Liver Transplantation
Liz Highleyman

Despite improvements in treatments, many people with hepatitis C still develop cirrhosis and liver cancer. As disease progresses to the point where the liver is unable to carry out its important functions (end-stage liver disease, or ESLD), a liver transplant is usually the only option. In the United States and Europe, hepatitis C is the most common reason for liver transplantation. While much remains to be learned about liver transplantation, the current picture contains both good news and bad.

The good news is that liver transplant survival rates have increased steadily in recent decades with the development of improved surgical techniques, more experience with post-transplant medical management, and better immunosuppressive drugs. The one-year post-transplant survival rate has increased from about 30% in the 1970s to 85-90% today, and the five-year survival rate is about 75-80%.

The bad news is that there is a severe and worsening shortage of donor livers. There are currently more than 17,000 people on the United Network for Organ Sharing (UNOS) liver waiting list; in 2004, about 6,000 liver transplants were performed. Given this discrepancy between supply and demand, about 10% of patients die each year while on the waiting list.

A process is in place to ensure that the most appropriate candidates receive available cadaver livers (livers from deceased persons). In 2002, UNOS adopted a new system called MELD (Model for End-Stage Liver Disease) that uses three lab tests – bilirubin, creatinine, and prothrombin time – to predict how likely patients are to die. Previously, candidates were assigned a status based on symptoms of decompensation such as ascites, bleeding varices, itching, blood clotting problems, or encephalopathy. The MELD system is intended to give priority to patients who need new livers most urgently, rather than those who have been waiting longest. According to a study in the January 2004 issue of Liver Transplantation, the number of liver transplants increased by 10% and the waiting list mortality rate fell by nearly 4% after MELD was adopted.

But the new allocation scheme remains controversial since it tends to prioritize patients with specific causes of liver disease (especially liver cancer) and does not take into account other factors that might make certain patients higher priority candidates. As such, researchers are studying new metrics for allocation. T.I. Huo and colleagues, for example, reported in the June 2005 Journal of Hepatology that the change in MELD score over time may be a more accurate predictor of mortality risk than the MELD score at a single time point.

Given the shortage of donor livers, new methods have been developed to extend the supply, including split liver and living donor liver transplantation. The liver is the only organ in the body that can regenerate itself. Thus, a cadaver liver may be split into two pieces and transplanted into two recipients, where each piece will grow into a fully functioning organ. Split liver transplants produce the best results when the larger right lobe is given to an adult and the smaller left lobe goes to a child. In some cases, split liver transplants may be appropriate for two adults, depending on donor and recipient size. In the future, the split liver procedure may become more widely used if researchers figure out a way to accelerate liver regeneration.

In a living donor transplant, a piece of liver is taken from a live person, usually a relative (although livers do not require close genetic matching like some other organs). Pioneered in the late 1980s, several thousand living donor liver transplants have been performed to date, and the procedure now accounts for about 5% of all liver transplants. While living donor transplants have the potential to dramatically increase the supply of organs, the procedure is not without risk to the donor. A study published in the February 27, 2003 New England Journal of Medicine found that 65 of 449 donors (14.5%) experienced at least one complication, including bile leakage, infection, and excessive bleeding. In 2002, a living donor at Mount Sinai Hospital in New York City died of an infection after donating a section of his liver to his brother, but such deaths are very rare. Occasionally, under very specific circumstances, a “domino” procedure may be done in which one patient receives a new donor liver and that patient’s old liver is then given to a second recipient.

In the January 2006 Journal of Hepatology, Mylene Sebagh and colleagues compared the outcomes of split liver, living donor, and domino procedures at a single center in France. They found that the rate of acute and chronic organ rejection was similar among the groups, but acute rejection was more severe in the split liver group. The split liver group was also more likely to experience biliary complications (40% for split liver, 26% for living donor, 8% for cadaver donor), possibly because bile ducts are more heavily damaged when the liver is divided into sections. In general, the survival rate for split and living donor transplants is similar to the rate for cadaver transplants, but some evidence suggests people with hepatitis C do less well with living donor organs (to be discussed next issue).

There have also been proposals to use “less than optimal” livers to expand the supply, including organs from older donors. But this is a risky option. As reported in the March 2005 Archives of Surgery, Derek Moore and colleagues found that the three most important factors affecting post-transplant survival and quality of life were donor age, recipient’s UNOS urgency status, and cold ischemic time (the amount of time liver is kept on ice, without a supply of oxygen, after removal from the donor). The five-year graft survival rate was 72% when the liver came from a donor younger than 60 years, compared with 35% when the donor was age 60 years or older. In another study, 14% of HCV positive patients who received livers from donors younger than 30 years experienced recurrent post-transplant cirrhosis, compared with 45% of those who received livers from donors age 31-59, and 52% who received organs from donors older than 59.

An exception to the optimal liver rule may apply for people with HIV and/or HCV. Today, livers from HCV positive people, HIV positive people – and even groups considered “high risk,” including HIV negative gay men – are not accepted for transplants. Studies suggest that HCV positive patients who receive HCV-infected livers fare no worse than those who receive HCV-free organs. Since the advent of highly active antiretroviral therapy (HAART), numerous studies have shown that HIV positive people with well-controlled HIV disease (i.e., undetectable or low HIV viral load, CD4 cell count of at least 200, no opportunistic infections) have post-transplant survival rates similar to those seen in HIV negative individuals. Dozens of HIV positive liver transplants have been performed to date, and lawsuits have forced insurers to cover them. HIV/HCV coinfected people tend to experience faster liver disease progression than HIV negative people, and (as reported in the November 2005 issue of Liver Transplantation) HIV positive individuals are more likely to die on the liver waiting list – even if they do not have more severe HIV disease or liver disease. Some experts believe coinfected patients should be given higher priority for transplants, but this is difficult due to the scarce liver supply. Use of livers from HIV positive or at-risk donors may be a partial solution for this population.

The 17,000 people on the liver waiting list today is up from about 3,000 in 1993. The number is only expected to grow as people infected with HCV decades ago begin to develop end-stage disease or liver cancer. From a social standpoint, the severe organ shortage has prompted calls for policy changes, such as the “presumed consent” system – already in place in some European countries – under which people are automatically considered potential organ donors unless they explicitly opt out. In terms of living donor transplants, it is crucial to ensure that prospective donors are truly making an informed, voluntary decision without financial or other types of pressure.

Liver transplant patients with hepatitis C face an additional challenge: HCV almost always infects the donated liver and may cause a new round of fibrosis progression. Post-transplant HCV recurrence will be discussed in the next issue of the HCV Advocate.

References:
 •Brown, R. et al. A survey of liver transplantation from living adult donors in the United States. New England Journal of Medicine 348(9): 818-825. February 27, 2003.
 •D’Amico G. Developing concepts on MELD: delta and cutoffs. Journal of Hepatology 42(6): 790-792. June 2005.
 •Freeman, R.B. et al. United Network for organ sharing organ procurement and transplantation network liver and transplantation committee: Results of the first year of the new liver allocation plan. Liver Transplantation 10(1): 7-15. January 2004.
 •Huo, T.I. et al. Evaluation of the increase in model for end-stage liver disease (∆MELD) score over time as a prognostic predictor in patients with advanced liver cirrhosis: risk factor analysis and comparison with initial MELD and Child-Turcotte-Pugh score. Journal of Hepatology 42(6): 826-832. June 2005.
 •Moore, D. et al. Impact of donor, technical, and recipient risk factors on survival and quality of life after liver transplantation. Archives of Surgery 140(3): 273-277. March 2005.
 •Ragni, M. et al. Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease. Liver Transplantation 11(11): 1425-1430. November 2005.
 •Roland M et al. 1- to 3-year outcomes in HIV-infected liver and kidney transplant recipients. 12th Conference on Retroviruses and Opportunistic Infections, Boston, February 22-25, 2005. Abstract 953.
 •Sebagh, K. et al. Cadaveric full-size liver transplantation and the graft alternatives in adults: A comparative study from a single center. Journal of Hepatology 44(1): 118-25. January 2006.

Child score at transplantation, rejection episodes, tumor number, total tumor burden, or bilobar tumor did also not affect survival.

In addition, the team observed that survival was not affected by pathologic Tumor, Nodes, Metastasis stages.

There was no significant difference in survival when patients were grouped according to the recently proposed simplified Tumor, Nodes, Metastasis staging.

The team noted no difference in survival with grouping patients according to the United Network for Organ Sharing staging system for hepatocellular carcinoma.

The researchers observed that encapsulation of the tumor and á-fetoprotein levels significantly affected patient survival.

The 5-year patient survival with poorly differentiated hepatocellular carcinoma was 44%.

The team found that patients with moderately or well-differentiated hepatocellular carcinoma had 5-year survival rates of 67% and 97%, respectively.

The 5-year survival of patients with micro- or macro-vascular invasion was 49% vs 77% for patients without vascular invasion.

Multivariate analysis showed that histological grade of differentiation and macroscopic vascular invasion are independent predictors of survival.”

Dr Zavaglia's team commented, “Histological grade of differentiation and macroscopic vascular invasion, as assessed on the explanted livers, are strong predictors of both survival and tumor recurrence in patients with cirrhosis who received transplants for hepatocellular carcinoma.”

Am J Gastroenterol 2005: 100(12): 2708
19 December 2005

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