ADVANCES IN HEPATOLOGY C u r r e n t D e v e l o p m e n t s i n t h e Tr e a t m e n t o f H e p a t i t i s a n d H e p a t o b i l i a r y D i s e a s e
Section Editor: Eugene R. Schiff, MD
The Current State of Liver Transplantation Robert S. Brown, Jr, MD, MPH
Chief, Division of Liver Disease and Transplantation Columbia University College of Physicians and Surgeons New York-Presbyterian Hospital
G&H What are the current baseline criteria for liver transplant candidacy? RB First and foremost, patients must have acute or chronic liver disease that has failed medical therapy. However, the definition of “failed” therapy can vary from one transplant center to another. Essentially, the patient’s condition must justify the mortality risk of transplantation, which, without complicating factors, is approximately 10%. Transplantation should also be reserved for patients in whom it will reasonably provide a curative effect. These patients include those presenting with acute liver failure from a variety of causes, chronic liver failure, predominantly from hepatitis C, and certain malignancies contained within the liver. Malignancies that have spread outside the liver cannot be cured by liver replacement. In fact, they would be worsened due to the need for immunosuppressive therapy posttransplant, which would actually encourage their spread. G&H Is cancer screening a standard procedure before transplant surgery? RB Yes. For all transplant candidates it is important to look extensively for any evidence of cancer outside the liver. For example, patients need up-to-date colonoscopy and mammography examinations, as appropriate, because transplant and immunosuppression increase the risk of malignancy and would increase the risk of spread.
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G&H Can you describe the process of transplant candidate prioritization? RB Patients are prioritized in two categories. Patients with acute liver failure are given first priority, known as United Network for Organ Sharing (UNOS) Status 1. Examples include patients who develop sudden hepatitis A or B or those whose livers are damaged due to medication toxicity or who experience failure of an initial transplant. These patients comprise less than 10% of all transplants. Patients with chronic liver disease comprise the majority of the transplant list and are prioritized based on their Model for End-Stage Liver Disease (MELD) score. MELD is a mathematical model initially developed to predict mortality in patients undergoing transjugular intrahepatic portosystemic shunting (TIPS). It has since been shown to be the best predictor of short-term (ie, 90-day) mortality in patients awaiting transplantation. Use of the MELD system for prioritization has been shown to improve outcomes, especially in terms of pretransplant mortality, because it allows surgeons to identify patients who are approaching liver failure and prioritize them for transplant first. Posttransplant mortality has remained the same or improved, despite transplanting sicker patients. G&H Is there any downside to strict prioritization by MELD? RB MELD does not measure morbidity and mortality related to two factors. The first is hepatocellular carcinoma (HCC), which arises predominantly in the setting of chronic hepatitis B and C. HCC has been accounted for in the MELD system by giving added priority to patients with small tumors. These patients have been shown to do very well with transplant. However, patients who have tumors just above the cut-off size are not prioritized as transplant candidates under MELD because they generally have good liver function. The second group is comprised of patients with portal hypertension with encephalopathy or ascites. Patients who have ascites alone can undergo a TIPS procedure or receive a shunt to reduce portal pressures. However, in
patients with encephalopathy, there is no recourse under MELD in order to accelerate transplantation and no alternative therapy. In these situations, living donor liver transplantation is often the only option. G&H Is the current pool of donors for liver transplant fulfilling the needs of patients in the United States? RB The biggest problem in transplantation today is that there are not enough donors for the people who need organs. Because donor networks for distribution are organized locally and regionally, there are variations across the country in terms of patient access. Areas with a population density that is consistently high across the region, like the metropolitan areas of the Northeast (Boston, New York, Washington) and most parts of California, have the most severe shortages. Urban centers like Dallas, Atlanta, Miami, and other cities in the Midwest and South, tend to have less severe shortages. The end result is that candidates in these regions can often receive transplants at lower MELD scores. G&H How would you characterize the health and quality of the current donor pool and how is this affecting transplant success? RB In the United States, we have a population that is aging and is also more prone toward obesity. As a result of these factors and profound donor shortage, transplant centers are accepting and using more and more older and overweight donors. Overall, the increased acceptance of organs has led to an increased number of organs being available, not a decrease. Further, acceptance of marginal donors has not led to worse posttransplant outcomes, most likely because of improvements in transplant technique over the years. This is true across the board in transplant patients, with the possible exception of those with hepatitis C, who are possibly the only group of patients disadvantaged by the use of older donors or those with livers containing significant fat. G&H Can you discuss living donor transplantation? RB Living donor liver transplantation, in experienced centers, has success rates equal to deceased donor transplant and lowers pretransplant mortality if patients are in an area of severe donor scarcity. Living donor transplant is most appropriate for patients with MELD scores between 15 and 25. Patients who are sicker should likely have deceased donor transplants. Patients disadvantaged by MELD because, for example, they have portal hypertension coupled with a relatively low MELD score, or those with a cancer and a long waiting time, can be offered liv-
ing donor transplant as a lifesaving alternative. Initially it was thought that outcomes for hepatitis C patients receiving a living donor transplant were worse than with a deceased donor but that has turned out not to be the case, both in large single-center experiences as well as in analyses from the UNOS database and the National Institutes of Health Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL). There is a mortality risk to the donor in a living donor transplant but that risk is small, less than 0.5%. G&H How early should a referring gastroenterologist consult with a transplant center and send candidates for examination? RB With the advent of the MELD system for prioritization of candidates, the advantages of early listing, in terms of accruing waiting time and additional priority, no longer apply. However, there are still advantages to early evaluation. Patients with a MELD score over 10 or any complication of liver disease that correlates with the former minimum listing criteria (ie, Child-Turcotte-Pugh score of 7) are good candidates for initial evaluation. It has been shown that patients who are referred to a transplant center have more regular screening for HCC and are more closely observed. Most importantly, if patients have a problem that could preclude transplant in the future, it may be easier to fix prior to the development of advanced decompensated cirrhosis. Cardiac problems, for example, if found while still at an early stage of liver disease, could be corrected by surgery. However, if such a problem were not addressed until the time of transplant, surgery of any sort may not be an option. Insurance issues and psychosocial barriers are also better dealt with well in advance, rather than at the last moment. G&H Is there a standard set of screenings or medical therapies that help prepare a patient for the transplant operation? RB The most important process for the pretransplant patient is one of education. Patients and their families need to be informed about the rigors of transplant and postoperative care. Medical evaluations at this time are largely noninvasive. Cardiopulmonary testing should be done to determine any factors for surgical risk. Age-appropriate cancer screening needs to be performed. Finally, a detailed evaluation of the liver needs to be done. The most invasive test required for most patients is a colonoscopy in patients over 50 years of age. Patients should also meet with a psychiatrist and a social worker and be assessed for addiction and addiction recovery options, if applicable. All of this can be done in as little as 48 hours but it generally takes place over the course of 1 or 2 months.
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Pretransplant medical therapies are the same as those standard for management of any liver cirrhosis. Portal hypertensive bleeding is treated with beta-blockers or banding, ascites are treated with diuretics, and encephalopathy with lactulose or rifaximin (Xifaxin, Salix). In some hepatitis C patients, viral eradication is attempted pretransplant, often with a low accelerating dose regimen (LADR). Patients with hepatitis B are administered appropriate antiviral therapy.
donors. We are also focused on better prevention and management of end-stage liver disease (eg, through hepatitis B vaccination and treatment and earlier hepatitis C treatment). In the past 5–10 years, the point has been reached where recurrent hepatitis B can be eradicated in virtually every patient who undergoes transplantation. We would like to reach the same goal with hepatitis C patients.
G&H Can you outline a standard-of-care scenario for posttransplant patients?
Habib S, Berk B, Chang CH, et al. MELD and prediction of post-liver transplantation survival. Liver Transpl. 2006;12:440-447.
RB Following transplant, patients spend, on average, 1–2 weeks in the hospital. After release, they would return for weekly blood tests and visits to determine liver function and general health. Immunosuppressive medications, in the form of a 2- or 3-drug regimen with slowly tapering doses, are administered immediately after transplant, as are medications to prevent common infections, particularly cytomegalovirus and Pneumocystis carinii pneumonia. For patients with hepatitis C, protocol liver biopsies are frequently performed; at our institution they are done at 3 months and 1 year postoperatively, then annually. Liver biopsies are also performed to evaluate any patients with abnormal liver function test results. The frequency of visits to the transplant center decreases gradually from weekly to biweekly, and then monthly by the end of the first year after transplantation. At this point in time, many patients have been reduced to monotherapy for immunosuppression, usually with tacrolimus (Prograf, Astellas) or cyclosporine. They undergo lab tests every 1–2 months and are examined at the transplant center every 6–12 months. Overall, the 1-year survival rate is approximately 90% and the 5-year rate of survival is approximately 85%. In patients with recurrent disease, particularly hepatitis C, there is a significant ongoing morbidity and mortality. Life expectancy for patients without recurrent disease after 5 years is roughly equivalent to age-matched controls. G&H Are there any emerging technologies or therapies that might change the practice of liver transplantation in the near future? RB If current and planned trials of the oral hepatitis C inhibitors prove successful at rapidly lowering viral load, the possibility of eliminating hepatitis C prior to transplantation will become much more likely. There has also been an enormous interest in developing artificial livers for temporary or chronic support but that technology is still years away from practical application. For the moment, most physicians are concentrating on improving access to transplantation by exploring alternate donor sources, including the expansion of donor criteria and use of living
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Suggested Reading
Gaglio PJ, Brown RS Jr. Who should treat liver transplant patients? The transplant hepatologist or the gastroenterologist? Part I: The transplant hepatologist. J Hepatol. 2006;44:655-657. Moss J, Lapointe-Rudow D, Renz JF, et al. Select utilization of obese donors in living donor liver transplantation: implications for the donor pool. Am J Transplant. 2005;5:2974-2981. Brown RS. Hepatitis C and liver transplantation. Nature. 2005;436:973-978. Yokoi H, Isaji S, Yamagiwa K, et al. The role of living-donor liver transplantation in surgical treatment for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2006;13:123-130. National Institutes of Health Adult to Adult Living Donor Liver Transplantation Cohort Study. Available at: www.nih-a2all.org. Brown RS Jr, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348:818-825. United Network for Organ Sharing. Available at: www.unos.org. Shiffman ML, Stravitz RT, Contos MJ, et al. Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation. Liver Transpl. 2004;10:1248-1255. Russo MW, Galanko J, Beavers K, et al. Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States. Liver Transpl. 2004;10:340-346.
Section Editor: Eugene R. Schiff, MD
The Current State of Liver Transplantation Robert S. Brown, Jr, MD, MPH
Chief, Division of Liver Disease and Transplantation Columbia University College of Physicians and Surgeons New York-Presbyterian Hospital
G&H What are the current baseline criteria for liver transplant candidacy? RB First and foremost, patients must have acute or chronic liver disease that has failed medical therapy. However, the definition of “failed” therapy can vary from one transplant center to another. Essentially, the patient’s condition must justify the mortality risk of transplantation, which, without complicating factors, is approximately 10%. Transplantation should also be reserved for patients in whom it will reasonably provide a curative effect. These patients include those presenting with acute liver failure from a variety of causes, chronic liver failure, predominantly from hepatitis C, and certain malignancies contained within the liver. Malignancies that have spread outside the liver cannot be cured by liver replacement. In fact, they would be worsened due to the need for immunosuppressive therapy posttransplant, which would actually encourage their spread. G&H Is cancer screening a standard procedure before transplant surgery? RB Yes. For all transplant candidates it is important to look extensively for any evidence of cancer outside the liver. For example, patients need up-to-date colonoscopy and mammography examinations, as appropriate, because transplant and immunosuppression increase the risk of malignancy and would increase the risk of spread.
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G&H Can you describe the process of transplant candidate prioritization? RB Patients are prioritized in two categories. Patients with acute liver failure are given first priority, known as United Network for Organ Sharing (UNOS) Status 1. Examples include patients who develop sudden hepatitis A or B or those whose livers are damaged due to medication toxicity or who experience failure of an initial transplant. These patients comprise less than 10% of all transplants. Patients with chronic liver disease comprise the majority of the transplant list and are prioritized based on their Model for End-Stage Liver Disease (MELD) score. MELD is a mathematical model initially developed to predict mortality in patients undergoing transjugular intrahepatic portosystemic shunting (TIPS). It has since been shown to be the best predictor of short-term (ie, 90-day) mortality in patients awaiting transplantation. Use of the MELD system for prioritization has been shown to improve outcomes, especially in terms of pretransplant mortality, because it allows surgeons to identify patients who are approaching liver failure and prioritize them for transplant first. Posttransplant mortality has remained the same or improved, despite transplanting sicker patients. G&H Is there any downside to strict prioritization by MELD? RB MELD does not measure morbidity and mortality related to two factors. The first is hepatocellular carcinoma (HCC), which arises predominantly in the setting of chronic hepatitis B and C. HCC has been accounted for in the MELD system by giving added priority to patients with small tumors. These patients have been shown to do very well with transplant. However, patients who have tumors just above the cut-off size are not prioritized as transplant candidates under MELD because they generally have good liver function. The second group is comprised of patients with portal hypertension with encephalopathy or ascites. Patients who have ascites alone can undergo a TIPS procedure or receive a shunt to reduce portal pressures. However, in
patients with encephalopathy, there is no recourse under MELD in order to accelerate transplantation and no alternative therapy. In these situations, living donor liver transplantation is often the only option. G&H Is the current pool of donors for liver transplant fulfilling the needs of patients in the United States? RB The biggest problem in transplantation today is that there are not enough donors for the people who need organs. Because donor networks for distribution are organized locally and regionally, there are variations across the country in terms of patient access. Areas with a population density that is consistently high across the region, like the metropolitan areas of the Northeast (Boston, New York, Washington) and most parts of California, have the most severe shortages. Urban centers like Dallas, Atlanta, Miami, and other cities in the Midwest and South, tend to have less severe shortages. The end result is that candidates in these regions can often receive transplants at lower MELD scores. G&H How would you characterize the health and quality of the current donor pool and how is this affecting transplant success? RB In the United States, we have a population that is aging and is also more prone toward obesity. As a result of these factors and profound donor shortage, transplant centers are accepting and using more and more older and overweight donors. Overall, the increased acceptance of organs has led to an increased number of organs being available, not a decrease. Further, acceptance of marginal donors has not led to worse posttransplant outcomes, most likely because of improvements in transplant technique over the years. This is true across the board in transplant patients, with the possible exception of those with hepatitis C, who are possibly the only group of patients disadvantaged by the use of older donors or those with livers containing significant fat. G&H Can you discuss living donor transplantation? RB Living donor liver transplantation, in experienced centers, has success rates equal to deceased donor transplant and lowers pretransplant mortality if patients are in an area of severe donor scarcity. Living donor transplant is most appropriate for patients with MELD scores between 15 and 25. Patients who are sicker should likely have deceased donor transplants. Patients disadvantaged by MELD because, for example, they have portal hypertension coupled with a relatively low MELD score, or those with a cancer and a long waiting time, can be offered liv-
ing donor transplant as a lifesaving alternative. Initially it was thought that outcomes for hepatitis C patients receiving a living donor transplant were worse than with a deceased donor but that has turned out not to be the case, both in large single-center experiences as well as in analyses from the UNOS database and the National Institutes of Health Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL). There is a mortality risk to the donor in a living donor transplant but that risk is small, less than 0.5%. G&H How early should a referring gastroenterologist consult with a transplant center and send candidates for examination? RB With the advent of the MELD system for prioritization of candidates, the advantages of early listing, in terms of accruing waiting time and additional priority, no longer apply. However, there are still advantages to early evaluation. Patients with a MELD score over 10 or any complication of liver disease that correlates with the former minimum listing criteria (ie, Child-Turcotte-Pugh score of 7) are good candidates for initial evaluation. It has been shown that patients who are referred to a transplant center have more regular screening for HCC and are more closely observed. Most importantly, if patients have a problem that could preclude transplant in the future, it may be easier to fix prior to the development of advanced decompensated cirrhosis. Cardiac problems, for example, if found while still at an early stage of liver disease, could be corrected by surgery. However, if such a problem were not addressed until the time of transplant, surgery of any sort may not be an option. Insurance issues and psychosocial barriers are also better dealt with well in advance, rather than at the last moment. G&H Is there a standard set of screenings or medical therapies that help prepare a patient for the transplant operation? RB The most important process for the pretransplant patient is one of education. Patients and their families need to be informed about the rigors of transplant and postoperative care. Medical evaluations at this time are largely noninvasive. Cardiopulmonary testing should be done to determine any factors for surgical risk. Age-appropriate cancer screening needs to be performed. Finally, a detailed evaluation of the liver needs to be done. The most invasive test required for most patients is a colonoscopy in patients over 50 years of age. Patients should also meet with a psychiatrist and a social worker and be assessed for addiction and addiction recovery options, if applicable. All of this can be done in as little as 48 hours but it generally takes place over the course of 1 or 2 months.
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Pretransplant medical therapies are the same as those standard for management of any liver cirrhosis. Portal hypertensive bleeding is treated with beta-blockers or banding, ascites are treated with diuretics, and encephalopathy with lactulose or rifaximin (Xifaxin, Salix). In some hepatitis C patients, viral eradication is attempted pretransplant, often with a low accelerating dose regimen (LADR). Patients with hepatitis B are administered appropriate antiviral therapy.
donors. We are also focused on better prevention and management of end-stage liver disease (eg, through hepatitis B vaccination and treatment and earlier hepatitis C treatment). In the past 5–10 years, the point has been reached where recurrent hepatitis B can be eradicated in virtually every patient who undergoes transplantation. We would like to reach the same goal with hepatitis C patients.
G&H Can you outline a standard-of-care scenario for posttransplant patients?
Habib S, Berk B, Chang CH, et al. MELD and prediction of post-liver transplantation survival. Liver Transpl. 2006;12:440-447.
RB Following transplant, patients spend, on average, 1–2 weeks in the hospital. After release, they would return for weekly blood tests and visits to determine liver function and general health. Immunosuppressive medications, in the form of a 2- or 3-drug regimen with slowly tapering doses, are administered immediately after transplant, as are medications to prevent common infections, particularly cytomegalovirus and Pneumocystis carinii pneumonia. For patients with hepatitis C, protocol liver biopsies are frequently performed; at our institution they are done at 3 months and 1 year postoperatively, then annually. Liver biopsies are also performed to evaluate any patients with abnormal liver function test results. The frequency of visits to the transplant center decreases gradually from weekly to biweekly, and then monthly by the end of the first year after transplantation. At this point in time, many patients have been reduced to monotherapy for immunosuppression, usually with tacrolimus (Prograf, Astellas) or cyclosporine. They undergo lab tests every 1–2 months and are examined at the transplant center every 6–12 months. Overall, the 1-year survival rate is approximately 90% and the 5-year rate of survival is approximately 85%. In patients with recurrent disease, particularly hepatitis C, there is a significant ongoing morbidity and mortality. Life expectancy for patients without recurrent disease after 5 years is roughly equivalent to age-matched controls. G&H Are there any emerging technologies or therapies that might change the practice of liver transplantation in the near future? RB If current and planned trials of the oral hepatitis C inhibitors prove successful at rapidly lowering viral load, the possibility of eliminating hepatitis C prior to transplantation will become much more likely. There has also been an enormous interest in developing artificial livers for temporary or chronic support but that technology is still years away from practical application. For the moment, most physicians are concentrating on improving access to transplantation by exploring alternate donor sources, including the expansion of donor criteria and use of living
246
Gastroenterology & Hepatology Volume 2, Issue 4 April 2006
Suggested Reading
Gaglio PJ, Brown RS Jr. Who should treat liver transplant patients? The transplant hepatologist or the gastroenterologist? Part I: The transplant hepatologist. J Hepatol. 2006;44:655-657. Moss J, Lapointe-Rudow D, Renz JF, et al. Select utilization of obese donors in living donor liver transplantation: implications for the donor pool. Am J Transplant. 2005;5:2974-2981. Brown RS. Hepatitis C and liver transplantation. Nature. 2005;436:973-978. Yokoi H, Isaji S, Yamagiwa K, et al. The role of living-donor liver transplantation in surgical treatment for hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2006;13:123-130. National Institutes of Health Adult to Adult Living Donor Liver Transplantation Cohort Study. Available at: www.nih-a2all.org. Brown RS Jr, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348:818-825. United Network for Organ Sharing. Available at: www.unos.org. Shiffman ML, Stravitz RT, Contos MJ, et al. Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation. Liver Transpl. 2004;10:1248-1255. Russo MW, Galanko J, Beavers K, et al. Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States. Liver Transpl. 2004;10:340-346.
