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| Lack of livers for transplants makes doctors
less selective Sunday, May 09, 2004 By Christopher Snowbeck, Pittsburgh Post-Gazette Because of the chronic shortage of livers available for transplant, the University of Pittsburgh Medical Center and hospitals across the country are turning to "expanded-criteria" donors to recover livers that previously would have been passed over. The practice raises ethical questions, some believe, and the New York Health Department announced last month it would create a committee to study the trend in the wake of an investigation at a liver transplant unit in Rochester, N.Y. The current transplant chief at UPMC ran the Rochester unit during some of the years investigated by New York officials. Although these livers are obtained from donors who are older or sicker than considered optimal, it's far from clear that there's anything wrong with the trend. Use of livers from expanded-criteria donors helped UPMC in 2002 reverse a 12-year decrease in the number of liver transplants performed at Oakland hospitals. Patient and graft survival for 2002 showed one of the best outcomes ever for the Pitt program, said transplant administrator William Morris. Dr. Goran Klintmalm, chairman of the Baylor Regional Transplant Institute in Dallas, said it's still not clear whether there's a higher incidence of impaired liver function -- and worse patient survival -- after these transplants, but he remains a strong proponent. The practice is simply a continuation of an old story in which surgeons experiment to see which organs can be used, so more people can be helped, he said. "There is nothing today that would say these organs, in the long term, provide a worse survival or worse function -- we don't have the data to say that," said Klintmalm. "What we can say is that the rate of primary nonfunction of livers has gone down over the years, in spite of expanding the donor criteria." A conflict involving the allocation of expanded-criteria organs culminated last year with the transplant program at the VA Pittsburgh Healthcare System breaking away from the University of Pittsburgh Medical Center. New York investigators noted several instances where it was unclear if patients at Strong Memorial Hospital in Rochester were told about the "expanded-criteria" status of the donors from which livers were recovered. Part of the problem in assessing how well livers from expanded-criteria donors work is that there is no single definition that describes them. Some are simply old. Initially, donors over the age of 50 were thought to provide livers that didn't perform well, but donors in that age group now provide nearly 30 percent of all livers, wrote Dr. Ronald Busuttil, the liver transplant chief at the University of California Los Angeles, in a paper published last year. Organs that have been on ice for a long time, and therefore have a greater risk of what's called "ischemic injury," also fall into this category. These injuries can impair liver function. Expanded-criteria donors can have any of a variety of health problems, such as hepatitis or high levels of fat in the liver. Depending on the health problem, doctors use different strategies to minimize the risk to recipients. Even gender can be a factor, according to Busuttil. A transplanted liver is more likely to fail when male recipients receive female donor organs, he wrote. Because of the heterogeneous nature of the expanded category, there aren't good numbers that show how many are used each year. Nor are there good studies that show how well they work, said Dr. Andrew Klein, a transplant surgeon at Johns Hopkins University. Klein does not necessarily oppose surgeons using the organs, but noted a key ethical question raised by the practice. "It's clear that the organs recovered from patients who are physically extending the criteria, those livers will work better in someone who is less sick," Klein said. "Is it ethically justifiable to expose someone who is not in immediate need of liver replacement to a liver that may have an increased risk of not functioning? That's really where the rubber hits the road." That's also a question raised by the recent investigation in New York. The New York Health Department issued a $20,000 fine in April to Strong Memorial Hospital in Rochester for problems in its liver transplant unit. In one case, the hospital failed to document why a patient who had a favorable short-term survival rate without a transplant was given a liver from an expanded-criteria donor. Problems subsequently occurred with the liver, forcing the patient to undergo a second liver transplant. When that patient was treated at Strong Memorial Hospital, Dr. Amadeo Marcos had already left the Rochester transplant program for his current position as liver transplant chief at UPMC. But Marcos was still at Strong Memorial in the first half of 2002, when another recipient received care that was questioned by state investigators. The 2002 patient required a second transplant after the organ from an expanded-criteria donor failed. But there was no clear documentation that the patient was informed that such a transplant was being offered, investigators said, nor was it clear that the risks were communicated. Marcos would not grant an interview for this article. William Morris, the transplant administrator at UPMC, said his program would not comment on patients treated elsewhere. Morris was director of the organ procurement organization at Strong Memorial Hospital at the time of the 2002 transplant, however. In general, UPMC fully informs patients of the risks and benefits of transplant surgeries by having them sign a detailed consent form, Morris said. Morris could not say how many expanded-criteria livers UPMC has used since August 2002, when Marcos came to Pittsburgh. But in general, the organs have worked well. "Outside of live donors, we have not seen any significant difference in graft survival between any kind of donors used at UPMC, in Dr. Marcos' tenure or before," he said. "The definition of both patients who can benefit instead of dying, and organs that will serve is in constant evolution." Livers from expanded-criteria donors often are not a good match with the sickest patients, said Dr. Abraham Shaked, a liver transplant surgeon at the University of Pennsylvania. Therefore, the livers are sometimes poorly handled by the current allocation system, which often directs donor livers to the sickest patients on the waiting list, he said. That was UPMC's argument in last year's dispute with the VA, where VA officials were concerned that VA patients were being bypassed in favor of patients at UPMC who were less sick. Expanded-criteria donors have become a large part of the liver supply at Penn, Shaked said, and the results have often been encouraging. But he questioned how any center could affirmatively state that livers from marginal donors are doing as well as livers from all other donors. "If they were doing so well, why would you call them marginal donors to begin with?" he asked. To bioethicist Arthur Caplan, it is dangerous territory. "There are enormous ethical problems," said Caplan, also from Penn. "The pressures to find more organs are enormous, so judgments about what's marginal are clouded by the shortage and scarcity. ... There's both the drive to save lives and the desire to stay busy, so to speak. They're both there." http://www.post-gazette.com/pg/04130/313595.stm -------------------------------------------------------------------------------- (Christopher Snowbeck can be reached at csnowbeck@post-gazette.com or 412 263-2625.) |
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The treatment options for patients with acute liver failure
are few, and survival odds are challenging. But doctors in Los Angeles say
one solution may be a bioartificial liver that can be used in these
patients to help maintain survival before transplantation.
Boosting Survival Odds It's the first, large-scale, prospective, randomized trial evaluating the effectiveness of any artificial liver support, stated Achilles Demetriou, M.D., Ph.D., who heads the department of Surgery at Cedars-Sinai, and was the study's principal investigator. Currently, standard treatment for acute liver failure consists of intensive, supportive care that is aimed at maintaining patient survival long enough so that the liver can either recover spontaneously, or a donor organ becomes available for transplantation. Chronic Versus Acute Liver Failure The condition is diagnosed when a massive loss of liver cells causes severe liver dysfunction and life-threatening complications within 6 months since the start of symptoms. When this dysfunction occurs within the first 8 weeks after symptoms start appearing, it is known as fulminant. When it occurs in the period between 8 weeks and 6 months, it is known as subfulminant. In either case, few patients survive the resulting fluid build-up in the brain, catastrophic bacterial infections, multi-organ failure, blood-clotting abnormalities, respiratory problems, kidney failure, or other potential complications. It's estimated, in fact, that up to 80 percent of patients will die unless they can undergo a liver transplant. A patient with acute liver failure initially has all the symptoms of hepatitis: fatigue, nausea, vomiting or jaundice. At a certain point, most patients become confused or sleepy. They can also bleed from the stomach or gums, and can bruise easily due to poor blood clotting. Early on, this condition can be difficult to diagnose because it resembles other illnesses and can be fairly rare.3 The causes of acute liver failure can include medication interactions, overdoses, metabolic disorders and some types of hepatitis infections. Culmination of Animal Trials Demetriou and his team found that 71 percent of the patients survived for at least 1 month following the bioartificial liver treatment, compared to only 62 percent of those undergoing standard care. The results were even better when patients who had liver function complications following transplantation were excluded—a 73% versus 59% 30-day survival rate. How the Bioartificial Liver Works During a treatment, blood is drawn from a vein through a catheter, and plasma is separated from the serum and pumped through a charcoal column and oxygenator before it reaches the bioreactor. "The blood is removed at a fixed rate, detoxified and treated in the various components of the bioartificial liver, reconstituted, and returned to the patient at the same rate at which it is being removed," explained Demetriou. "Just before the patient is treated, the pig liver cells are thawed, reactivated and attached to small beads that serve as a scaffold for the cells." "We put the cells and beads into the cartridge, and when the patient's plasma flows through the fibers, the pig liver cells detoxify it and replace missing nutrients," Demetriou said. Each treatment can be completed in about 6 hours, and
the benefits last about 24 hours, the study researchers said. In most
cases of acute liver failure, a series of treatments may only need to be
given for a few days or several weeks. "Typically, within that time, the
patient's condition is going to improve because his or her own
liver kicks in, or a liver will be
available for transplantation," Demetriou said.
People who receive partial
liver transplants find that their livers
re-grow faster than their donors afterwards, says a new study from the
University of Minnesota.1
Both the donor and recipient do have rapid liver regeneration in the months following their surgery, but recipients re-grow their liver completely at a faster rate, doctors in the departments of Surgery and Radiology reported. Still, there are no apparent ill-effects of this slower regeneration, said Abhinav Humar, M.D., an associate professor of General and Transplant Surgery at the University of Minnesota, and the study's first author. Liver Re-Growth After Surgery Three months after the transplants were performed, the 65 surviving participants underwent computed tomography (CT) to measure how much their liver volume had increased over that period. "At 3 months postoperatively, liver donors had attained 78.6% of their ideal liver volume, less than the percentage for right-lobe living donor recipients, right-lobe split-liver transplant recipients, and left-lobe split-liver transplant recipients," Humar and his colleagues reported. Split-liver transplantation is a procedure in which a liver from a cadaver is split in two, and the larger section is used to transplant an adult, and the smaller section is used for a pediatric or adolescent liver transplant procedure.2 "When liver size at the third postoperative month was compared with the liver size immediately postoperatively, living donors had a 1.85-fold increase," the researchers wrote. "This was smaller than the increase seen in right-lobe living donor recipients, right lobe split-liver transplant recipients and left-lobe split-liver transplant recipients." Compared to measurements taken immediately after surgery, recipients had a 2.2-fold increase in liver volume three months later. No Associated Risks Found "I don't think there are any negative factors with the donors," Humar told Priority Healthcare. "There may be positive factors, however, with the recipients. Immunosuppression may be contributing, or the fact that they were in liver failure before their transplant may be contributing." To support that assertion, Humar and his team found that donors' liver function was usually completely normal within a week of the operation, so the decreased liver volume relative to the ideal over the long term may not be clinically significant, the doctors wrote. "It's important to remember that this may have no clinical relevance since 80% of a normal liver is more than adequate for anyone, and there is likely not to be any ill effects associated with having only 80% [volume]," Humar stressed. The reasons why living donors' livers re-grow at a slower pace, and wind up with a lesser overall volume later, are still "unclear", he and his team concluded. Liver Transplantation in Liver
Disease Living-donor liver transplants were first performed in children in the 1980s. This evolved as a solution for the long waiting times for cadaver organs, and a high death rate on the waiting list, as a result. It is believed that living-donor liver transplants are performed on half the children who need new livers. In some medical centers, up to 25% of all adults receive living-donor transplants. In fact, the use of living-donor transplantation is climbing rapidly. More than 500 of these transplants have been performed in the last 3 years alone in the United States.2 Whole organ transplants are more common than split-liver transplantation. In whole-organ transplants, surgeons remove the recipient's old liver, and replace it with the donor's entire liver. While performed less often, the advantages of split-liver transplantation are that two patients can benefit from one donor, and that both receive a "perfect" donor rather than a "marginal" one.4 The other form of liver transplantation is known as a reduced-size transplant, in which a large donor liver can be used in a smaller recipient when the recipient is critically ill. In adults, the surgeon typically divides the liver, and implants only one lobe, whichever is considered optimal for the recipient. But there is somewhat of a lower success rate with more complications associated with this procedure.4 Interest in liver regeneration after transplantation has been increasing in recent years, simply because the number of partial liver transplants (both living donor and split) has, itself, been escalating, Humar said. 1. Liver regeneration after adult living donor and
deceased donor split-liver transplants. Liver Transpl 2004
Mar;10(3):374-8.
Doctors are advocating an alternative treatment approach
for minimal hepatic encephalopathy (MHE), a liver condition that can also
cause brain dysfunction in some patients. MHE can cause changes in
behavior, intelligence, consciousness and neuromuscular function, experts
say. Minimal hepatic encephalopathy is a more subtle version of the overt
form, causing only minimal dysfunction. Since ammonia has been shown to
play a key part in the development of overt hepatic encephalopathy,
treatment options for MHE have also focused on reducing ammonia levels.
Synbiotics: An Alternative for MHE? Flora is the medical term for the various microorganisms that exist in the body. When MHE occurs, the liver cannot properly detoxify and metabolize toxic substances in the body. As a result, these toxic substances, like ammonia, build up in the bloodstream. This ammonia can also be created by intestinal bacteria.2 What Are Synbiotics? To evaluate the effects of synbiotics and fermentable fiber on microorganisms living in the intestinal tract, as well as MHE, the scientists conducted a pilot study of 55 patients with the disease. Twenty of them were treated for a month with a daily synbiotic preparation, another 20 took fermentable fibers for 30 days, and the remaining 15 received a placebo for a month. At the 1-month mark, all patients were re-screened for MHE, and the researchers also evaluated the levels of intestinal flora in three separate fecal samples. Those were compared with the findings of intestinal flora of 20 healthy volunteers. Comparing Notes There were benefits for cirrhotic patients in the study, as well. Both treatments appeared to have significantly altered the intestinal flora of patients with cirrhosis, said the study investigators. At the start of the study, the cirrhotic patients with MHE were found to have significant fecal overgrowths of E. coli and Staphylococcus. Treatment with the synbiotic preparation reduced these levels to those of the healthy individuals. Treatment with placebo did not change the counts of any of the intestinal flora, the investigators found. "Our study is the first to examine the impact of synbiotics and fermentable fiber on MHE and other aspects of hepatic function in patients with cirrhosis," the study authors reported. "We conclude that treatment with synbiotics or fermentable fiber alone is an alternative to use of non-absorbable disaccharides, such as lactulose, for the management of MHE in patients with cirrhosis. Significant reductions in viable counts of potentially pathogenic [disease-causing] gut flora occur with both treatments." Lactulose is a laxative that is used to prevent bacteria in the intestines from making toxic ammonia.2 'Impressive and Exciting'
"We expect this research to stimulate further interest in the study of gut flora therapy, and the 'gut-liver' axis, because the liver does, indeed, care about the gut," they wrote. 1. Liu Q, Duan ZP, Ha da K et al. Synbiotic modulation
of gut flora: Effect on minimal hepatic encephalopathy in patients with
cirrhosis. Hepatology 2004 May;39(5):1441-9. John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications. Quality of Life in Long-Term Liver Transplant Recipients with Hepatitis CCatherine Rongey, W. Ray Kim, Rachel A. Pedersen, Michael Malinchoc, E. Rolland Dickson, Marlon F. Levy
Background Liver transplantation (OLT) fundamentally improves quality of life (QOL) of recipients. Although hepatitis C (HCV) recurs frequently after OLT, long-term, longitudinal data about QOL of OLT recipients with HCV are not available.
Aims a) To compare longitudinally QOL in OLT recipients with HCV to those with other diagnoses b) To determine impact of post transplant HCV recurrence on quality of life c) To describe impact of quality of life on patients with long term transplant survival
Methods QOL data have been collected prospectively in a multicenter database using the NIDDK-QA form, the reliability and validity of which have been established previously. Summary scores were calculated according to a published algorithm (Hepatology 2000) for each domain of the instrument, namely liver symptoms (LS, possible scores: 0-4), physical function (PF: 0-100), health satisfaction (HS: 1-7), and overall well-being (WB: 2.1-14.7). In all domains, higher scores indicate better QOL.
Results The longitudinal cohort consisted of 1041 adult primary OLT recipients between 1990 and 1995 who responded to the QOL survey at OLT evaluation. These included 247 with HCV, 321 with cholestatic disease (PBC and PSC), and 473 with all other diagnoses. At baseline, QOL in HCV patients was comparable to that in other groups except for PF (mean (SD) score 27.9 (25.5) for HCV, 35.0 (26.4) for cholestatic and 31.2 (26.8) for others). In the table, at 1-2 years following OLT, patients with HCV had significantly lower QOL compared to others in all domains. However, at 5 years, these differences disappeared, especially between HCV and 'other' patients. These trends were at least in part due to the fact that HCV patients remaining in the cohort at 5 years had had a significantly better QOL at 1-2 years than those in whom 5 year data were not available (dead or lost to follow-up), including PF (70.1 vs 55.9, p<0.01), HS (5.5 vs 5.0, p=0.01) and WB (11.8 vs 10.9, p=0.02) domains.
Conclusions At 1-2 years post OLT, recipients with HCV have QOL demonstrably inferior to those with other diagnoses. However, longer term data suggest that HCV patients who survive without succumbing to recurrent disease do maintain good QOL.
The authors also noted: a) Patients with HCV that were transplanted had the lowest survival rate b) HCV Patients reported consistently lower physical functioning after transplantation, but no significant difference over time c) HCV patients that survive long term transplant maintain a good quality of live
http://www.hcvadvocate.org/news/reports/ DDW_2004/Liver%20Transplantation1.htm#LT1
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Preemptive Therapy with Combination Pegylated Interferon and Ribavirin in Liver Transplant Recipients with Hepatitis C VirusGuy W. Neff, Christopher B. O'Brien, Kamran Safdar, Phil Ruiz, Pablo Bejarano, Marzia Montalbano, Eugene R. Schiff
Background % Treated for Depression
Drug Tolerability Vogel PEG IFNα 2a 180µg for 48 weeks n = 25
Khatib PEG IFNα 2b 0.5µg/kg + RBV 400mg for 48 weeks n = 36
Levitsky PEG IFNα 2b 1.0µg/kg + RBV 400mg for 48 weeks n = 31
Neff PEG IFNα 2b 1.5µg/kg + RBV 60mg for 48 weeks n=29
Preemptive PEG IFNα 2b 0.5µg/kg + RBV 20mg for 48 weeks
EOT and SVR Khatib PEG IFNα 2b 0.5µg/kg + RBV 400mg for 48 weeks n = 36
Neff PEG IFNα 2b 1.5µg/kg + RBV 600mg for 48 weeks n = 29
Preemptive PEG IFNα 2b 0.5µg/kg + RBV 200mg for 48 weeks n = 14
Introduction The management protocols for recurrent HCV are diverse and the issues are complex, including the effectiveness of preemptive therapy. We present results of a retrospective review of liver transplant recipients receiving preemptive therapy of pegylated alpha-2b interferon and ribavirin within 4 months of transplant.
Aims We wanted to determine if preemptive therapy with peginterferon alfa 2b and ribavirin for recurrent HCV post liver transplantation is safe and effective.
Methods All recipients were started on combination pegylated alpha-2b interferon (0.5mcg/kg) and ribavirin (200-400 mg/d) therapy within 16 weeks of liver transplantation. Dose escalation was as follows: increase in pegylated alpha-2b interferon 0.5mcg/kg every 4 weeks until 1.5mcg/kg and ribavirin 200 mg/d every 4 weeks until 800-1000 mg/d. The therapy was followed for at least 48 weeks of therapy. The diagnosis of HCV recurrence was determined histopathologic findings with inflammation along with viral recurrence using COBAS AMPLICOR Hepatitis C virus Test, version 2.0 and COBAS AMPLICOR HCV MONITOR TEST-version 2.0 assays. Histology was graded and staged according to the Batts and Ludwig classification. The diagnosis of recurrent hepatitis was based on the presence of portal lymphocytic infiltrates, interface hepatitis, and lobular necroinflammatory injury in the absence of other findings that could indicated a different pathology.
Results 14 transplant recipients were included in the study: female 5(36%), males 9 (64%) mean age (50yrs), mean time from OLT was 6.7 weeks, Caucasians 8 (57%) and Hispanics 6 (43%). 3 patients remained serologically negative for HCV 3/15 (20%) for a 48 week period and 3 patients dropped their serum HCV PCR 2 logs (20%). The remaining 8 patients were viremic throughout the 48 week period. The side effects included: clinical depression 6 (43%) of which treatment was stopped in 2 while 2 improved to near baseline with SSRI therapy, thrombocytopenia (< 50K) 3 (20%), 1 (7%) require treatment cessation, neutropenia 3(20%) all responding to filgastrim. Serum ALT normalized in 5/14 (36%). 4 patients remained on therapy for 48 consecutive weeks. One death was noted as a result of fungal sepsis, and one patient experienced HAT. SVR was attained in 2/14 (14%), both tissue HCV PCR was negative at time of 48 week biopsy.
Conclusion These results show that preemptive therapy was poorly tolerated while benefiting only a small portion of our cohort (20%). http://www.hcvadvocate.org/news/reports/DDW_2004/Abstracts.htm#DDW11
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What is the Anticipated Half-Life of a Liver Allograft?Alastair D. Smith, Carlos E. Marroquin, Erick B. Edwards, Janet E. Tuttle-Newhall, Bradley H. Collins, Dev M. Desai, Paul C. Kuo
Purpose What are the relative benefits of orthotopic liver transplantation (OLT) in the face of concomitant diseases that may confer shorter patient survival than could be anticipated from the graft? Patient and liver allograft survival, by transplant indication, are unknown, but this information would further inform appropriate allocation of this precious and scarce resource. The purpose of this study was to determine liver allograft and patient half-lives.
Patients and methods The United Network for Organ Sharing scientific registry was reviewed between January 1st 1988 and December 31st 1996 for all orthotopic liver transplants. The estimated half-life for liver allografts, defined as the time point at which 50% of grafts in a cohort of transplanted patients had failed, was calculated using Kaplan-Meier analysis. Estimated allograft half-lives were stratified by diagnosis, and first or subsequent transplant. Patient half-life, defined as the time point at which 50% of patients in a transplanted cohort were dead, was calculated also.
Results
Conclusions Patients with immune forms of chronic liver disease had the longest graft and patient half-lives, suggesting that this patient group has most to gain from OLT, particularly when compared with patients undergoing OLT for chronic HCV liver disease. The very short graft half-life for patients receiving a second or subsequent allograft suggests that re-transplantation should be reserved for patients with excellent functional status only. http://www.hcvadvocate.org/news/reports/DDW_2004/Abstracts.htm#DDW11 |
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May 29 04
