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Recent Developments in |
Liver Transplantation | ||
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Prior to the availability of liver transplantation, the management of end-stage liver disease was limited to efforts to correct and control the complications associated with cirrhosis, and to comfort measures when all other avenues had been exhausted. In the last decade, however, orthotopic liver transplantation has become an accepted treatment for patients with end-stage liver disease. Although the general management of advanced liver disease has changed little over the past few decades, hepatologists must now factor in the effects of their therapeutic endeavors on possible liver transplantation in the future. In addition, management of the patient following transplantation has led to a wide variety of new challenges.
The indications for orthotopic liver transplantation may be divided into two general categories: complications of end-stage liver disease and decreased quality of life. Clearly, patients with variceal bleeding, refractory ascites, and hepatic encephalopathy have a decreased quality of life due to the significant morbidity and potential mortality of each of these complications. Another population of patients with chronic liver disease, but lacking these complications and possibly even lacking cirrhosis on liver biopsy, may have an equally diminished quality of life due to profound fatigue, pruritus refractory to medical management, or recurrent episodes of bacterial cholangitis due to biliary strictures. These patients have a similar need for liver transplantation, despite what may seem a much less serious illness.
In most cases, the indication for transplantation is easily recognized by the referring physician. Occasionally, however, lesser known indications for transplantation may arise and should prompt referral to a liver transplant center. Osteopenia, for example, is a common complication in patients with chronic cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis.1,2 Patients with these diseases should be referred if they have evidence of a low bone mineral density and vertebral body or rib fractures occurring spontaneously or with minimal trauma. Malnutrition occurs commonly in patients with end-stage liver disease, occasionally without other life-threatening complications. Evidence of marked muscle wasting should prompt referral. Lastly, hepatocellular carcinoma without evidence of extrahepatic disease is an indication for liver transplantation at some centers. Other hepatic malignancies such as cholangiocarcinoma or metastatic disease are contraindications to transplantation at most centers.
Any list of indications for transplantation must be accompanied by a list of contraindications. Absolute contraindications to liver transplantation include HIV seropositivity, the presence of extrahepatic malignancy, the presence of active infection or severe organ impairment (excluding renal insufficiency), active substance abuse, a poor social support system, and the inability to comply with a medical regimen. These factors are relatively consistent among transplant centers, but other factors may vary. Chronic hepatitis B is viewed as a contraindication to liver transplantation at some centers due to the high rate of recurrence. Transplantation for hepatocellular carcinoma is not performed routinely at many centers. Because of this variability, any patient with even a remote potential as a liver transplant candidate should be discussed with a hepatologist or surgeon at a transplant referral center.
The timing of referral for liver transplantation plays a crucial role in the management and survival of patients with end-stage liver disease. As waiting lists (Figure 1) and waiting times lengthen, the condition of the patient at the time of referral is of critical importance. Obviously, a patient with multiple complications of end-stage liver disease at the time of referral will likely require hospitalization at some point prior to transplantation. Not surprisingly, patients with higher United Network for Organ Sharing (UNOS) priority levels; ie, hospitalized patients, clearly have lower survival rates than patients out of the hospital at the time the donor organ becomes available.3 Thus, most transplant centers encourage referring physicians to make preliminary contacts at the first sign that transplantation may be indicated. Most transplant hepatologists would rather err on the side of prudence and see a patient "too early" than lose a patient who is referred "too late." Unfortunately, the number of patients dying on transplantation waiting lists is increasing (Figure 2).
Assessing prognostic factors accurately remains an unresolved challenge. Prognostic models have been developed for patients with primary biliary cirrhosis and primary sclerosing cholangitis.4,5 Investigators at the Mayo Clinic have developed sophisticated mathematical formulas, utilizing both clinical and biochemical factors, that determine the chance of survival at specific time points. Both equations, however, depend heavily on the serum bilirubin. Furthermore, the equations cannot factor in such intangibles as pruritus, profound fatigue, or recurrent bouts of bacterial cholangitis. Thus, even though these models are useful investigational tools, they appear to offer little help in day-to-day clinical management.
Figure 1. Number of patients awaiting orthotopic liver transplantation in the United States by year. From: UNOS scientific registry. Liver allocation data examined. UNOS Update 1991;7(10):12-13.
Figure 2. Number of patients who die per year while awaiting liver transplantation in the United States. From: UNOS scientific registry. Liver allocation data examined. UNOS Update 1991;7(10):12-13.
Creating a timetable for referral is difficult. Most transplant centers agree, however, that the following factors should prompt referral: refractory variceal bleeding, recurrent bouts of hepatic encephalopathy, refractory ascites especially in the face of renal insufficiency, recurrent bacterial cholangitis, refractory pruritus, and severe hepatic osteodystrophy. Lastly, profound fatigue should also prompt referral even if none of the other factors is present. Again, these are only guidelines, and any question should prompt a phone call to the nearest transplant center.
Viral hepatitis has become a difficult problem for transplant centers both before and after transplantation. Hepatitis B recurs in the transplanted liver in 80%-90% of patients.6 Hepatitis C is found in 20% to 30% of patients at most transplant centers, and infection of the allograft occurs in 40%-45% of patients at one year posttransplant.7 These figures have led to the exclusion of hepatitis B patients from transplantation at many centers and careful consideration of patients with hepatitis C.
If either of the hepatitis viruses could be eradicated prior to the time of transplantation, posttransplant morbidity would likely be decreased. Unfortunately, therapeutic options are limited to alfa-interferon, an agent used with limited success in the nontransplant setting. In one study of 18 patients with clinically apparent cirrhosis secondary to hepatitis B, 33% had sustained loss of hepatitis B virus DNA and hepatitis B e antigen, similar to the 35%-40% response rates in nontransplant patients.8 Unfortunately, thrombocytopenia and leukopenia, common complications of alfa-interferon therapy, occur frequently in cirrhotic patients due to hypersplenism. In addition, malaise and fatigue due to interferon are tolerated more poorly in cirrhotics than in patients with uncomplicated chronic active hepatitis. A similar investigation in patients with hepatitis C has not been done. In light of the poor results of liver transplantation for patients with viral hepatitis, however, alfa-interferon therapy should be considered for use pretransplant for those with chronic active hepatitis due to HBV or HCV.
Perioperative administration of hepatitis B immune globulin (HBIG) has been used as passive immunprophylaxis in the liver allograft recipient. Since replication of the hepatitis B virus in extrahepatic sites is thought to be the source of infection,9 high doses of hepatitis B surface antibody are thought to bind circulating hepatitis B virus and prevent infection of the transplanted liver. In a review of the European experience using this approach, patients with hepatitis B-related cirrhosis had a 48% survival rate at 3, 4, and 5 years.10
Significant predictors of survival included the presence of hepatitis delta virus superinfection, the absence of hepatitis B virus DNA and hepatitis B e antigen prior to transplantation, and transplantation for fulminant hepatitis. These findings suggest that the absence of active viral replication independent of the use of HBIG was a key factor in survival posttransplant.
Studies in the United States have been limited because of the lack of an intravenous formulation of HBIG. Several centers have used the intramuscular formulation given as an intravenous infusion. Others have used smaller doses intramuscularly. These methods are less than optimal. Fortunately, an intravenous formulation of HBIG will be available for a U.S. multicenter trial in early 1996.
Transplantation for hepatocellular carcinoma is controversial in this age of scarce donor organs. Initial results showed a three-year survival of approximately 30%.11 The use of neoadjuvant chemotherapy prolongs the survival of patients treated with liver transplantation for hepatocellular carcinoma compared to those who do not receive neoadjuvant chemotherapy. Twenty patients given pre- and post-transplant doxorubicin (10 mg/m2 per week, total cumulative dose 200 mg/m2) had a three-year actuarial survival of 59%, with an actuarial tumor-free survival at three years of 54%.12 Five patients (25%) died of recurrent tumor; three died of recurrent hepatitis B. The presence of vascular invasion on histologic section was a poor prognostic factor.
Other options for pretransplant therapy of hepatocellular carcinoma include ethanol ablation of small tumors and chemoembolization. Chemoembolization can be difficult in the cirrhotic patient the lack of adequate hepatic synthetic reserve can lead to additional hepatic decompensation due to liver cell necrosis.
Although indications for transplantation will vary from center to center, most will agree that the presence of extrahepatic malignancy is an absolute contraindication to liver transplantation. Patients should be routinely evaluated with magnetic resonance imaging of the abdomen, computerized tomography of the chest, Doppler study of the hepatic vasculature, and a bone scan/skeletal survey. Any suggestion of impaired portal venous flow by thrombus should be evaluated with a hepatic angiogram. Evidence of portal venous thrombosis in the face of hepatocellular carcinoma is a contraindication to transplantation.
Survival following liver transplantation for alcoholic liver disease is no different from that in patients transplanted for other conditions.13 However, ethical dilemmas complicate the selection of alcoholic patients for liver transplantation. Should a patient with self-inflicted disease compete equally with other patients? Participation in a pretransplant alcohol rehabilitation program is required by many centers, though the success of this strategy in predicting post-transplant abstinence is unknown. Most transplant centers use a six-month period of sobriety as an initial screening criterion. Unfortunately, this test is a poor indicator of subsequent abstinence. Furthermore, severe liver disease prevents many from completing a six-month test. Additional factors relevant to the evaluation of patients with alcoholic liver disease include other substance abuse, the presence of a social support system, other psychiatric illnesses, and recidivism following previous treatment programs.
Pulmonary arterial hypertension occurs in approximately 2% of patients with portal hypertension.14 Pathologically, the small pulmonary arteries reveal plexogenic pulmonary arteriopathy with early medial hypertrophy, intimal cellular proliferation, and late dilatation and plexiform lesions. Patients complain of exertional dyspnea, though many are symptom-free when pulmonary hypertension is discovered at the time of liver transplantation. Any dyspneic patient considered for liver transplantation should undergo echocardiography and, when indicated, right heart catheterization. Liver transplantation in this patient population can reverse pulmonary hypertension, but predictive factors are lacking.15 Improvement may take as long as a year. One patient followed at Baylor University Medical Center developed more severe pulmonary hypertension following transplantation. Our approach is to evaluate these patients with a prostaglandin E1 (PGE1) infusion; a lack of response suggests "fixed" hypertension, and is a contraindication to liver transplantation. Whether a decrease in pulmonary arterial pressures with PGE1 infusion correlates with a decrease following liver transplantation is the subject of ongoing studies.
Viral Hepatitis: Infection of the liver allograft with the hepatitis B virus is frequent even in the face of passive immunoprophylaxis. Any patient with elevated transaminases transplanted for hepatitis B-related disease should have repeat viral serologies and a hepatitis B virus DNA level. Liver biopsy findings consistent with only a mild acute hepatitis may be seen at reinfection and are nonspecific. Immunoperoxidase stains for hepatitis B surface and core antigens should be performed. In occasional patients, a rapid and severe course characterized by cholestasis and a moderate rise in serum transaminases may be seen16 and can lead to graft failure in as little as 2.5 months. Treatment of recurrent hepatitis B has met with limited success. Alfa-interferon is of little use.17 Retransplantation in this population is followed by prompt infection of the second allograft, with graft failure in as few as four to five months.18 Most transplant centers, in fact, will not retransplant for recurrent hepatitis B infection.
Infection of the allograft with the hepatitis C virus post-transplantation is also common, although this does not usually lead to early graft failure. Although long-term follow-up data for patients with recurrent HCV infection are not available, anecdotal experience suggests a more prolonged course than for hepatitis B patients, with the possibility of graft failure five to ten years following the onset of histologic hepatitis. Posttransplantation hepatitis C infection is also difficult to treat. Alfa-interferon appears to normalize transaminases and decrease HCV-RNA levels in a small percentage of patients, similar to its effect in nontransplant patients. The immunomodulatory effects of alfa-interferon raise concern about possible precipitation of an episode of either acute or ductopenic rejection. Anecdotal experience at several centers indicates that this does not occur. Due to insufficient information on the response of hepatitis C infection in the liver transplant population, however, therapy with alfa-interferon should be considered only after discussion with a transplant center. The use of other antiviral agents for posttransplant hepatitis C patients has not been studied.
Cholestatic Liver Diseases: Recurrence of primary biliary cirrhosis posttransplant was first reported in the early 1980s.19-21 Histologically, distorted bile duct epithelial cells, lymphoid portal inflammation, and scattered granulomas suggest recurrent disease. These findings, however, are nonspecific and may be indistinguishable from those of acute cellular rejection, graft-versus-host disease, hepatitis C, or ductopenic (chronic) rejection. The relatively low rate (<5%) of recurrent disease is likely due to posttransplant immunosuppressive therapy. Unfortunately, therapy for recurrent primary biliary cirrhosis is non-existent. Ursodeoxycholic acid may have some benefit in the nontransplant patient. Change in immunosuppressive regimen from cyclosporine to tacrolimus can also be considered.
Changes on the cholangiogram that are consistent with primary sclerosing cholangitis can occur following liver transplantation, usually due to ischemia from hepatic artery stenosis or thrombosis.22 If an ischemic etiology cannot be identified, recurrent primary sclerosing cholangitis should be considered. Ductopenic rejection, which can produce an arterial vasculopathy with similar ischemic changes, is another possibility. No disease-specific therapy is currently available for recurrent primary sclerosing cholangitis.
Hepatocellular Carcinoma: For patients transplanted for localized hepatocellular carcinoma, disease recurrence, particularly in the face of vascular invasion, is common. Interestingly, in the study using neoadjuvant chemotherapy, only one of six patients with recurrent tumor had evidence of tumor recurrence in the liver allograft.12 Initial recurrences in the other five cases were in the mesentery, bones, mediastinum, and lungs. Therapy for recurrent disease differs little from that in nontransplant patients. Resection and radiation should be used as indicated. Additional chemotherapeutic agents for use posttransplant can be considered but should be discussed with the transplant center prior to their use.
Biliary tract complications can occur in up to a third of liver transplant recipients.23 Within the first thirty postoperative days, leaks at the T-tube site, duct-to-duct anastomosis, and choledochojejunostomy anastomosis are most common. Late complications usually include proximal or distal hepatic duct strictures, narrowing at the anastomoses (both duct-to-duct and choledochojejunostomy), papillary dysfunction or stenosis, and sludge or stone formation in the biliary tree. A therapeutic endoscopist skilled in the use of ERCP can frequently treat these complications and avoid additional trips to the operating suite. Endoscopic ampullary sphincterotomy is often adequate treatment for a leak at the T-tube site. If a leak at the anastomosis or a stricture exists, balloon dilation of the stricture and insertion of a 7 to 12 French stent allows diversion of bile into the duodenum. The stent should be removed three to four months following insertion to prevent stent occlusion and cholangitis. A cholangiogram to assess patency after stent removal should be obtained to determine whether the stent can be left out or should be reinserted.
Sphincter of Oddi dysfunction may occur in as many as 5% of patients following liver transplantation,24 possibly due to disruption of innervation of the sphincter. In a small number of patients, sphincterotomy and stent placement have produced improvement in hyperbilirubinemia. Sphincter of Oddi dysfunction may also contribute to the increased risk of posttransplant choledocholithiasis, though the increased lithogenicity of bile following transplantation is primarily responsible.25
Hyperlipidemia is relatively common following liver transplantation. Between 50% and 60% of patients have elevated cholesterol levels two to three years following liver transplantation; hypertriglyceridemia is present in 60%-70%.26 Lipid levels do not correlate with obesity, diabetes mellitus, steroid dose, or cyclosporine levels. The etiology of hyperlipidemia is likely multi-factorial, though cyclosporine is clearly a factor.27,28 Whether hyperlipidemia in these patients will ultimately increase their risk of atherosclerotic vascular disease is not yet known. Dietary and/or medical therapy should be considered as for nontransplant patients with hyperlipidemia.
Obesity is a common though poorly studied problem in liver transplant recipients. In a study of 28 patients, 21 gained weight after transplantation, with the majority of the weight increase occurring by 16 months posttransplant.29 These patients had an increased incidence of hypertension, hyperlipidemia, and abnormal hepatic biochemistries. Complications of obesity including degenerative joint disease, cardiovascular events, and hypertension will likely occur in this population. Weight reduction should be strongly recommended.
Graft-versus-host disease (GVHD) has been reported within the first 60 days following transplantation.30 Fever, pancytopenia, diarrhea, and a maculopapular rash were seen in the setting of chimerism; ie, the presence of both recipient and donor lymphocytes in the peripheral blood. Unlike GVHD in bone marrow transplant recipients, the liver is not involved because the alloreactive lymphocytes are derived from the liver and recognize the liver as self. In spite of treatment with increased immunosuppression, the prognosis is poor.
Mixed chimerism of the lymphocytes can also be seen posttransplant in the absence of GVHD. This phenomenon has been reported in patients undergoing liver transplantation for type IV glycogen storage disease and Gaucher's disease.31 Mixed lymphoid chimerism may indicate a state of immune tolerance and a decreased need for immunosuppression following transplantation. In fact, some patients may have normal graft function following total withdrawal of immunosuppression. This approach has been tested at the University of Pittsburgh in a group of patients with stable allograft function at least five to seven years posttransplant. Obviously, because of potential life-threatening complications, withdrawal of immunosuppression should only be done under the direction of the transplant center.
Liver transplantation is now an accepted therapy for end-stage liver disease, but potential problems for the transplant candidate and the transplant recipient must be anticipated and addressed promptly. Hepatologists and gastroenterologists will continue to play an important role in the care and management of patients both before and after liver transplantation.
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