futility of retransplantation in many debilitated recipients with a failing graft caused by recurrent HCV infection.²⁵ By contrast, the introduction of highly effective antiretroviral therapy has allowed consideration of liver transplantation in human immunodeficiency virus (HIV)–infected patients with decompensated liver disease, typically caused by either HCV or HBV infection.²⁶ Still, absolute and relative contraindications remain. An absolute contraindication (Table 95-2) to liver transplantation is a clinical circumstance in which the likelihood of a successful outcome is so remote that liver transplantation should not be offered. A relative contraindication implies a suboptimal likelihood of a good outcome, although liver transplantation may still be considered in some patients.

Table 95-2 Absolute Contraindications to Liver Transplantation

* ICP, intracranial pressure; CPP, cerebral perfusion pressure; CPP, equals the mean arterial pressure minus ICP.

The role of liver transplantation in the management of HCC has become better defined with the recognition that a large tumor burden is associated with a high probability of metastatic spread within a short time of liver transplantation.²⁷ Some tumor characteristics predictive of a poor outcome, most notably vascular invasion, may only be apparent once the explant is examined, despite the sophistication of current imaging techniques. Although results of liver transplantation for cholangiocarcinoma have been poor because of a high rate of tumor recurrence, a subset of patients with hilar tumors may benefit from multimodal therapy and liver transplantation. The results of liver transplantation remain poor for angiosarcoma, and its recognition pre–liver transplantation remains an absolute contraindication. By contrast, at least some patients with epithelioid hemangioendothelioma have been transplanted successfully, despite an extensive tumor burden, with documented regression of extrahepatic metastases.

For a transplantation candidate with a prior extrahepatic malignancy, therapy needs to have been curative, with the resection specimen indicating a low likelihood of metastatic spread. A two-year recurrence-free interval is adequate for most nonhepatic malignancies prior to liver transplantation, but for breast cancer, colon cancer, and malignant melanoma, a longer period following resection is desirable.²⁸ Myeloproliferative disorders frequently underlie Budd-Chiari syndrome (see Chapter 83), but fortunately their evolution to acute leukemia is not accelerated following liver transplantation.²⁹

Ongoing alcohol or recreational drug use remains an absolute contraindication to liver transplantation. If continued abuse is a concern, random toxicology screens are appropriate. Although medicinal marijuana may be used legitimately for palliation, most transplantation programs discourage the use of marijuana because of concerns about the overall compliance of users and possible pulmonary side effects, as well as some evidence that its use may adversely affect the course of liver disease (a point that may be moot in a patient already listed for liver transplantation). A history of prescription narcotic abuse is also a cause for concern because it may contribute to difficulties with pain management post–liver transplantation. Non-narcotic alternatives should be attempted for the management of chronic pain. Other analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) also are contraindicated in persons with end-stage liver disease because of potential renal and gastrointestinal complications. Cigarette smoking is prohibited in liver transplantation candidates as well because of its multiple adverse effects, including an associated risk of hepatic artery thrombosis and malignancy post–liver transplantation.³⁰ With the increasing use of herbal compounds and other so-called health products, a discussion of their unproven efficacy and unknown toxicities and caution against their use in the post–liver transplantation setting because of the potential for drug interactions are appropriate (see Chapter 87).³¹

The careful medical evaluation necessary prior to liver transplantation frequently uncovers important comorbidities, typically cardiac and pulmonary. Although patients with decompensated cirrhosis were previously thought to be somewhat protected against coronary artery disease (CAD) because of low afterload, reflecting peripheral vasodilatation, decreased hepatic synthesis of cholesterol, and increased circulating estrogen levels, cirrhotic patients have a prevalence of CAD at least as great as that of an age-matched control population.³² Risk factors for CAD in cirrhotic patients include a high prevalence of diabetes mellitus. Additional risk factors in the post–liver transplantation period include immunosuppressive drugs that contribute to systemic hypertension, hyperlipidemia, and obesity. Assessment of cardiac risk in cirrhotic patients may be inadequate because of poor physical stamina during routine stress testing. Administration of dobutamine mimics the physiologic effects of exercise and is used with stress echocardiography to exclude clinically significant CAD in liver transplant recipients with cirrhosis. Patients who reach 85% of the maximal predicted heart rate without an abnormality on stress echocardiogram have a low likelihood of peri- and postoperative ischemic cardiac events.³³ Discrete coronary artery stenoses can be managed by angioplasty and stenting pre–liver transplantation. Although surgical bypass grafting may be contraindicated because of a significant perioperative risk of excessive bleeding in a patient with decompensated cirrhosis, such surgery, if successful, may render a patient an acceptable candidate for liver transplantation. Pre–liver transplantation cardiac evaluation may overestimate cardiac performance. impaired cardiac function may become apparent only after the protective effect of the decreased systemic vascular resistance that characterizes cirrhosis is lost after liver transplantation, when afterload increases because of the hypertensive effects of the primary immunosuppressive agents and when overvigorous volume repletion may occur.³⁴ Specific forms of cirrhosis may be associated with extrahepatic manifestations that diminish long-term survival. For example, lethal cardiac arrythmias may result in poorer survival in patients who undergo liver transplantation for decompensated cirrhosis caused by hemochromatosis.³⁵

Pulmonary evaluation in the liver transplantation candidate may reveal abnormal arterial oxygenation (see Chapter 92). Although severe chronic obstructive pulmonary disease or pulmonary fibrosis precludes liver transplantation, respiratory restriction as a result of ascites or diminished respiratory muscle strength caused by chronic illness is reversible and does not preclude liver transplantation. Even patients who undergo liver transplantation for α₁-antitrypsin deficiency may show improvement in pulmonary function tests postoperatively.³⁶ The hepatopulmonary syndrome (HPS) is characterized by the triad of chronic liver disease, pulmonary vascular dilatations (with right-to-left shunting), and hypoxemia.³⁷ The diagnosis is suggested by the finding of a Pao₂ value of less than 70 mm Hg on an arterial blood gas determination obtained from the patient in the supine position. Definitive diagnosis is made by the demonstration of intrapulmonary vascular dilatations by contrast-enhanced echocardiography (which is the most sensitive technique), perfusion lung scanning with ^99mTc–labeled macroaggregated albumin, or pulmonary arteriography. Detection of contrast in the left side of the heart within several beats after its appearance in the right atrium indicates intrapulmonary shunting. Predictors of potential reversibility of HPS after liver transplantation include younger age, a lesser degree of preoperative hypoxemia, and adequate correction of hypoxemia with inspiration of 100% oxygen (Pao₂ >200 mm Hg).³⁸ In the majority of patients with HPS, hypoxemia resolves within several months of liver transplantation, although a protracted period of ventilatory support in the immediate postoperative period may be required. Because of the potential for improvement with liver transplantation, extra MELD points may be allocated to a patient with HPS. HPS must be distinguished from portopulmonary hypertension, because the latter is associated with high perioperative mortality and frequently unchanged pulmonary hemodynamics despite liver transplantation. Specifically, documentation of a mean pulmonary arterial pressure greater than 35 mm Hg, pulmonary vascular resistance greater than 300 dynes • s • cm⁻⁵, and cardiac output less than 8 L/minute are indicative of a high perioperative risk because the patient will be unable to increase the cardiac output appropriately in response to altered intra- and postoperative hemodynamics. Vasodilator therapy may reduce pulmonary arterial pressure and permit liver transplantation.³⁹

Hepatic hydrothorax is a frequent manifestation of portal hypertension characterized by collection of a transudate in the pleural cavity, usually on the right side and often with relatively little ascites remaining in the abdominal cavity (see Chapter 91). Hepatic hydrothorax can be particularly difficult to manage and often requires repeated thoracentesis or placement of a TIPS pre–liver transplantation.⁴⁰ The temptation to insert a permanent chest tube needs to be resisted because a chest tube can lead to infection in the pleural cavity with the risk of fistula formation. Similarly, interventions such as pleurodesis or pleural decortication should be avoided because hepatic hydrothorax can be controlled only by a reduction in portal pressure.

Active uncontrolled extrahepatic infection is an absolute contraindication to liver transplantation, which should be deferred if sepsis is suspected. In a patient with decompensated cirrhosis, an unexplained clinical deterioration such as altered mental status or systemic hypotension in the absence of gastrointestinal hemorrhage must be presumed to reflect sepsis and is an indication to start broad antibiotic coverage while culture results are awaited. Liver transplantation, however, may be the only option for a patient with recurrent bacterial cholangitis in the setting of PSC (see Chapter 68). Repeated bouts of spontaneous bacterial peritonitis need to be controlled by antibiotic therapy prior to attempting liver transplantation (see Chapter 91). A particularly ominous finding is fungemia, which is typically impossible to eradicate in a debilitated cirrhotic patient and precludes liver transplantation.

An important technical consideration in the liver transplantation candidate is the presence of vascular abnormalities that may increase the difficulty of surgery. With increased surgical experience, however, such abnormalities, most notably portal vein thrombosis, are less likely to be obstacles to liver transplantation. More extensive vascular thrombosis with involvement of the superior mesenteric vein may require extensive vascular reconstruction.⁴¹ The presence of a prior portosystemic shunt, particularly a nonselective (side-to-side or end-to-side) portocaval shunt, increases the technical complexity of liver transplantation but is no longer regarded as a contraindication. With the widespread use of TIPS to control manifestations of portal hypertension, including variceal hemorrhage, intractable ascites, and hydrothorax, without disrupting the vascular anatomy, TIPS is now the most frequent shunt encountered in liver transplant recipients and does not usually present an additional operative challenge during liver transplantation.

Age restrictions have been relaxed in liver transplantation candidates, although close attention must be paid to comorbid conditions in older patients that not only increase the risk of perioperative mortality, but also may decrease the likelihood that the liver transplant recipient will be able to return to an active lifestyle, particularly because severe liver disease may cause more debility in older than in younger patients.⁴² Because a subset of robust older recipients have good outcomes after liver transplantation, candidates in their late 60s or even older who are otherwise in good health should not be precluded a priori from liver transplantation.

The differential diagnosis of renal insufficiency in patients with advanced liver disease includes hepatorenal syndrome, which is potentially reversible. Renal failure remains an important predictor of a poor outcome post–liver transplantation (see Chapter 92).⁴³ Typically, renal dysfunction in patients with decompensated cirrhosis reflects a variety of insults, including sepsis, hypotension, and use of nephrotoxic medications. In liver transplant recipients with decompensated cirrhosis, renal insufficiency severe enough to require dialysis has been associated consistently with poorer patient outcomes. Assessment of the potential for improvement following liver transplantation is critical. A rule of thumb is that return of adequate renal function is unlikely after liver transplantation if dialysis has been required for more than one month prior to liver transplantation. Inclusion of the serum creatinine level in the MELD score reflects the major prognostic importance of renal insufficiency in patients with advanced liver disease. A consequence of this recognition has been an increased rate of combined liver-kidney transplantation in the MELD era of liver transplantation, with a consequent depletion in the supply of kidneys for patients awaiting isolated deceased-donor renal transplantation.⁴⁴ An important reflection of impaired free-water handling in patients with decompensated cirrhosis is dilutional hyponatremia. Consequences of hyponatremia include altered mental status with more profound degrees of hyponatremia and an increased risk of calcineurin-induced neurotoxicity after liver transplantation (see later). Incorporation of the serum sodium level into the MELD formula (MELDNa) may increase the prognostic accuracy of the MELD score, particularly in patients with relatively low MELD scores.⁴⁵

A major systemic manifestation of decompensated cirrhosis is malnutrition. Loss of muscle mass increases the likelihood of perioperative morbidity, with a need for more protracted ventilator support and poorer patient survival. Peripheral edema and ascites make changes in body weight or anthropometric measurements unreliable for assessing nutritional status in a patient with advanced cirrhosis. More profound nutritional deficiencies may reflect the specific cause of cirrhosis, as in a malnourished alcoholic person with multiple vitamin and electrolyte deficiencies or a patient with cholestatic liver disease and depletion of fat-soluble vitamins as a result of small intestinal malabsorption. Evaluation by a dietitian is an integral part of the assessment of the liver transplantation candidate. Attempts to improve the nutritional status of liver transplantation candidates have included enteral and parenteral feeding, which may result in improvement, albeit modest, in some patients.⁴⁶ An increasingly obese liver transplantation candidate pool is raising concerns about the role of obesity in the pathogenesis of NAFLD and in postoperative mortality resulting from cardiovascular events, as well as postoperative complications such as wound infections.⁴⁷

TRANSPLANTATION EVALUATION AND LISTING

The details of the formal liver transplantation evaluation vary from center to center, but the essentials are to establish that liver transplantation is indicated in the management of the potential recipient’s liver disease, the patient has no comorbidities severe enough to preclude transplantation, and the patient has adequate emotional and social resources to undergo a major surgical procedure and continue on long-term immunosuppression afterward (Table 95-3). Generally in the United States, clearance is needed from the patient’s insurance carrier before the extensive testing necessary for liver transplantation evaluation is undertaken. The patient is seen by a transplantation surgeon, hepatologist, psychiatrist, dietitian, and social worker, with additional consultations as clinically indicated. As increasingly frailer and older candidates are evaluated, identifying potential causes of perioperative morbidity, such as carotid artery stenosis, is imperative. Detailed abdominal imaging is performed not only to screen for HCC, but also to uncover vascular abnormalities such as portal vein thrombosis that may make surgery technically challenging. Disease-specific issues need to be addressed, such as the likelihood of recidivism in the alcoholic patient or management of a large tumor burden in the patient with HCC. The appropriateness of liver transplantation for each candidate is then discussed formally at a meeting of the patient selection committee with input from the members of the transplantation team. If the patient’s candidacy is deemed to be appropriate, formal listing is undertaken with UNOS by matching of the recipient by blood type and weight with potential deceased donors. Once listed, the patient’s priority for organ allocation is determined by the MELD score, based either on the pure score consisting of the serum bilirubin level, serum creatinine level, and INR or that score plus additional points awarded for specific indications, such as HCC. Waiting time on the list is no longer a determining factor. With the critical and seemingly intractable shortage of deceased-donor organs, a major challenge for UNOS and organ retrieval agencies elsewhere in the world has been to develop an equitable system of allocation in an effort to ensure that hepatic allografts are not used for patients whose prognosis without liver transplantation remains good. Patients with a MELD score of less than 15 appear have a better survival without transplantation than with transplantation. As shown in Figure 95-3, the MELD score has been shown to correlate with the three-month survival rate. Patients with a MELD score of less than 10 are ineligible for active listing with UNOS unless they are eligible to receive extra points because of an additional complication of liver disease, such as HCC or HPS.

Table 95-3 Transplantation Evaluation Process

From O’Leary JG, Lepe R, Davis GL. Indications for liver transplantation. Gastroenterology 2008; 134:1764-76, with permission.

Figure 95-3. Relationship between the three-month survival rate and Model for End-stage Liver Disease (MELD) score in patients with cirrhosis.

Once the evaluation process is complete and the patient is accepted for liver transplantation, financial clearance is sought from the patient’s private, state, or federal insurer to fund the procedure. Unfortunately, criteria for coverage for liver transplantation vary among insurers; however, in the United States, if Medicare, the major federal payor, funds a particular indication for liver transplantation, the other insurance carriers generally follow suit.

DISEASE-SPECIFIC INDICATIONS

HCV, hepatitis C virus; RNA, ribonucleic acid.

Once recurrent HCV infection in the graft progresses to cirrhosis, overt hepatic decompensation is frequent. In contrast to recurrent HBV infection, effective prophylaxis against recurrent HCV infection has not been possible (Fig. 95-4).³ Current treatment strategies generally fall into three categories: (1) pretransplantation antiviral therapy; (2) preemptive therapy started in the early post–liver transplantation period before the development of clinically apparent acute hepatitis C; and (3) post-transplantation therapy at the time of diagnosis of acute hepatitis C or for established or severe chronic hepatitis C.³ The approach followed by most transplantation centers is to initiate antiviral therapy when clinically significant evidence of recurrent HCV infection is identified (as defined by either grade 3 or 4 (of 4) hepatic inflammation or a fibrosis stage of F2 or more). Accurate assessment of the efficacy of treating recurrent HCV infection is difficult, however, because most reported studies have been uncontrolled, single-centered, and small in size.

Figure 95-4. Probability of hepatic decompensation in patients with cirrhosis resulting from recurrent hepatitis C following liver transplantation.

(From Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 2000; 32:852-8, with permission.)

Interferon alpha monotherapy generally has been ineffective in treating established recurrent hepatitis C (see Chapter 79). When interferon is combined with ribavirin, the rate of virologic response is increased, but at the cost of frequent and potentially severe side effects.³ Leukopenia is a particularly vexing problem in patients undergoing such treatment, and adjunctive administration of granulocyte colony–stimulating factor (G-CSF) may permit continuation of interferon therapy. The long-acting pegylated interferons have been evaluated in a number of clinical trials. Generally, prophylactic interferon-based regimens administered shortly post–liver transplantation in an effort to prevent graft reinfection have resulted in low rates of sustained virologic response.⁵⁷

On the basis of reports of rejection and graft loss in renal transplant recipients treated with interferon, as well as preliminary experience in liver transplant recipients, concern has been raised that therapy with interferon increases the risk of graft rejection (although as noted earlier the distinction between recurrent HCV infection and graft rejection is difficult even on histologic grounds).⁵⁸ Increasingly, recurrent HCV infection is recognized as the cause of graft failure in transplant recipients, and the dilemma arises as to whether repeat liver transplantation in affected patients is justified.²⁵ A subset of patients retransplanted for graft loss caused by recurrent hepatitis C have reasonable survival rates, if they do not have deep jaundice or renal failure at the time of retransplantation (see later).

ACUTE LIVER FAILURE

Acute liver failure (ALF) is an uncommon but important indication for liver transplantation because of its high mortality rate but excellent outcomes with prompt liver transplantation (unless major neurologic complications have occurred). ALF is defined as the onset of hepatic encephalopathy within 26 weeks of the initial recognition of acute liver disease and reflects a variety of causes (see Chapter 93). Despite an abrupt onset, antecedent chronic liver disease is absent, and hepatic recovery is possible. In the past, liver transplantation for ALF resulted in poorer patient survival rates than those for benchmark indications, such as PBC. Subsequent experience, however, has shown that excellent patient survival rates are possible if ALF is identified early in its course and the patient is listed for liver transplantation before irreversible complications, especially neurologic, have supervened.⁵⁹ The absence of papilledema on funduscopy and of typical features of cerebral edema on computed tomography (CT) of the head do not preclude the presence of cerebral edema complicating worsening encephalopathy; therefore, direct intracranial pressure monitoring may be required to detect and manage this frequently lethal complication of ALF. Direct intracranial pressure monitoring can only be recommended, however, if local neurosurgical expertise and interest are available, because a high rate of complications has tempered enthusiasm for use of this technique in many centers. Specific criteria to identify patients with ALF who are unlikely to recover spontaneously without liver transplantation are shown in Table 95-5. The challenge in managing patients with ALF is to avoid unnecessary liver transplantation in patients who will recover spontaneously, while not delaying liver transplantation in patients in whom the only option for survival is liver transplantation. The role of liver-assist devices in managing ALF, either as definitive therapy or as a “bridge to transplantation,” remains an area of active investigation (see Chapter 93).

Table 95-5 Criteria for Liver Transplantation in Acute Liver Failure

INR, international normalized ratio.

From Keeffe EB. Liver transplantation: Current status and novel approaches to liver replacement. Gastroenterology 2001; 120:749-62, with permission.

CHOLESTATIC LIVER DISEASE

PBC and PSC continue to be relatively common indications for liver transplantation in many transplantation centers and have had a key role in the development of disease models for liver disease, with PBC serving as a benchmark for patient and graft survival. Development of the Mayo disease models to predict the course of cholestatic disorders has aided in decision making regarding timely referral for liver transplantation (see Chapters 68 and 89). Patients with PBC and PSC should be referred for liver transplantation evaluation if their Mayo risk scores predict a one-year survival rate of less than 95%. The Mayo model to predict survival in patients with PBC incorporates the serum bilirubin level, albumin level, patient’s age, prothrombin time, and presence of edema, whereas the model to predict survival in patients with PSC includes the serum bilirubin level, patient’s age, serum AST level, variceal bleeding, and serum albumin level. These models, however, do not take into account prominent and frequently disabling complications of cholestatic liver disease, such as pruritus, osteopenia, or, in PSC, recurrent bouts of bacterial cholangitis and have now been effectively superseded by the MELD score, which is used to determine organ allocation. Despite the generally excellent results of liver transplantation for the cholestatic disorders, concern has increased that they may recur in the graft.

Biliary stricturing similar to that in the native diseased liver can be identified in a minority of patients following liver transplantation for PSC and may represent recurrent disease.⁵ Differentiation of recurrent disease from other important causes of graft injury such as chronic rejection or ischemia may be difficult. Recurrent PSC results in nonanastomotic stricturing of the intrahepatic biliary tree. Although some improvement in symptoms can be obtained by balloon dilation and stent placement, long-term graft viability is reduced. Graft loss caused by recurrent PBC appears to be less frequent than that for PSC. Management of recurrent PBC includes excluding other causes of hepatic dysfunction. Primary immunosuppression with tacrolimus has been implicated in recurrence of PBC by some, but not all, investigators. A controversial issue is whether colectomy in transplant recipients with PSC and associated inflammatory bowel disease reduces the risk of recurrent PSC.⁶⁰

HEPATIC MALIGNANCY

HCC is the most common primary hepatic malignancy and results in more than 600,000 deaths annually worldwide, usually in patients with underlying cirrhosis. A notable exception is chronic HBV infection, in which HCC can arise in the absence of cirrhosis (see Chapter 94). Tumors with diameters of less than 2 cm discovered incidentally in the explanted liver typically do not have an adverse effect on patient survival. The likelihood of tumor recurrence increases markedly, however, with greater tumor burden, vascular invasion, and the presence of multiple lesions. Liver transplantation is the most definitive treatment of HCC; indeed, 26% of patients who received a liver allograft between 2002 and 2007 had HCC, an observation that reflects the frequency of HCC in cirrhotic patients and the awarding of extra priority to patients with this indication for liver transplantation.⁶¹

Improvements in outcome of liver transplantation for HCC in the 2000s are almost entirely attributable to better patient selection rather than improved surgery or adjuvant therapy.⁶² The preoperative metastatic workup should include a bone scan and chest CT in addition to abdominal imaging. Portal vein occlusion in a patient with HCC is regarded as evidence of metastatic spread and precludes liver transplantation. On the basis of the seminal experience reported by Mazzaferro and colleagues from Milan, generally accepted criteria for liver transplantation in patients with HCC have included a tumor diameter of less than 5 cm, if the tumor is solitary, or no more than three lesions, with the diameter of the largest lesion measuring no greater than 3 cm.⁶³ Survival rates comparable to those for transplantation for decompensated cirrhosis in the absence of complicating HCC (75% at four years) have been reported. With the growing success of liver transplantation for HCC, the Milan criteria have been criticized as being excessively restrictive by excluding many patients who otherwise would have done well with a low risk of recurrence after liver transplantation.⁶² Various expanded criteria have been proposed to extend the limits of tumor size and number while preserving patient survival rates.^64,65

After initial adoption of the MELD score for organ allocation, increased priority was given to patients with HCC who met the Milan criteria, in recognition of the potential for cure of HCC by liver transplantation and the concern that a protracted wait for liver transplantation could result in an increase in tumor burden and metastatic spread. Adoption of the MELD score has resulted in proportionally more patients with HCC undergoing liver transplantation.⁶¹ In addition, waiting times for patients with HCC to receive a deceased donor organ have decreased significantly, and the number of patients dropping out from the waiting list because of advanced-stage disease has also decreased. In the most recent modification of allocation policies, fewer additional MELD score points have been added for the diagnosis of HCC because of the relatively good short-term prognosis of patients with a small HCC.⁶¹ Concern has been expressed that cirrhotic recipients without HCC are now disadvantaged because of the preference given to patients with HCC.

Several adjuvant interventions have been reported in patients transplanted for HCC (see Chapter 94).¹⁷ Recurrent tumor occurs frequently in the graft, and the rationale for adjuvant therapy has been to eliminate micrometastatic disease that typically is disseminated via the vascular system. Conventional systemic chemotherapy administered perioperatively as well as for varying durations before and after liver transplantation, and usually incorporating doxorubicin, is of uncertain benefit. A potentially important strategy for expanding the criteria for liver transplantation in patients with HCC is to downstage the tumor with the use of locoregional therapy so that the Milan criteria are met; whether this approach ultimately improves patient survival remains to be determined.⁶⁵ For example, TACE administered directly into the tumor arterial supply is often employed to reduce tumor burden during the often protracted wait for liver transplantation. This intervention can be hazardous in patients with decompensated cirrhosis, and its benefit in patients with favorable tumor characteristics remains to be determined. Radiofrequency ablation is used increasingly to manage HCC. Confounding the management of the liver transplantation candidate with HCC, however, is the frequent observation that the tumor burden in the explant is significantly underestimated by preoperative imaging studies. Despite these caveats, a subset of patients with HCC can be cured by liver transplantation and would not have tolerated surgical resection of the tumor because of associated cirrhosis. Oral therapy of HCC with sorafenib will undoubtedly be expanded into liver transplantation populations.

The fibrolamellar variant of HCC presents in younger adults without underlying cirrhosis and, as a result, often manifests only when the tumor burden is already large. Extensive resection can be tolerated because cirrhosis is absent. Liver transplantation may be performed in patients who have recurrent tumor after resection. Tumor recurrence after liver transplantation may be relatively indolent and, although not as infrequent as was once thought, survival rates are acceptable.⁶⁶ Hepatoblastoma is a rare pediatric tumor that also occurs in the absence of underlying parenchymal liver disease. Initial management consists of surgical resection; adjuvant chemotherapy is indicated for metastatic disease. Liver transplantation is an option when the tumor cannot be resected (see Chapter 94).

Cholangiocarcinoma remains the only major primary hepatic tumor for which a definitive role for liver transplantation has been difficult to establish. The results of liver transplantation for cholangiocarcinoma diagnosed preoperatively have been so poor that its presence has been regarded as a contraindication to liver transplantation, and even tumors discovered only incidentally in the explant have a high recurrence rate. A subset of patients with a hilar location of the tumor and absence of nodal involvement have been reported to have good five-year survival rates. The extent of cholangiocarcinoma frequently is more extensive than suspected on pre–liver transplantation imaging; often there is local, lymphatic, and perineural spread. The addition of en bloc pancreaticoduodenectomy has not resulted in improved survival after liver transplantation. Newer approaches to treatment have included preoperative irradiation and chemotherapy, and careful intraoperative tumor staging followed by liver transplantation, with encouraging preliminary results (see Chapter 69).

METABOLIC DISORDERS

Patients with congenital hepatic enzyme deficiencies and other inborn errors of metabolism may be cured by liver transplantation⁶⁷ (see Chapters 74 to 76). Metabolic disorders potentially cured by liver transplantation fall into two broad categories: diseases dominated clinically by obvious hepatocellular disease (e.g., Wilson disease, hemochromatosis) and those without any clinical evidence of liver disease (e.g., primary hyperoxaluria, familial hypercholesterolemia). Although metabolic disorders are most prominent as indications for liver transplantation in the pediatric population, important adult diseases managed by liver transplantation include Wilson disease and hemochromatosis. Substantial neurologic improvement can occur following liver transplantation for Wilson disease in patients who present with decompensated cirrhosis with neurologic involvement. A Wilsonian crisis with severe hemolysis is an indication for urgent liver transplantation; chelation therapy is ineffective in such cases. Hemochromatosis has been associated with poorer outcomes following liver transplantation than have other forms of cirrhosis because of increased rates of adverse cardiac and infectious outcomes. Ongoing studies will clarify whether iron depletion before liver transplantation improves survival rates after liver transplantation. Iron reaccumulation in the grafts of patients transplanted with hemochromatosis is a theoretical concern, and continued iron depletion is not typically required.⁶⁸

Liver transplantation also has been performed in patients with a variety of systemic disorders, including adult polycystic disease, and as a curative procedure in combination with renal transplantation for primary hyperoxaluria, in which end-organ damage is confined to the kidney but the metabolic defect is hepatic. Liver transplantation has been successful in arresting manifestations of familial amyloid polyneuropathy, with the explant, which is the source of the abnormal protein, available for use in a “domino” fashion in an older recipient who will not live long enough for neurologic injury to develop.⁶⁹ The biliary cirrhosis associated with cystic fibrosis also has been managed successfully with liver transplantation, although patients remain at risk of infectious and other complications of this systemic disorder.

NONALCOHOLIC FATTY LIVER DISEASE

NAFLD is now recognized as a major cause of chronic liver disease, including cirrhosis and HCC, and is implicated in many cases of cirrhosis (formerly termed cryptogenic) (see Chapter 85). Many of the key precipitants of NAFLD—obesity, hyperlipidemia, and diabetes mellitus—are exacerbated by the post-transplantation immunosuppressive regimen.⁷⁰ Recurrence of NAFLD post–liver transplantation causes graft injury, although graft loss does not typically result. De novo NAFLD after liver transplantation has also been described. In the absence of any specific therapy for NAFLD, therapeutic efforts after liver transplantation should center on weight control, optimal diabetic management, and use of a lipid-lowering regimen.

VASCULAR DISORDERS

Budd-Chiari syndrome is characterized by hepatic venous outflow obstruction with a presentation that often mimics decompensated cirrhosis (see Chapter 83).⁷¹ Important associations are myeloproliferative disorders, hypercoagulable states, and vena caval webs. Medical approaches to management often are disappointing and fail to retard progression to liver failure and death. Examination of liver biopsy specimens may be helpful in determining whether the therapeutic approach should be decompression with a portosystemic shunt or liver transplantation. Good long-term results have been described in patients who undergo prompt TIPS or portosystemic shunt surgery, but patients with advanced fibrosis on a liver biopsy specimen should undergo liver transplantation. Although many patients have an underlying myeloproliferative disorder, an accelerated progression to leukemia or bone marrow failure is not typically observed after liver transplantation. Long-term anticoagulation is continued in liver transplant recipients transplanted for Budd-Chiari syndrome.

Sinusoidal obstruction syndrome (SOS) is a similar disorder manifested by necrosis of zone 3 hepatocytes and fibrous obliteration of the central venule lumen. Most commonly seen after bone marrow transplantation (BMT), SOS may lead to hepatic failure and death in up to 25% of patients despite an otherwise successful BMT. Although experience with liver transplantation for hepatic complications of BMT is limited,⁷² it appears to be the only intervention that consistently alters the course of advanced SOS. Similarly, liver transplantation has been shown to be effective in the management of severe post-BMT graft-versus-host disease with predominantly hepatic involvement (see also Chapter 34). Hypocoagulable (e.g., hemophilia A and B) as well as hypercoagulable (e.g., protein C and S deficiencies) hematologic disorders have been cured with liver transplantation.

AUTOIMMUNE HEPATITIS

Failure of immunosuppressive therapy to arrest progression of severe autoimmune hepatitis with the development of hepatic decompensation is an indication for liver transplantation (see Chapter 88).⁷³ The presence of human leukocyte antigen (HLA)-DR3 is associated with a lower likelihood of a therapeutic response to immunosuppressive therapy in patients with autoimmune hepatitis. Excellent long-term survival is usual after liver transplantation, although the autoimmune diathesis may result in higher rates of acute cellular rejection. In addition, recurrent autoimmune hepatitis has been recognized increasingly and may require higher maintenance doses of immunosuppression. Graft survival is generally not diminished by recurrent autoimmune hepatitis.⁵ Recurrent disease mimics the features of disease in the native liver, is associated with hypergammaglobulinemia and autoantibodies, and is generally responsive to glucocorticoids.

OTHER INDICATIONS

A variety of other diagnoses have been reported as indications for liver transplantation (see Table 95-1). Adult polycystic disease with marked abdominal distention resulting from multiple hepatic cysts that are not amenable to resection has been treated successfully by liver transplantation. If chronic kidney disease is present, a combined liver-renal transplantation is indicated. Cerebral imaging is indicated to exclude intracranial aneurysms, which are a feature of this syndrome (see Chapter 94). Liver transplantation also is indicated in cases of multiple adenomas associated with glycogen storage disease and not only eliminates the risk of progression to HCC but also corrects the underlying metabolic disease (see Chapter 76). Diseases with multiorgan involvement for which liver transplantation has been performed include Alagille syndrome, amyloidosis, and sarcoidosis (see Chapters 35 and 62).

SURGICAL ASPECTS OF LIVER TRANSPLANTATION

Once a potential deceased organ donor is identified, the local organ procurement organization coordinates harvesting and supplies pertinent donor medical information to centers with suitable potential recipients listed with UNOS. In contrast with other types of organ transplants, including kidney and bone marrow transplants, absence of HLA compatibility does not appear to affect liver graft survival, and donor-recipient matching is based only on ABO blood compatibility and physical characteristics such as the recipient’s weight. In critically ill recipients, an ABO-incompatible organ may be implanted, with the recognition that graft survival may be diminished.⁷⁴ In addition to screening serologic studies and routine liver biochemical testing, particular attention is paid to the donor’s medical history, including cardiovascular instability and need for pressor support before determination of brain death.

With the critical shortage of deceased organ donors, expansion of the donor pool has included acceptance of donors ages 70 years and older. As noted earlier, however, use of older donors in recipients with HCV infection may lead to more severe HCV recurrence, potentially limiting the use of older donors in at least some recipients. The typical donor has had a catastrophic head injury or an intracerebral bleed with brain death but without multisystem organ failure. Electrolyte imbalance and hepatic steatosis in the donor are particular concerns because they are predictors of subsequent graft nonfunction. Analogous to the MELD score, a “donor risk index” has been derived to assess the likelihood of good graft function.⁷⁵ Key adverse factors include older donor age (especially >60 years of age), use of a split or partial graft, and a non–heart-beating donor, from which the organs are harvested after the donor’s cardiac output ceases, in contrast with the more typical deceased donation in which the organs are harvested prior to cardiovascular collapse. Use of non–heart-beating donors is associated with reduced rates of long-term graft survival and an increased risk of biliary complications and correlates with the duration of “warm ischemia” after cardiovascular collapse and before retrieval of the organ.

The harvesting team makes a visual and, if necessary, histologic assessment of the donor organ. Particular note is made during the harvesting procedure of anatomic variants in the hepatic arterial supply that need to be preserved to ensure graft viability. Once the circulation is interrupted, the organ is rapidly infused with cold preservation solution. Donor iliac arteries and veins are also retrieved in case vascular grafting is required. After its arrival at the recipient institution, further vascular dissection, with arterial reconstruction if necessary, is performed before implantation.

Splitting cadaveric donor livers either in situ during harvesting or ex vivo on return to the transplantation center allows two recipients to receive portions of the same hepatic allograft, if graft volume and quality are sufficient. An adult cadaveric liver is divided into two functioning grafts. The left lateral segment (segments 2 and 3) is used for a pediatric recipient, and the right trisegment (segments 4 to 8) is used for an adult recipient. Acceptable graft and patient survival rates can be obtained with split grafts, although high-risk unstable recipients may have poorer outcomes with this technique. Figure 95-5 shows the segmental anatomy of the liver, which forms the basis of dissection for both split and living-donor liver transplantation.

Figure 95-5. Segmental anatomy of the liver in the superior and inferior views. Segment VIII is visible only on the superior view, and segment I (caudate lobe) is visible only on the inferior view.

(From Keeffe EB. Liver transplantation: Current status and novel approaches to liver replacement. Gastroenterology 2001; 120:749-62, with permission.)

IMMUNOSUPPRESSION

Administration of immunosuppressive agents following liver transplantation is divided into induction (initial) and maintenance (long-term) phases. In addition, episodes of acute cellular and chronic ductopenic rejection require therapy. A wide array of immunosuppressive agents are currently used.⁷⁹ In practice, new immunosuppressive agents are introduced for use in renal transplantation before they are applied to liver transplantation. Therefore, the need for effective antirejection regimens in other areas of solid organ transplantation is great (see also Chapter 34). The primary goal of immunosuppression is to prevent graft rejection and loss; a secondary goal is to avoid the adverse consequences of the antirejection regimen.⁸⁰

A list of the commonly used immununosuppressive agents, routes of administration, methods of monitoring, and common adverse effects is shown in Table 95-7. Common drug-drug interactions are shown in Table 95-8. The calcineurin inhibitors cyclosporine and tacrolimus are the basis for a majority of induction and maintenance immunosuppressive regimens. Both agents have substantial toxicity. Tacrolimus is now favored over cyclosporine for primary immunosuppression. In addition, patients may be converted from cyclosporine to tacrolimus following glucocorticoid- or OKT3-refractory rejection, late rejection (>6 months post–liver transplantation), histologically diagnosed chronic rejection, severe cholestasis, intestinal malabsorption of cyclosporine, or cyclosporine toxicity (e.g., hirsutism, gingivitis, severe hypertension). When used as rescue therapy for chronic rejection, tacrolimus is less effective once the serum bilirubin levels rise above 10 mg/dL, underscoring the importance of early recognition of chronic rejection. Although implicated in hepatic artery thrombosis as well as delayed wound healing and infections, sirolimus, an inhibitor of the protein mTOR (mammalian target of rapamycin), has been used increasingly in liver transplantation as a calcineurin-sparing strategy and also in patients transplanted for HCC to reduce tumor recurrence.⁸¹ Another newer agent is basiliximab, a monoclonal antibody directed against CD25, which may be an alternative to glucocorticoids as an induction agent in liver transplantation.⁸²

Table 95-8 Clinically Relevant Drug Interactions with Immunosuppressive Drugs

Considerable differences exist among transplantation centers in the rate at which the level of induction immunosuppression is reduced to avoid toxicity and lessen the risk of recurrent disease. Generally, the strategy includes tapering and in some cases discontinuing maintenance glucocorticoids.⁸³

POSTOPERATIVE COURSE

INITIAL PHASE TO DISCHARGE FROM HOSPITAL

Because of the complexity of liver transplantation and the often markedly decompensated state of liver transplant recipients, invasive monitoring with arterial and pulmonary venous lines is necessary in the first few postoperative days. If a T-tube has been placed, dark copious bile provides evidence of satisfactory graft function. The patient’s overall status, including neurologic recovery from anesthesia, urinary output, and cardiovascular stability, also reflect graft function. Routine antimicrobial prophylaxis includes bowel decontamination with oral nonabsorbable antibiotics, perioperative systemic broad-spectrum antibiotics, antifungal agents, and ganciclovir to prevent cytomegalovirus (CMV) infection. Markedly abnormal liver biochemical test levels are typical during the initial 48 to 72 postoperative hours and reflect a number of insults to the graft, including ischemia following harvesting, during preservation, and on subsequent reperfusion. The overall trend in serum aminotransferase levels should be downward, with a corresponding improvement in coagulopathy and a falling serum bilirubin level. Thrombocytopenia in the immediate postoperative period reflects a variety of processes, including residual splenomegaly, medications, and, importantly, reduced graft function.

Worrisome clinical features include scanty, pale bile if a T-tube has been used, metabolic acidosis, depressed mentation, and the continued need for pressor support with worsening liver biochemical test levels. Hepatic artery thrombosis needs to be excluded promptly by Doppler ultrasound and is an indication for urgent retransplantation. Hepatic artery thrombosis is more common in pediatric recipients because of the smaller size of the vessels. Antiplatelet therapy is now administered routinely to reduce the risk of hepatic artery thrombosis.⁸⁴ Primary nonfunction of the graft is also an indication for urgent retransplantation and is suggested by the absence of bile production in the first several hours after transplantation, as well as an unstable overall clinical status. Donor characteristics that are associated with an increased likelihood of primary nonfunction include marked hepatic steatosis and profound hyponatremia. If graft function is adequate, however, pressor support can be tapered and ventilator weaning parameters monitored to facilitate extubation, although the recipient who is markedly debilitated from advanced cirrhosis may require several days of ventilatory support. Poor graft function and renal insufficiency also can impede weaning from the ventilator.

Within the first week after liver transplantation, liver biochemical test levels should steadily improve as ischemia and reperfusion injury resolve. Acute cellular rejection becomes an important and frequent cause of graft dysfunction at one week and beyond and is suggested by a rise in serum aminotransferase, alkaline phosphatase, and bilirubin levels. Because the biochemical features are nonspecific, the threshold for performing a liver biopsy to evaluate other diagnostic possibilities, which include slowly resolving reperfusion injury, biliary tract obstruction, and cholestasis related to sepsis, should be low. Histologic findings characteristic of acute cellular rejection are bile duct injury, portal inflammation with eosinophils, and, with more severe injury, endotheliitis (Fig. 95-6). High doses of glucocorticoids (1000 mg of methylprednisolone or the equivalent), followed by a taper (200 to 20 mg/day) extending over several days, constitute first-line therapy. A response is suggested by a return of liver biochemical test levels toward normal values.

Figure 95-6. Histopathology of acute cellular rejection of a liver graft. A, The portal tract shows a lymphocytic and plasma cell infiltrate that spills over into the periportal hepatocytes and bile duct. B, The central vein shows attachment of lymphocytes to the endothelium (endotheliitis).

(From Cotran RS, Kumar V, Collins T, editors. Robbins’ pathologic basis of disease. 6th ed. CD-ROM. Philadelphia: WB Saunders; 1999, with permission.)

For the occasional patient with presumed acute cellular rejection who fails to have a biochemical response to glucocorticoids, immunosuppression may be enhanced with the monoclonal antibody OKT3. Liver biopsy should be repeated first to confirm a lack of histologic response before more intensive therapy is initiated and to exclude other important causes of graft dysfunction such as ischemia.

The ability of recurrent HCV infection to mimic virtually all the features of acute cellular rejection histologically has led to a reevaluation of the need to treat apparent acute cellular rejection aggressively under all circumstances. Routine (protocol) liver biopsies also have fallen out of favor because histologic evidence of acute cellular rejection can be noted in the absence of worsening graft function with no apparent clinical significance. A cholangiogram should be obtained routinely prior to clamping the T-tube, if one is present; a nonsustained rise in liver biochemical test levels can be anticipated as a result. The timing of various infectious complications following liver transplantation is shown in Figure 95-7.

Figure 95-7. Time course of various infectious complications in liver transplant recipients. CMV, cytomegalovirus; EBV, Epstein-Barr virus; VZV, varicella-zoster virus.

(From Everson GT, Kam I. Immediate postoperative care. In: Maddrey WC, Schiff ER, Sorrell MF, editors. Transplantation of the liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p 131.)

A number of other important medical issues are common in the first weeks following liver transplantation (Table 95-9). Neurologic dysfunction can present as an acute confusional state or seizures, and the differential diagnosis includes the lingering effects of hepatic encephalopathy, electrolyte imbalance, poor graft function, sepsis, uremia, and side effects of medications. A particular concern is the development of neurologic toxicity caused by the major immunosuppressive agents. Overly rapid correction of hyponatremia perioperatively has been implicated in the genesis of central pontine myelinolysis, with evidence of demyelination demonstrable on magnetic resonance imaging. Management includes correcting the electrolyte imbalance if present and reducing the dose of calcineurin inhibitor, which can be facilitated by the use of mycophenolate mofetil.⁸⁵ Diabetes mellitus, which is common in persons with cirrhosis, can occur for the first time in the postoperative period and usually requires insulin to control. HCV infection further increases the risk of post–liver transplantation diabetes mellitus.⁸⁶ Renal impairment post–liver transplantation may reflect a number of factors, including slowly resolving pre–liver transplantation hepatorenal syndrome or renal failure of other causes, intraoperative hypotension resulting in acute tubular necrosis, and, importantly, the nephrotoxic effects of cyclosporine and tacrolimus, which cause renal afferent arteriolar vasoconstriction and a corresponding reduction in glomerular filtration rate. Adjunctive therapy with mycophenolate mofetil allows a reduction in the doses of cyclosporine and tacrolimus while providing adequate immunosuppression. Short-term hemodialysis may be necessary until renal function improves. In the first three to four weeks post–liver transplantation, infections are typically bacterial and related to surgical complications such as intra-abdominal bleeding, bile leak, or wound infection.

Table 95-9 Medical Complications in the Immediate Post-Transplantation Period

Infections

Bacterial

Viral

Cytomegalovirus

Epstein-Barr virus

Fungal

Aspergillosis, mucormycosis

Candidiasis, torulopsosis

Pneumocystis jiroveci pneumonia

Respiratory complications

Acute respiratory distress syndrome

Hepatopulmonary syndrome

Pneumonia

Portopulmonary hypertension

Pulmonary edema

Acute kidney injury

Cardiovascular disease

Cardiomyopathy

Hemochromatosis

Idiopathic hypertrophic subaortic stenosis

Hypertension

Myocardial ischemia

Valvular heart disease

Neurologic complications

Central nervous system hemorrhage

Central pontine myelinolysis

Ischemic events

Seizures

Coagulopathy

Disseminated intravascular coagulation

Thrombocytopenia

Diabetes mellitus

 

From Everson GT, Karn I. Immediate postoperative care. In: Maddrey WC, Schiff ER, Sorrell MF, editors. Transplantation of the Liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001, with permission.

LONG-TERM MANAGEMENT

HEPATIC RETRANSPLANTATION

Although improved immunosuppressive regimens have led to a lower rate of graft loss because of chronic rejection, recurrence of the underlying liver disease has been recognized increasingly as a cause of graft failure, as illustrated most strikingly in HCV-infected recipients.⁹⁷ The rates and severity of recurrent diseases are highly variable and probably related to a complex interplay among host factors (including the underlying liver disease), therapeutic regimens (e.g., immunosuppression, antiviral treatment), and possibly genetic variability of the allograft (perhaps through effects on the nature and magnitude of the inflammatory response within the graft). Understanding the full effect of recurrent disease, especially nonviral disease, on patient and graft survival will require long-term follow-up studies. For example, although the rate of histologic recurrence of viral hepatitis is greatest in the first year following liver transplantation, recurrent PBC or PSC develops in less than 5% of patients by the first year, whereas more than 20% demonstrate histologic recurrence 10 years after liver transplantation.⁹⁸ As patients enter their second and third decades following liver transplantation, the number of patients who require retransplantation may deplete the donor pool further. This issue is compounded by the observation that patients who undergo retransplantation experience an approximate 20% overall reduction in the rate of survival but consume an increased amount of resources when compared with primary transplant recipients. On the basis of these considerations, a number of investigators have developed models to predict survival following retransplantation, especially for HCV infection (Table 95-11 and Fig. 95-8). For example, the liver transplant recipient with jaundice, graft failure caused by recurrent HCV infection, and renal failure has a markedly diminished likelihood of surviving retransplantation. Although these models only estimate the probability of survival for an individual patient and do not take into account the patient’s quality of life, they can be used as adjuncts to clinical judgment. Application of retransplantation to low-risk patients is associated with survival comparable to that for primary liver transplantation; determining whether retransplantation is justified in patients with high-risk scores will require prospective studies. In the current era of extreme organ shortage, the utility of primary and repeat transplantation (i.e., duty to promote the best outcome in the aggregate) needs to be considered. An analysis by Burton and colleagues, using the Cobbs-Douglas equation, has demonstrated that for primary liver transplantation, maximal utility is achieved by allocating organs at the highest MELD score (i.e., “sickest first”). For retransplantation, however, maximal utility for HCV and non-HCV diagnoses is achieved at MELD scores of 21 and 24, respectively. Utility starts to decline at MELD scores greater than 28.²⁵

Table 95-11 Multivariate Models Developed to Predict Survival Following Liver Retransplantation

NO. OF PATIENTS	PROGNOSTIC PREDICTIVE FACTORS	COMMENTS
1356	Recipient’s age, bilirubin and creatinine levels, UNOS status, and cause of graft failure	UNOS database used; HCV positivity and donor age are significant predictors by univariate analysis83
70	Recipient’s age, UNOS status, inpatient status, serum bilirubin and creatinine levels	King’s College84
418	Recipient’s age, mechanical ventilatory status, serum bilirubin and creatinine levels	University of Pittsburgh85
150	Recipient’s age group (pediatric vs. adult), mechanical ventilatory status, organ ischemia time >12 hr, serum bilirubin and creatinine levels	UCLA86
447	Interval to retransplantation (better prognosis if within 30 days)	Mayo Clinic; limited to patients with PBC or PSC87
207	Bilirubin and serum creatinine levels	UNOS database used; limited to HCV-positive patients retransplanted for causes other than primary nonfunction88

HCV, hepatitis C virus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; UNOS, United Network for Organ Sharing.

From Rosen HR. Disease recurrence following liver transplantation. Clin Liver Dis 2000; 4:675-89, with permission.

Figure 95-8. Survival of 1356 patients undergoing hepatic retransplantation stratified into low-risk, medium-risk, and high-risk groups using prognostic predictive factors listed in Table 95-11 (P < 0.00001 by Wilcoxon rank sum).

(From Rosen HR, Madden JP, Martin P. A model to predict survival following hepatic retransplantation. Hepatology 1999; 29:365-70.)

A multicenter U.S. study of 272 patients (73 retransplanted for causes not related to HCV) indicated that one- and three-year survival rates following retransplantation were equivalent in HCV-positive and HCV-negative patients. These data were likely shaped by selection bias, considering that nationally more than one third of patients with HCV-related allograft failure are not even considered for retransplantation and only half of those reevaluated are even relisted. This study also showed that MELD scores greater than 30 are associated with particularly poor survival following retransplantation.⁹⁹

Major challenges remain in liver transplantation, including the shortage of donor organs, threat of recurrent disease, and morbidity associated with lifelong therapeutic immunosuppression. Nevertheless, the availability of liver transplantation has transformed the lives of patients with advancing liver disease and their health care providers from an ultimately futile effort to manage the complications of cirrhosis into a life-prolonging and life-enhancing intervention.