Indications

As the outcome of liver transplantation has improved, the indications have expanded to include any patient with compromise of life from chronic liver insufficiency, chronic liver disease with acute decompensation, acute liver failure, and enzyme deficiencies (Table 27-1). Liver transplantation is also indicated to a limited degree for patients with primary liver tumors.

Table 27-1 Indications for Liver Transplantation

The first issue regarding candidacy for transplantation is whether a given patient would benefit from liver replacement. The second issue that must be addressed is whether the patient can withstand the challenge of a liver transplantation surgery. Compromise in cardiac or pulmonary function may prohibit the patient as a candidate. In some cases, failure of an additional organ system may dictate combination transplantations. Although kidney-liver transplantations are relatively common, heart-liver and lung-liver transplantations are rarely performed.⁵

Regardless of the specific cause of liver disease, patients with chronic liver disease who have deteriorated tend to present with common signs and symptoms. These include coagulopathy, thrombocytopenia, muscle wasting, gynecomastia, ascites, varices, encephalopathy, and renal insufficiency. These physiologic perturbations may lead to life-threatening complications; patients with ascites are susceptible to spontaneous bacterial peritonitis or the development of a peritoneal-pleural fistula. Gastrointestinal bleeding is the potential complication of varices.

An acute exacerbation of chronic liver disease can be triggered by sepsis, gastrointestinal bleeding, or progressive renal insufficiency. Some diseases, such as Wilson’s disease or autoimmune hepatitis, may present with an acute decompensation without a prior diagnosis of liver disease.

The production of many essential proteins originates in the liver. The inborn errors of metabolism reflect failure of production of crucial enzymes in the liver. Liver transplantation cures the disease by replacing the liver cells with competent metabolic pathways; it is recommended for those diseases in which there is no central nervous system compromise.

Fulminant Hepatic Failure

Fulminant hepatic failure refers to the acute onset of liver failure with the absence of previous liver disease. The entity is defined as the presence of encephalopathy within 8 weeks of jaundice.

In addition to encephalopathy, the disease is characterized by jaundice, coagulopathy, metabolic acidosis, and renal insufficiency. Encephalopathy may progress to coma. Once a patient reaches stage 4 encephalopathy, the rate of successful treatment without transplantation ranges from 5% to 20%, depending on the cause.⁶ Its most common cause in the United States and England is acetaminophen overdose,⁷ either accidental or intentional. In Asia, acute hepatitis from hepatitis B viral infection is the most common cause.⁸ In a significant number of cases the specific cause is unknown. Acetaminophen overdose carries a relatively good prognosis without transplantation if the metabolic functions related to the liver are maintained.

The key to successful liver transplantation for fulminant hepatic failure is early recognition and listing for transplantation, avoidance of cerebral edema, prevention of infection, and timely transplantation. Brain death from cerebral edema is a common cause of death in these patients. Depending on the cause and potential for liver regeneration, the liver assist device or hepatocyte transplantation may be an alternative to liver transplantation, but these modalities are experimental at this time.

Hepatitis C and Liver Transplantation

Chronic hepatitis C infection is the most common indication for transplantation in the West. In the United States, it is estimated that 5 million individuals are infected with hepatitis C. In approximately 20% of these patients, a chronic injury state develops in the liver, with progression to cirrhosis and liver insufficiency. Hepatitis C can be subdivided into five groups or serotypes. The most common U.S. serotype is genotype 1. Type 1 is less responsive to antiviral medication than genotype 2 or 3.

Hepatitis C infection recurs after transplantation because the virus resides in tissues other than the liver. The aggressiveness of the recurrent hepatitis C after liver transplantation cannot be predicted; risk factors include donor age, treatment for acute rejection, and level of hepatitis C viremia at the time of transplantation.⁹ Another factor that predicts hepatitis C reinfection severity after transplantation is the treatment for rejection after transplantation (with additional steroids or antilymphocyte preparations).¹⁰ Transplantation of a liver from a donor older than 40 years is associated with a greater risk of recurrent cirrhosis than from a younger donor. Hepatitis C treatment with interferon and ribavirin is effective in approximately 50% of patients prior to transplantation and in 30% to 40% of patients post-transplantation.¹¹ It has been suggested that pretransplantation treatment of patients for whom a live donor has been identified can be followed by planned transplantation as a rescue therapy. The success of pretransplantation treatment of hepatitis C depends on the level of viremia in the recipient. The limitations to treatment with interferon and ribavirin are bone marrow suppression and the systemic inflammatory response associated with their administration. In cirrhotic patients, splenic sequestration of platelets and neutrophils limit preoperative therapy with interferon and ribavirin.

Chronic hepatitis C infection is also an important risk factor for the development of hepatocellular carcinoma (HCC). It has been estimated that the current rise in the incidence of HCC reflects the United States hepatitis C epidemic of the 1960s through 1970s.¹²

Hepatitis B

Chronic hepatitis B infection is the most common cause of chronic liver disease in endemic regions of Asia and Africa, and the most common cause of death from hepatitis worldwide.¹³

The hepatitis B vaccine is effective in inducing the formation of antibodies that will protect against hepatitis B exposure. As the use of hepatitis B vaccine spreads worldwide, one can look forward to an overall decrease in the incidence of hepatitis B infection over time.

In the past, hepatitis B was a major problem after transplantation, with rapid reinfection of the graft. Effective therapy with antiviral agents and hyperimmune globulin has largely eradicated disease recurrence after transplantation.

Primary Biliary Cirrhosis

Primary biliary cirrhosis is a form of autoimmune cholestatic liver disease, with inflammatory injury to the bile ducts. It is a chronic cause of hepatic insufficiency and is characterized by autoimmune markers and some response to immunosuppressants.¹⁴ This disease is more common in females. The disease may recur years after transplantation but its recurrence is unlikely to progress to the need for retransplantation.

Primary Sclerosing Cholangitis

This is an autoimmune disease that is more frequent in males. It progresses over the years to a cholestatic picture associated with scarring of the intrahepatic and extrahepatic bile ducts. The disease is associated with ulcerative colitis in approximately 90% of patients. In a small number of patients (<10%), the process is associated with cholangiocarcinoma.¹⁵ The bile duct involvement in primary sclerosing cholangitis dictates the use of choledochojejunostomy in patients undergoing liver transplantation. Primary sclerosing cholangitis may also recur after transplantation, although its recurrence is rare.

Alcoholic Liver Disease

Chronic alcohol abuse may cause scarring in the liver, leading to cirrhosis with decompensation. Patients who stop the use of alcohol can prevent progression of the disease. Alcoholic liver disease may be seen in association with other chronic insults to the liver, such as chronic hepatitis C and, in this setting, is more likely to progress to decompensation. Most transplantation centers require abstinence from alcohol after transplantation and a period of abstinence (usually 6 months) prior to transplantation to demonstrate the patient’s understanding of the contribution of alcohol to the disease and a commitment to abstinence.

Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis¹⁶ reflects a pending epidemic of liver disease associated with the epidemic of obesity and metabolic syndrome in the United States. Fatty infiltration of the liver, with inflammation and subsequent injury and fibrosis, are the histologic features. The associated metabolic syndrome and diabetes dictate evaluation of the coronary arteries of these potential recipients. Nonalcoholic steatohepatitis may recur after transplantation.

Biliary Atresia

Biliary atresia is the most common indication for liver transplantation in the pediatric patient. The incidence is 1 in 40,000 live births and is a major concern in the infant with persistent jaundice after birth. Its diagnosis is made with liver biopsy and the finding of an absent extrahepatic bile duct at the time of laparotomy. Its cause is unclear.

Affected infants are treated with hepaticojejunostomy (Kasai procedure). The success of this procedure is dictated by surgery soon after birth and the size of the bile ducts in the bile duct plate. Post–Kasai cholangitis may hasten the need for transplantation. An early indication for transplantation in children is a failure to grow. Intervention with transplantation at this stage may allow catch-up growth. At transplantation, the Roux-en-Y procedure is required for biliary drainage.

Contraindications

Patients with liver disease are extensively evaluated to determine their candidacy for transplantation. Cardiac, pulmonary, and renal functions are assessed. Patients are also seen by a social worker or other mental health professional for psychosocial evaluation. Each patient is individually evaluated to determine the risk-benefit ratio. There are generally accepted absolute and relative contraindications to transplantation. In general, contraindications reflect the expectation of a poor outcome.

Systemic infections are considered contraindications to transplantation and uncontrolled bacterial and fungal infections are absolute contraindications to transplantation. Infections in the liver, such as cholangitis, may be an exception to this rule. HIV infection is considered by some groups to be a contraindication but several studies have shown outcomes comparable to those of matched control patients if the virus is controlled.¹⁷

Failure of another organ may be a contraindication to transplantation if that organ cannot be replaced or expected to recover. Kidney transplantation accompanies liver transplantation in 5% of cases. On occasion, liver-heart transplantation is performed for diseases such as amyloidosis; combined liver-lung transplantation for diseases such as cystic fibrosis has been performed in rare circumstances.⁵

Patients with chronic liver disease can develop pulmonary manifestations of their liver disease. Portopulmonary hypertension is considered a contraindication with persistent pulmonary artery pressures higher than 50 mm Hg in the presence of elevated pulmonary vascular resistance.¹⁸ Hepatopulmonary syndrome becomes a contraindication to transplantation when the PaO₂ does not demonstrate marked improvement with the administration of 100% oxygen.¹⁹

Inability to care for the transplanted organ adequately because of continued drug or alcohol abuse or lack of commitment to immunosuppressive drugs is considered a contraindication to transplant. Continued commitment to immunosuppressive drugs is difficult to assess pretransplantation; in some series, noncompliance has been reported to be up to 35%.²⁰

Anatomic considerations may be relative contraindications to liver transplantation. The presence of portal vein thrombosis may be overcome by removal of the thrombose or jump graft to the superior mesenteric vein. With complete thrombosis of the portal system, portal inflow from the infrahepatic vena cava has been used, although use of this procedure is rare and morbidity is high.

Metastatic HCC is considered an absolute contraindication to transplantation, related to poor outcome from metastatic disease. The risk of metastatic disease after liver transplantation is dependent on the size and number of HCC(s) in the liver. The Milan criteria for liver transplantation for HCC (single nodule <5 cm, or less than three nodules, the largest of which is <3 cm) are used to predict the risk of recurrent disease after transplantation. Patients who meet these criteria have a risk of recurrence that is less than 20% whereas patients outside the criteria have a recurrence rate of approximately 60%.²¹ The Milan criteria are currently used to define acceptable candidates for transplantation in the United States; patients who meet Milan criteria are given extra priority for transplantation. There is a controversy regarding transplantation for patients outside the Milan criteria and there is an interest in finding other methods of identifying those patients who have a low recurrence risk after transplantation. In the future, molecular biomarkers may prove reliable for selecting patients who will benefit from transplantation.

Organ Shortage, Model for End-Stage Liver Disease, and Liver Distribution

The decision of whether a patient is a candidate for transplantation and what priority a given patient should have is dictated in part by the relative shortage of deceased donor donors. Despite substantial governmental and community efforts, the needs of the 15,000 patients awaiting transplantation are not met by the approximately 5000 or so donors.²²

With recognition of the improved outcomes of liver transplantation in the 1980s, transplantation programs proliferated. Livers were allocated to programs and teams rather than patients, with the transplantation center selecting the most appropriate recipient for a given donor. Because of the concept that the organs should be allocated to patients rather than centers, lists of patients were created and ordered according to the patient’s time waiting on the list and the organs offered to the patients.

The current system of liver distribution in the United States depends first on the level of the local organ procurement organization, then to the 11 United Network for Organ Sharing (UNOS) regions, and then shared on a national basis. A patient’s priority on the waiting list is based on his or her medical status as determined by the model for end-stage liver disease (MELD) score, which reflects the likelihood of death within 3 months. The MELD score assigns points that reflect the severity of liver disease. The score is based on a formula that considers bilirubin and creatinine levels and the international normalized ratio (INR).²³

Model for End-Stage Liver Disease Formula

The components of the MELD score were chosen because they represent objective criteria that can be reviewed and verified as compared with ascites and encephalopathy, which were used previously (as part of the Childs-Pugh score) but are subjective and cannot be readily verified. The use of the MELD score to determine liver distribution has led to a significant decrease in the rate of death of potential recipients on the waiting list because it allows livers to be directed to the sickest patients. Patients with a high MELD score at the time of transplantation have slightly poorer survival following transplantation (Table 27-2).

Table 27-2 Concordance With 3-Month Mortality

For patients with low MELD scores, less than 15, the risk of death while waiting for transplantation is less than the risk of death after transplantation.²⁴ The current allocation system therefore discourages transplantation of patients with MELD scores less than 15 by allocating a liver to all the higher MELD score patients in the region before allowing local use in patients with scores less than 15. These last two concepts, that sicker patients have a greater risk of poor outcome after liver transplantation and that relatively healthy patients, whose outcomes are worse with transplantation than if they remained on the waiting list, suggest that both pretransplantation and posttransplantation outcomes should be considered in the allocation of livers. Currently, the use of the MELD score only weighs the pretransplantation outcomes, and death on the waiting list has been reduced since the initiation of MELD. It has been proposed that the MELD score be replaced as a means to distribute organs with a system that determines potential survival benefit after transplantation, or a combination of survival benefit prior to and after transplantation for patients with chronic liver disease.²⁵

For some patients, the risk of death or dropout from the list may not be reflected in the laboratory values in the MELD score. For example, patients with HCC benefit from transplantation, even when their laboratory test results are normal. To allow transplantation, an exception is made and additional MELD points are assigned to these patients.²⁶ This approach is used to transplant these patients prior to their tumors becoming so extensive that patients fall outside the limits of criteria for liver transplantation. It is also used for diseases such as amyloidosis.

Pediatric donors are distributed to pediatric patients preferentially. The scoring used in pediatric patients is referred to as the pediatric end-stage liver disease (PELD) score.²⁷

Patients with acute liver failure such as fulminant hepatic failure are given the highest priority (status 1) for donor organs to avoid the development of cerebral edema and other fatal outcomes. Status 1 supersedes the MELD score in the organ allocation process.