Liver Transplantation

This activity is made possible by an unrestricted educational grant from Fujisawa Healthcare, Inc.

Cosme Manzarbeitia, MD; Susan L. Smith, MN, PhD

Disclosures

March 28, 2003

Contraindications to Liver Transplantation

As long-term survival improved, the absolute and relative contraindications to OLT changed, steadily becoming fewer. At the time of the NIH Consensus Development Conference, contraindications included alcoholism, tumors other than primary hepatic tumors, and psychosocial and economic factors such as inability to understand the implications of the procedure or inability to pay. However, patients with all of these conditions and/or situations are now transplanted on a case-by-case basis. Absolute contraindications are conditions in which the outcomes of liver transplantation are so poor that it should not be offered. Relative contraindications are conditions that have a negative impact on survival, but not to the extent that they should be categorically withheld.

The combination of preexisting local or systemic infection outside the hepatobiliary system (such as peritonitis, pneumonia, or bacteremia) and the necessity of postoperative immunosuppressive therapy place the patient at great risk for a fatal infection and, therefore, preclude successful liver transplantation. Likewise, because the operative procedure is so physiologically rigorous, significant cardiovascular or pulmonary disease decreases the likelihood of surviving the perioperative or postoperative period. In general, contraindications include compensated cirrhosis, extrahepatic malignancy, severe and uncontrolled extrahepatic infection, advanced cardiopulmonary disease, multisystem organ failure, active substance abuse, and anatomic abnormalities that preclude performing the surgical procedure of liver transplantation.

Malignancy is a problem that requires careful consideration in the evaluation of the liver transplant candidate. Ironically, the initial indications for human OLT mandated that the patient have a hepatic malignancy. The rationale was that because of the highly experimental nature of the procedure and low survival rates, it was not justifiable to subject a patient with non-neoplastic disease to the procedure. Today, however, advanced hepatic malignancy (greater than stage III) is, in most cases, considered a contraindication to OLT.

Primary hepatic tumors are epithelial, mesenchymal, or mixed in origin. Of these, epithelial tumors are the most common and include hepatocellular carcinoma (HCC), cholangiocarcinoma, mixed hepatocholangiocarcinoma, hepatoblastoma, and a number of other rare tumors.

There is no effective chemotherapy for most types of liver tumors, and the resectability rate is quite low. Thus, OLT represents the only possible therapy for most patients with a primary malignancy of the liver. The surgical procedure for this group of patients is generally simpler from a technical perspective than in patients with ESLD because the clinical picture of a patient with a malignant liver tumor is much different from that of the typical patient evaluated for OLT. Unlike a patient with ESLD, a patient with a primary hepatic malignancy who is in relatively good physical condition does not have cutaneous stigmata of advanced liver disease and usually has well-compensated cirrhosis with absent or mild portal hypertension.

Hepatocellular carcinoma (HCC). HCC is a malignant tumor derived from hepatocytes and frequently occurs in association with chronic liver disease, especially cirrhosis. Liver transplantation for early-stage (stage I and II with a negative metastatic workup) HCC is associated with survival rates comparable to those when OLT is performed for other indications. In most cases, liver transplantation is preferable to resection of HCC, particularly in the presence of underlying cirrhosis, but tumor progression and/or death while awaiting transplantation is a significant problem. And, immunosuppressive regimens necessary for prevention and treatment of rejection are thought to accelerate tumor growth. Using the Milan criteria,[20] 3-year posttransplant survival was 83% with only 8% recurrence if transplantation was performed for a single HCC < 5 cm in diameter, or for up to 3 separate HCC lesions, each < 3 cm in diameter. The recurrence rate of HCC found incidentally at the time of transplantation is very low.

The Model for End-Stage Liver Disease (MELD)[21] scoring system, discussed in the section Medical Necessity below, has recently been applied to patients with HCC awaiting liver transplantation. A priority MELD weight of 24-29 points is given to patients with HCC who met the Milan criteria while awaiting transplantation. Under this system, transplantation in patients with HCC increased 3.5-fold over a corresponding time interval from the prior year; 86% to 91% of patients with HCC received a transplant within 3 months of being issued a priority MELD score. There has been no detectable trend toward increased use of priority scores to obtain transplants on a preferential basis. Analysis of the Milan criteria and other systems will continue in an effort to refine criteria for entry of patients with HCC into the UNOS liver transplant waiting list.

Cholangiocarcinoma. Sclerosing cholangitis, a major indication for OLT, is frequently associated with cholangiocarcinoma. Cholangiocarcinoma is an intrahepatic malignant tumor consisting of cells that resemble biliary epithelium. OLT for patients with cholangiocarcinoma has historically been controversial, and such treatment has been abandoned by most programs. When performed alone for unresectable cholangiocarcinoma, OLT is often associated with early disease relapse and limited survival. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Encouraging results have been published by the Mayo Clinic group.[22] A small group of patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. The authors concluded that OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma.

Metastatic malignancy. Survival after OLT for metastatic disease is rare. Because the liver is the organ most frequently associated with metastatic tumors, before any patient undergoes OLT for malignant hepatic disease, every attempt is made to rule out metastatic disease. Computed tomography (CT) of the abdomen, lungs, and head; chest x-ray evaluation; nuclear magnetic resonance imaging (MRI); bone scanning; and other tests are commonly performed. Unfortunately, micrometastases are frequently undetectable and may not be discovered until abdominal exploration at the time of surgery. For patients with a high index of suspicion for metastatic disease, despite workup findings that do not confirm the diagnosis, it is common practice to explain to the patient before surgery that transplantation may not be able to be done, and a "backup" patient is prepared so that the organ does not go unused.

Alcoholic cirrhosis. The most common cause of cirrhosis in the United States and the western hemisphere is ALD. Therefore, patients with alcoholic cirrhosis represent the largest number of potential adult OLT recipients. Alcoholic cirrhosis, however, has historically been a relative contraindication to OLT for several reasons: (1) the high risk of patient noncompliance associated with the alcoholism, (2) other medical disorders associated with alcoholism, such as cardiomyopathy, chronic pancreatitis, cerebral atrophy, and protein-calorie malnutrition, and (3) the generally worse outcome in alcoholics compared with nonalcoholics (on the basis of early reports).[23] However, more recent reports confirm a good prognosis when appropriate protocols for abstinence are strictly adhered to and adequate psychosocial support systems are in place.[24]

The criteria used to determine whether to transplant the patient with ALD vary among transplant centers. Clearly, the patient who is an active alcoholic is at very high risk for psychological morbidity and an unsuccessful outcome, and is not usually considered a candidate. On the other hand, the patient who has demonstrated some period of sobriety is considered by most transplant teams to be a potential candidate. Although the establishment of arbitrary waiting periods is not supported by the medical literature, the minimal length of time that a patient must have been sober before being considered for OLT ranges from 6 months to 2 years. A further step taken by many transplant centers to ensure the best chance for successful outcome is the requirement that patients also have completed an alcohol treatment or rehabilitation program. The reader is referred to Surgical Clinics of North America, Volume 3, Number 3, 1999, for a comprehensive review of OLT for alcoholic liver disease.

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