Standardized evaluation consent forms for living liver donors needed

PUBLIC RELEASE DATE: 13-Mar-2014

Contact: Dawn Peters
sciencenewsroom@wiley.com
781-388-8408
Wiley

Call for liver transplant centers to incorporate an alibi in donor documents

New research reveals that 57% of liver transplant centers use living donor evaluation consent forms that include all the elements required by the Centers for Medicare and Medicaid Services (CMS) and 78% of centers addressed two-third or more of the items recommended by the Organ Procurement and Transplant Network (OPTN). The study published in Liver Transplantation, a journal of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, reviewed the living donor evaluation consent forms from 26 of the 37 transplant centers that evaluate living liver donors in the U.S.

In addition, the Yale researchers found that only 17% of transplant centers' evaluation consent forms offer an alibi to potential donors. An alibi is a statement of unsuitability for donation that a transplant center can provide to an individual who decides that he or she does not want to donate. The OPTN guidelines for living liver donors endorse the use of alibis to help ensure that individuals are free from undue pressure to donate.

The first successful U.S. living liver donor transplant was performed in 1989. Living liver donors account for 4% of the 7000 transplants occurring each year in the country. In contrast, approximately one-third of transplanted kidneys come from living donors. Prior studies suggest the relative infrequency of living liver donation is due to the complexity of the procedure and greater mortality and morbidity risk to living liver donors.

"Our study is the first to systematically examine written informed consent for living liver donor evaluation donation in the U.S.," explains lead author Dr. Carrie Thiessen from Yale School of Medicine in New Haven, Conn. "Our findings reinforce the need for standardization of living liver donor liver evaluation consent forms. We also recommend that written offers of alibis be included in consent forms to help preserve donor autonomy. Evaluation consent forms should explicitly address whether a transplant center will or will not disclose a potential donor's decision to decline donation, reason for opting out, and health details following withdrawal."

Dr. Thiessen concludes, "We hope that our study results will inform the current OPTN and UNOS efforts to revise national living liver donor policy and will aid transplant centers in improving the clarity of their living donor consent documents."

Dr. David Mulligan contributing author and Chair of the UNOS Liver & Intestine Committee agrees, "This study emphasizes the importance of building transparency in the living liver donor programs by standardizing the consent forms. The goal is to encourage more living donors to donate and that will only happen if donors fully understand the process for donating, the risks involved, and the course of recovery. Ultimately, the transplant community wants to make it as safe as possible for living donors who are providing a life-saving piece of their liver to patients with liver failure."

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This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact sciencenewsroom@wiley.com

Full citation: "Written Informed Consent for Living Liver Donor Evaluation: Compliance with CMS & OPTN Guidelines and Alibi Offers." Carrie Thiessen, Yunsoo A. Kim, Peter S. Yoo, Manuel Rodriguez-Davalos, David Mulligan and Sanjay Kulkarni. Liver Transplantation; (DOI: 10.1002/lt.23822) Published Online: February 24, 2014.

URL: http://doi.wiley.com/10.1022/lt.23822

Author Contact: Media wishing to speak with Dr. Sanjay Kulkarni, the paper's senior author, may contact the Yale-New Haven Hospital Transplant Center at 203-785-2565

About the Journal

Liver Transplantation is published by Wiley on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AASLD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit http://wileyonlinelibrary.com/journal/lt.

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NY-Presbyterian/Columbia reports laparoscopic living donor liver retrieval for adults

Provided by Medical News Today

Article Date: 30 Sep 2013 - 2:00 PDT 

A team of surgeons at NewYork-Presbyterian/Columbia University Medical Center is the first in the country to report a fully laparoscopic hepatectomy - the removal of a portion of the liver - from a living adult donor for adult and teenage recipients. The procedure advances transplant surgery and offers hope for addressing the significant shortage of liver donors.

In the September issue of the American Journal of Transplantation, the team, led by Dr. Benjamin Samstein, surgical director of the Living Donor Liver Transplant Program at NewYork-Presbyterian/Columbia and assistant professor of surgery at Columbia University Medical Center, reports on two of the center's five successful fully laparoscopic hepatectomies from living adult donors for adult and teenage recipients. The group is one of three teams in the world, and the only in the United States, reporting the successful procedure.

"This is a small step, but I think a useful one," says Dr. Samstein. "We're at the forefront of perhaps a new era for living-donor liver transplants."

Despite public awareness campaigns and other efforts aimed at raising the availability of donor organs, there is a nationwide shortage of deceased organ donations. Thus, living donors are an important source of organs to aid patients living with end-stage organ disease, particularly of the liver and kidneys.

The first successful living-donor liver transplant was performed in children in 1989 and subsequently extended to adults. Yet only about four percent of liver transplants are done with a living donor, compared with nearly 50 percent of kidney transplants, Dr. Samstein says. "Even though there is a tremendous need, we're not seeing the same use of living-donor livers as we are of living-donor kidneys," he says.

More than 90 percent of living-donor kidney transplants are done laparoscopically, explains Dr. Samstein, which results in reduced morbidity, scarring, and pain, as well as a quicker return to normal activities. Laparoscopic living-donor kidney removal has replaced the open approach in many centers around the world. Most liver donor surgeries, however, are still done through complex open surgery, leaving the donor with a greater risk of postoperative mortality, morbidity, and pain, as well as a recovery period that lasts, on average, eight to 12 weeks - two to three times longer than the recovery period for a laparoscopic kidney donor. Dr. Samstein says these factors may contribute to potential donors' hesitation or ineligibility.

While open hepatectomy remains the standard procedure for adult living-donor liver transplantation at most centers, a few strategies over the past several years have made the surgery less invasive. Researchers have succeeded in reducing the incision needed to remove a portion of the liver; they have also developed a hybrid technique that uses both open surgery and laparoscopy. This model has reduced postoperative pain for the donor.

In 2009, NewYork-Presbyterian/Columbia surgeons began doing fully laparoscopic hepatectomies on adult donors for transplantation into children. Pediatric recipients require only about 15 to 20 percent of a healthy adult liver for transplant. The liver has the unique ability to regenerate in both the donor and the recipient, growing and remodeling to form a complete, functioning organ. But adult recipients require a much larger portion of liver for successful transplant - about 30 to 35 percent - necessitating a more central cut through the donor liver. With three years of experience with hybrid and full laparoscopic techniques with more than 50 minimally invasive donor hepatectomies, the team was ready to expand laparoscopy to full left hepatectomies for adult recipients.

The current publication presents the details of two living adult donors who donated, through laparoscopic surgery, portions of their livers to others - the first, a 47-year-old man who donated to his young teenage daughter and the second a 28-year-old woman who donated to her mother-in-law.

While the recipient operation still requires an open procedure, the surgeons found the donor recovery in these cases to be half that of traditional open-surgery donation - from eight to four weeks - and substantially reduced even from the hybrid technique, with no additional postoperative donor complications. The donors also appeared to have less pain and lower risk of postsurgical hernia.

The authors caution that this procedure should be performed only in select cases and only by teams with significant experience in both living-donor procedures and laparoscopic liver surgery, as laparoscopic hepatectomies require specific training. "While donor comfort and recovery are extremely important issues, donor safety continues to be paramount and the adoption of new surgical techniques ultimately needs to demonstrate that it meets the standard of safety of old techniques before adopted," they write.

NewYork-Presbyterian/Columbia remains the only center in the country currently performing fully laparoscopic living-donor hepatectomies for transplant into both pediatric and adult recipients.

"Clinical innovation and scientific progress constitute the core of the Center for Liver Disease and Transplantation's mission," says Dr. Jean C. Emond, chief of transplantation at NewYork-Presbyterian/Columbia and the Thomas S. Zimmer Professor of Reconstructive Surgery (in Pediatrics) at Columbia University Medical Center. "While this fully laparoscopic approach is still new and in its infancy, this is an important step in furthering the goal of successful liver transplantation from generous living donors." Dr. Emond was a member of the team that pioneered living donor liver transplantation, which is now considered one of the most important advances in the treatment of severe liver disease.

About the Living Donor Liver Transplant Program at the Center for Liver Disease and Transplantation

The Living Donor Liver Transplant Program at NewYork-Presbyterian/Columbia University Medical Center is one of the largest living-donor liver programs in North America. The program has performed more than 220 living-donor liver transplants since its inception. The team has also performed more left lobe donations than any other living-donor liver program in North America and introduced fully laparoscopic donation for all pediatric living-donor liver transplants in 2009.

References:

Totally Laparoscopic Full Left Hepatectomy for Living Donor Liver Transplantation in Adolescents and Adults

American Journal of Transplantation - Volume 13, Issue 9, pages 2462–2466, September 2013 - DOI: 10.1111/ajt.12360

Authors: B. Samstein, D. Cherqui, F. Rotellar, A. Griesemer, K. J. Halazun, T. Kato, J. Guarrera, J. C. Emond

NewYork-Presbyterian Hospital/Columbia University Medical Center

Source

Need for liver transplants at all-time high

Illustration: P.K. Job.

May 1, 2012 By Vidyashree Dharmaraj

The waiting list for those wanting to undergo liver transplant seems to be endless with lack of awareness among living donors and absence of medical facilities.

The number of deaths related to liver disease has gone up by 25 per cent which is a record high, says Prof Dr Mohammed Rela, an authority on liver transplant.

He attributes this alarming increase to heavy drinking, obesity, besides Hepatitis B- and C-related liver diseases. Even as surgical care is lacking in India, Tamil Nadu has to its credit 150 transplants of which 120 are from live donors.

The need for live donors has gained significance because of the insufficient availability of cadavers for donation.

Stating that India is growing rapidly in terms of liver transplant with living donors, he said the West has been largely using organs from cadavers.

Elaborating, he said transplanting by means of a living donor originated in the East as it was not part of their tradition to donate the organs of the dead.

Tamil Nadu has to its credit 150 cadaver transplants performed in the last two years, which is way ahead of the national average.

But, unfortunately, the state requires at least 1,000 donors a year, he said, and added that Coimbatore district alone needs at least 250 liver donors annually.

Even as the living donor transplant technique is complex, India is now in a position to teach the West its expertise, said Dr K. Ravindranath, chairman and managing director of Global Hospital Group, Chennai.

On the male-female ratio pertaining to liver diseases, he said it is more common among men, and added that there were several children who could survive only by liver transplants.

However, only 3 per cent of those having liver problems will undergo liver transplant, he said.

Calling for a change in lifestyle, he said poor diet, including excess intake of fat, carbohydrates and lack of exercise added to excessive alcohol intake may end in chronic liver diseases.

With a view to facilitating liver transplants in Coimbatore, Global Health City, Chennai, and Kovai Medical Centre and Hospital have entered into a partnership to provide transplant facilities at affordable rates.

Dr K. Ravindranath, chairman and managing director, Global Hospital Group, said that Global Health in Chennai offers liver, pancreas transplantation for related diseases.

The aim of the facility in KMCH is to provide quality health care in Hepatobiliary and liver transplant facilities wherein specialists from Global Health City will visit KMCH on a weekly basis for one day OPD clinics, he said.

Dr Nalla G Palaniswami, chairman, Kovai Medical Centre and Hospital, said that the exchange of knowledge will be provided through scientific programmes and high end, complex surgeries will be referred to the Global Health City which has a comprehensive set up for organ transplant.

Organ donation related counseling will also be provided to patients or relatives, especially if a patient is declared brain dead.

The Chennai centre will also provide logistics to KMCH for timely organ retrieval. Further training will be provided to KMCH staff as per protocols accepted under the laws of the State, he added.

If the proposed air ambulance comes through, then treatment within the golden hour which is limited by the distance factor will be resolved.

With all the hospitals in Coimbatore showing concerted interest in air ambulance, the dream will come true, he said.

Source

Cleveland Clinic hopes to use more living donors for liver transplants

Associated Press file

The removal of part of a liver from a living donor is much more complicated anatomically than removing a donor kidney.

Published: Monday, April 23, 2012, 8:15 PM

By Angela Townsend, The Plain DealerThe Plain Dealer

Statistics on living liver donors

Since 1984, the Cleveland Clinic has performed nearly 1,700 liver transplants — more than half of Ohio's total. The University of Cincinnati Medical Center comes in second with 833 liver transplants. University Hospitals Case Medical Center has performed 526 liver transplants.

• Nationally, just over 100 of the country's 170 transplant centers have liver transplant programs; only one-third have performed more than 50 transplants from living donors.
• To date, the Cleveland Clinic has transplanted 49 livers from living donors, according to data from the Clinic and the Organ Procurement Transplant Network.
• Nationally, the number of living donors has dropped over the years. At its peak in 2001, there were 524. The last year in which there were more than 300 was 2005.
• Less than 4 percent of all liver transplants in 2011 came from living donors.

Source: Cleveland Clinic, Organ Procurement and Transplantation Network

CLEVELAND, Ohio -- After not performing liver transplants from living donors for a year, the Cleveland Clinic has ramped up its program to address a long transplant waiting list. The Clinic's goal for 2012 is to conduct 12 surgeries with living liver donors, at a pace of one a month.

That would be almost as many as the 14 liver transplants using living donors the Clinic did between 2008 and 2010. None of the liver transplants for 247 patients at the Clinic in 2011 involved living donors.

So far this year, four Clinic patients have received a portion of a liver from a living donor, equaling the number in 2010. For the past several years, the Clinic has been the only liver transplant center in Ohio to perform surgery using living donors.

Nearly 17,000 people are currently on the national liver transplant waiting list, 194 of them patients at the Clinic, said Dr. William Carey, director of the Hepatology (Liver) Center in the Clinic's department of gastroenterology.

"Only about one-fourth of patients [on the list] get a transplant every year," said Carey, who also is chairman of the Living Liver Donor Advocacy Team in the Clinic's Digestive Disease Institute. "There is a gap between the need and the reality that is almost exclusively the lack of donors."

Unlike people on the kidney-transplant waiting list who can have dialysis, someone with advanced liver disease who is awaiting transplant has no comparable option, and many are pretty close to death, Carey said. The removal of part of a liver from a living donor is much more complicated anatomically than removing a donor kidney, Carey said.

"This isn't restricted to just one center or one state," Carey said of the scarcity of living liver donors. Part of the decline has stemmed from highly publicized deaths of living donors, he said.

In 2010, two men -- one at the University of Colorado in Denver, the other at Lahey Clinic in suburban Boston -- donating parts of their livers died three months apart as a result of their surgeries. They were the third and fourth recorded deaths since 2000, out of the more than 4,500 living liver donors since 1989.

Those deaths, Carey said, are out of proportion to the relative risk.

"When it hits the news media . . . it does put a damp blanket over people's willingness to step forward and volunteer," he said.

Encouraging liver donors

The Clinic has taken steps to encourage liver donation, including a more user-friendly website, making sure all exam areas have brochures available that explain being a living donor and putting up informational kiosks.

"Volume makes a difference in terms of quality," said Carey, explaining what he calls the Clinic's "self-imposed" goal for 2012. There's no reason why other top transplant centers can't do the same thing, he said.

"There has to be an institutional commitment to get things done," he said. "That's really the only way we're going to make an impact.

"We as [an entire] community need to band together to increase donor-organ awareness," he said.

That increased awareness needs to include a closer tracking of all living donors after surgery, said Donna Luebke of Montville Township in Medina County, who has served as an independent donor advocate to Lorraine Hawks, whose husband, Paul Hawks, died in 2010 during surgery to donate part of his liver to his brother-in-law.

Since 2000, the follow-up on patient conditions has been mandatory for transplant centers, which must report to the United Network of Organ Sharing -- which manages the nation's organ-transplant system -- any problems experienced by living donors for a minimum of two years after surgery.

"There is no safety net for complications afterward," said Luebke, an associate in the Center for BioMedical Ethics at MetroHealth Medical Center. "Kidney donors at least can go on dialysis. But what can you do for a liver donor?"

Montefiore Medical Center in New York City has one of the newer liver transplant programs in the country, performing 65 transplants since its inception in 2008. Two have been from living donors.

"We would like to do about six [living donor transplants] per year," said Dr. Paul Gaglio, medical director of liver transplantation at Montefiore, one of New York's smaller transplant programs.

The target volume of any transplant center is driven not by the desires of those directing the program, but by the number of patients on the waiting list, Gaglio said.

"When we look at the option of living-donor liver transplantation, it's a very thoughtful process," he said. "Is it an appropriate option for the recipient? Is it a safe option for the potential donor? All decisions are made in a way to maximize outcomes and maximize the safety for the donor."

To help liver donors recover, the Clinic has a program that mirrors one begun in 2010 for kidney donors. Donor WIn (Wellness Initiative), helps patients regain their pre-surgery physical condition and activity.

Luebke, who also serves as a board member for Lifebanc, the organ-procurement organization for Northeast Ohio, said more work needs to be done to make available more organs from deceased donors. That means allowing organs to go anywhere in the country where they are needed most, not restricting their use to within their geographic region, whose borders are defined by the United Network of Organ Sharing.

"To me, the living are not the solution to the organ shortage," Luebke said.

When a living donor is the best option

For Roger Hartzell, however, the living -- specifically, his son David -- was the solution.

Hartzell of St. Clairsville (a few miles from the West Virginia border in Belmont County) is recuperating from a transplant performed by Drs. Bijan Eghtesad and Koji Hashimoto in January at the Clinic. David Hartzell, who lives outside of Lima, donated the right lobe of his liver.

Diagnosed in 2004 with liver disease, Roger Hartzell went through two years of testing before discovering cirrhosis that stemmed from his exposure to Agent Orange while serving in the Vietnam War.

The majority of patients who require a liver transplant have cirrhosis, in which scar tissue forms on the liver because of an injury or long-term disease. That scar tissue blocks the normal flow of blood through the liver that is essential for removing toxins.

Cirrhosis is caused by alcohol abuse, drug use and a couple of dozen other causes, including obesity and some inherited diseases.

For a year, a couple of different treatments helped Hartzell. Then he went to the Clinic for an evaluation. Doctors there decided to put him on the transplant waiting list.

A Clinic social worker in the liver-transplant department broached the idea of a living donor to Hartzell and his wife, Jane.

"We only have the one son," she said. The couple's response at the time? "Oh, no. We're not interested in that," she said.

But Hartzell's condition wasn't getting any better.

"I kind of realized that, after being on the list for a while, there weren't enough livers to go around," Hartzell said. His score in the Model for End-Stage Liver Disease system -- used to prioritize people on the waiting list -- wasn't accurately reflecting how sick he really was. Because his score was on the lower end, he wasn't moving up on the list.

"I didn't get really bad until the last year, and then I went down fast," he said, recounting being in and out of the hospital for the better part of a year. "If I didn't get a liver soon, I wasn't going to get one."

The last thing the Hartzells wanted to do, they said, was to put their son, a pharmacist, in harm's way.

"We went back and forth and finally came to the conclusion that David was probably his dad's only hope," said Jane Hartzell.

It took two weeks for Roger to muster up the will to ask David to consider being a donor.

"It is a major, major operation and something could go wrong," he said. "I wasn't really scared for myself. I was more concerned about David."

After listening to his father "hee-haw" around the question during a weekend visit last July, David said he didn't hesitate to say yes.

After tests to establish that father and son were the same blood type, he began the weeks-long process of a medical evaluation, and discussions with the surgeons and other Clinic staff.

"Understanding [the risk] was my biggest question at that point," said David, who exchanged emails and phone calls and spoke face-to-face with Clinic staff about the risks and potential difficulties.

With his questions answered, the surgery went forward.

Drs. Charles Miller, Federico Aucejo and Cristiano Quintini removed the right lobe (the larger of the liver's two lobes) of David's liver for transplant into his father.

David stayed in the hospital for one week. The following week, Roger was cleared to go home.

Both said they are recuperating well, albeit slowly.

Two months after surgery (the costs of both covered by Roger's insurance), David started gradually returning to work. He is exercising again, although nowhere near at his pre-surgery levels.

Roger no longer has to use a wheelchair or a walker, and he no longer has to take some of the medicine to deal with the effects of hepatic encephalopathy. That condition, which can occur when the liver is unable to remove toxins in the blood, affects brain function and causes confusion.

That has nearly disappeared.

On Monday, the Hartzells met for lunch before their follow-up appointments at the Clinic.

Father and son each received good reports from their physicians. Roger will return to the Clinic in July. And although David will have his blood tested every three months, his next visit won't be until January.

Before the Hartzells went home, they made one last stop together at the Clinic. They visited a man who, a few weeks after Roger's surgery, also underwent a transplant with a liver from his son.

Source

LIVER DISEASE IN KASHMIR CHALLENGES & HOPE

Non-alcoholic fatty liver disease (NAFLD) has taken us by storm globally

HEALTH BY PROF M S KHUROO

Liver disease is now established as the fifth most common cause of death after heart disease, stroke, chest infections and cancer. Disturbing is the data that unlike other major causes of mortality, liver disease is increasing over the years rather than declining. For medical fraternity worldwide, there have never been more challenges thrown by liver disease and yet there shall never be more tools/hope available with us to overcome these. Thus liver disease globally is passing through both-despair and hope; an excellent opportunity for many of us to exploit for the better.

Today we have a large pool of chronic carriers of hepatitis viruses across the globe. Estimated numbers of Hepatitis BVirus (HBV)& Hepatitis CVirus (HCV) infected worldwide are staggering -350 million and 500 million respectively. Of the 40 million HIV carriers, 3 million are infected with HBV and 4.5 million with HCV. It is estimated that HBV results in one million deaths worldwide yearly and HCV causes whooping 5 million deaths. End Stage Liver Disease (ESLD) and liver cancer constitute major causes of deaths related to HBV &HCV infections. Universal hepatitis B vaccination at birth in endemic areas has been shown to be highly effective in reducing carrier rates in children as well as the incidence of ESLD and liver cancer. Today 182 countries have now included hepatitis B vaccination in national immunization program and we must follow this in our EPI program aggressively to change the epidemiology of HBV in our country.

Hepatitis E virus (HEV) has turned out to be the most enigmatic human agent since we discovered the agent in 1980. HEV causes large-scale waterborne epidemics in developing countries involving hundreds and thousands of adult population. Around half to two-thirds of endemic hepatitis in such countries are caused by HEV. HEV has increased incidence and severity in pregnant women and is the commonest cause of acute liver failure in our society. In recent years, hepatitis E is recognized as a clinical problem in industrialized countries. HEV agent has entered in to food borne chain and is spread by consuming raw or undercooked pig livers available in super-markets in such countries. Recently we calculated HEV infections load globally. In 2005 an estimated 20 million incident HEV infections had occurred resulting in 3.3 million symptomatic cases, 70,000 deaths and 3000 stillbirths. In India alone, over 2.2 million cases of hepatitis E are thought to occur annually. Because of the impact of this infection globally it is imperative that measures be taken to control this python. Clean drinking water and safe sewage disposal are the corner stones of control, however, it may take more than hundred years before we get to drink a glass of clean portable water in India. Two HEV candidate vaccines have successfully completed phase 3 trials and ready for the prime time. As of today, HEV are not commercially available.

Non-alcoholic fatty liver disease (NAFLD) has taken us by storm globally. Kashmir is in the middle of an epidemic of metabolic syndrome and NAFLD. NAFLD is a potentially progressive liver disease and shall pose serious health problem to our community in near future. What could be the possible reasons for introduction of metabolic syndrome and NAFLD in our community of late? For sure the focus has to be our changing sedentary life style and changing food habits. You might be shocked to know that a plate of wazwan shared by 4 persons served 40,000 kilo-calories and indulgence in this delicacy shall throw any body’s metabolic system in to disarray and load liver with fat, similar to what binge drinking can do in the West. So if we need to fight this metabolic syndrome and liver disease caused by NAFLD, we need to be on roads and gyms rather than driving luxurious cars, go back to our delicious Haak (Cabbage) and rice rather than delicacy of Wazwan and maintain a body mass index at least under 25.

In this despair and hope for challenges posed by liver disease, where does liver transplantation stand? Should we talk about this esoteric advanced costly procedure once our community is infested with parasites, infections, poor portable water, bad sewage disposal and poor life style practices. My answer is yes and I shall dilate upon this to support this. It is worth mentioning that patients with ESLD and acute liver failure do not have the luxury of liver dialysis as those with renal failure patients have and liver transplant is the only hope for millions of such patients as of today. In spite of the shortage of organs and long waiting list of patients on cadaveric program Liver transplant has substantially changed management of such patients. Living Donor Liver Transplant has removed many bottlenecks and strengthened such programs in the West.

Today function has been organized to focus on awareness of liver transplant in our community. For this we have invited senior medical faculty and important members of civil society to compliment the visiting team. We have supported young physicians from various disciplines to attend this function and interact with the visiting team. It is our wish that these young minds develop interest in various aspects of liver transplant may be transplant hepatology, surgery, pathology, radiology and so on.

This interest and training shall help patients with liver diseases in Kashmir to get correct advice on transplant patients and also help those transplanted and on follow up in J&K. In future this may strengthen the ties with other transplant centers to develop a satellite liver transplant program in the State in coming years.

(Author is Ex-Director SKIMS Srinagar; Ex-Head Gastro & Liver Transplantation Program KFSH Riyadh; Director Digestive Disease Center Dr Khuroo’s Medical Clinic Srinagar Kashmir India)

Lastupdate on : Sat, 7 Apr 2012 21:30:00 Mecca time
Lastupdate on : Sat, 7 Apr 2012 18:30:00 GMT
Lastupdate on : Sun, 8 Apr 2012 00:00:00 IST

Source

Is it Safe to Donate Part of Your Liver?

Provided by The AGA Journals Blog

Posted on February 27, 2012 

by Kristine Novak, PhD, Science Editor

Donating part of your liver is just as safe as donating a kidney—donors of these organs have survival rates similar to the rest of the population, according to an article in the February issue of Gastroenterology.

With organ shortages, live-donor liver transplantation (LDLT) is a lifesaving alternative to transplantation from deceased donors for patients with end-stage liver disease. Since the introduction of LDLT 20 years ago, thousands of children requiring liver transplants have benefited from left lateral segment grafts from live donors. Adults now also receive liver transplants from live donors. However, the numbers of livers transplanted from live donors has fallen short of the initial expectations over the past 8 years, due to safety concerns.

To determine the safety and side effects of LDLT, Abimereki Muzaale et al. followed 4111 live liver donors in the US from April 1994 to March 2011. They determined rates of deaths from the Social Security Death Master File and compared survival data with those from live kidney donors and healthy participants of the National Health and Nutrition Examination Survey (NHANES) III.

The authors found that the 90-day mortality of living liver donors (1.7 per 1000 donors or 0.17%) did not differ significantly from that of living kidney donors (0.05%). The long-term cumulative mortality risk was comparable to that of live kidney donors and NHANES participants (1.2%, 1.2%, and 1.4%, respectively) at 11 years.

Kaplan–Meier curves of cumulative mortalities for live donors of livers, matched live donors of kidneys, and matched controls (participants in NHANES III).

There were 4 cases of nonfatal acute liver failure in living liver donors; 3 of these patients required deceased-donor liver transplantation.

In an editorial that accompanies the article, James Trotter and James Everhart state that these results are likely the best estimation of donor mortality, and that this information will be useful for clinicians in counseling potential LDLT donors and recipients. They add that the format of cross-referencing 2 databases provides an important study design for future estimates of donor mortality.

Previous studies reported that physical well-being of donors decreases after surgery, but returns to pre-donation levels within 1 year. Out-of-pocket expenses and lost wages have been estimated to average about $5,000 for donors, although this amount varies greatly.

Nonetheless, Trotter and Everhart say it is important to consider the intangible benefits of an altruistic act. Other benefits include having a loved one remain alive and returned to function, as well as a public health benefit—living donation allows another patient to receive a deceased donor liver, thereby decreasing the demand for deceased donor transplantation.

Trotter and Everhart conclude that the findings of Muzaale et al. set the standard for estimating donor mortality. “Because the liver community has been unable to establish a national database for donor outcomes, and there are no real prospects for such, the rigorous methodology utilized in this study will allow the best means of prospectively reporting living liver donor mortality risk in the future.” However, further studies are needed to determine long-term outcomes of LDLTs.

Read the article online.
Muzaale AD, Dagher NN, Montgomery RA, et al. Estimates of early death, acute liver failure, and long-term mortality among live liver donors. Gastroenterology 2012;273–280.

Read the accompanying editorial.
Trotter JF and Everhart JT. Outcomes among living liver donors. Gastroenterology 2012;207–210.

Source

Effect of Maintenance Therapy With Low-dose Peginterferon for Recurrent Hepatitis C After Living Donor Liver Transplantation

From Journal of Viral Hepatitis

Y. Ueda; H. Marusawa; T. Kaido; Y. Ogura; F. Oike; A. Mori; K. Ogawa; A. Yoshizawa; E. Hatano; A. Miyagawa-Hayashino; H. Haga; H. Egawa; Y. Takada; S. Uemoto; T. Chiba

Authors and Disclosures

Posted: 02/07/2012; J Viral Hepat. 2012;19(1):32-38. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n = 17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were −0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

Introduction

Cirrhosis and hepatocellular carcinoma caused by hepatitis C virus (HCV) infection is the leading indication for liver transplantation in Japan, the United States and western Europe. However, liver allograft infection with HCV following liver transplantation is universal, and almost all patients develop recurrent liver injury.^[1–6] The progression of recurrent hepatitis C is often accelerated and, without appropriate antiviral therapy, 10–25% of patients develop cirrhosis within 5 years after transplantation, resulting in poorer prognosis for HCV-positive recipients than HCV-negative recipients.^[7]

To prevent the progression of hepatitis C after liver transplantation, a combined therapy of pegylated interferon plus ribavirin is commonly administered.^[8,9] However, the efficacy of this combination therapy is limited: The mean sustained virological response (SVR) rate among patients with recurrent hepatitis C after liver transplantation was only 30% (range, 8–50%).^[10] Effective management of the remaining 70% of the patients who are unable to achieve SVR has not been established.^[11]

We recently reported the change in liver histology after combination therapy with interferon plus ribavirin in patients who have recurrent hepatitis C after living donor liver transplantations (LDLT). Among patients who did not achieve SVR, activity grade was not improved and fibrosis stage deteriorated. On the other hand, SVR was associated with reduced hepatic inflammation and suppression of liver fibrosis progression.^[12] Because the histological progression of non-SVR patients occurred mainly after interferon therapy was discontinued, we hypothesized that long-term, continuous interferon administration might be effective in slowing the progression of liver damage in these patients. Therefore, after our previous study, we prescribed a low-dose peginterferon maintenance therapy for non-SVR patients. Here, we evaluated the efficacy of this treatment by investigating long-term histological changes in these patients, as well as comparing them to the changes observed in SVR patients and non-SVR patients who did not receive maintenance treatment.

Methods

Eighty patients who had previously received the combination therapy with interferon and ribavirin (n = 40) or peginterferon and ribavirin (n = 40) for recurrent hepatitis C after LDLT at Kyoto University between January 2001 and April 2007 were retrospectively analysed.

Patients

Between March 1999 and December 2006, 141 patients with HCV-related liver diseases underwent LDLT at Kyoto University. Of these, 100 patients had been followed up for more than 6 months after LDLT in our hospital. Antiviral therapy was given to 80 patients with recurrent hepatitis C between January 2001 and April 2007. The remaining 20 patients did not receive the antiviral therapy because of no histological recurrence of hepatitis C in the follow-up period. To evaluate the histological progression caused by hepatitis C, patients who were diagnosed as having other causes of liver injury, such as biliary complications, chronic rejection, and de novo autoimmune hepatitis (AIH), were excluded. Patients who discontinued the treatment within 3 months because of worsening of liver function caused by hepatitis C were also excluded, because the rapid progression of these patients is not comparable to the long-term progression and inclusion of these patients would have led to overestimation of the progression in the patients who discontinued treatment. Patients were also excluded if they did not have a liver biopsy more than 2 years after the initiation of treatment, because this prevented an analysis of long-term histological changes.

Treatment Protocol and Definition of Responses to Treatment

After liver transplantation, patients with recurrent HCV liver disease underwent treatment with interferon–α–2b (3 or 6 mega units thrice weekly) plus ribavirin (400–800 mg/day orally) for the first 6 months. This was followed by interferon monotherapy for 6 months.^[12] This treatment protocol was employed between January 2001 through April 2004 inclusive. From May 2004 to April 2007, patients underwent combination antiviral therapy comprising peginterferon–α–2b (1.5 μg/kg body weight, weekly) and ribavirin (400–800 mg/day orally).^[13] Patients who became negative for serum HCV RNA within 12 months after initiating the treatment continued to receive the full (initial) dose for 8–22 months to achieve SVR; then, the treatment ended. Patients who were negative for serum HCV RNA for more than 6 months after completion of interferon therapy were defined as achieving SVR.

Patients who did not become negative for serum HCV RNA within 12 months of initiating the combination therapy, as well as patients who experienced a relapse after transient discontinuation of the treatment, continued to receive a low-dose peginterferon maintenance therapy (0.5–0.75 μg/kg of peginterferon-α-2b with or without ribavirin at 200 mg/day). Treatments occurred during the study period, May 2005–December 2009. During this time, the therapy was discontinued in patients with severe adverse events. Additionally, peginterferon treatments were discontinued when neutrophil and platelet counts fell below 500 and 30 000/μL, respectively, and ribavirin was discontinued when haemoglobin levels fell below 8 g/dL.

Histological Assessment

Liver biopsies were performed when patients' alanine aminotransferase (ALT) levels were more than twice the upper limit of normal, or at yearly intervals, with informed consent. Biopsy specimens were evaluated by two pathologists (H.H. and A.M.) with extensive experience in the pathology of liver transplantation. Necroinflammatory activity (A0–A3) and fibrosis stage (F0–F4) were assessed using METAVIR scores.^[14,15] Grading was defined as A0 (no activity), A1 (mild activity), A2 (moderate activity) or A3 (severe activity); staging was defined as F0 (no fibrosis), F1 (mild fibrosis), F2 (moderate fibrosis), F3 (severe fibrosis) or F4 (cirrhosis).^[14,15]

The following equations were used to analyse the histological changes:

1. Changes in activity grade = grade at final biopsy − grade at pretreatment biopsy, and
2. Changes in fibrosis stage = stage at final biopsy − stage at pretreatment biopsy.

Immunosuppression

Tacrolimus and low-dose steroid therapies were administered to induce immunosuppression.^[12,13,16] The lower limit of the target for whole blood tacrolimus level was 10–15 ng/mL during the first 2 weeks, 10 ng/mL during weeks 2–8 and 5–8 ng/mL thereafter. Four patients received cyclosporine microemulsions, rather than tacrolimus, to induce immunosuppression (Table 1). Steroid therapy was initiated at a dose of 10 mg/kg before graft reperfusion and then tapered from 1 mg/kg per day on the first day to 0.3 mg/kg per day until the end of the first month, followed by 0.1 mg/kg per day until the end of the third month. After that, steroid administration was terminated. Mycophenolate mofetil (MMF) was administered to patients who experienced refractory rejection or required reduction in tacrolimus or cyclosporine doses because of adverse events.

Virological Assays

Hepatitis C virus genotype was determined using a genotyping system based on polymerase chain reaction (PCR) of the core region using genotype-specific PCR primers.^[17] Serum HCV RNA load was evaluated once a month during treatment and 24 weeks after treatment, using PCR and an Amplicor HCV assay (Cobas Amplicor HCV Monitor; Roche Molecular Systems, Pleasanton, CA, USA).

Statistical Analysis

Wilcoxon and Kruskal–Wallis tests, chi-square tests and t-tests were used to analyse the continuous variables, categorical variables and histological changes, respectively. The Kaplan–Meier method was used to estimate the rates of patients who showed a progression of fibrosis to stage F3 or F4 after the initiation of the interferon therapy; log-rank tests were used to compare these rates among groups. Significance was defined as P < 0.05.

Results

Characteristics of Patients

Hepatitis C virus RNA concentrations and histological evidence were used to diagnose 80 patients with recurrent hepatitis C after LDLT. These patients were given one of two combination therapies: interferon and ribavirin (n = 40) or peginterferon and ribavirin (n = 40) at Kyoto University between January 2001 and April 2007. Thirty-one of the 80 patients who received the combination therapy achieved SVR (Fig. 1). Among the remaining 49 non-SVR patients, 23 (47%) received the low-dose peginterferon maintenance therapy, while 26 (53%) discontinued treatment within 12 months and did not receive low-dose peginterferon maintenance therapy as this was the patients' wish (n = 4), because of general fatigue (n = 4), recurrent hepatocellular carcinoma (n = 4), worsening of liver function (n = 3), biliary complications (n = 3), heart failure (n = 2), brain haemorrhage (n = 1), dementia (n = 1), sinusitis (n = 1), anaemia (n = 1), neutropenia (n = 1), and haemosputum (n = 1).

Figure 1. Flow diagram showing the outcome of interferon therapy for patients with recurrent hepatitis C after living donor liver transplantation and indicating the classification of patients in this study.

Of the 31 SVR patients, five were excluded because of chronic rejection (n = 3), biliary complications (n = 1) and de novo AIH (n = 1). Fifteen patients did not have liver biopsies more than 2 years after the initiation of the interferon therapy, mainly because liver function tests were normal. The remaining 11 patients were classified as the SVR group for analysis in this study. Among the 23 patients who received maintenance therapy, one patient with biliary complications and five patients who did not have liver biopsy more than 2 years after the initiation of therapy were excluded from the study. The remaining 17 patients were classified into the non-SVR-IFN group. Among the 26 patients who discontinued treatment within 12 months, three patients who initially experienced worsening of liver function were excluded because of the rapid progression of HCV; an additional three patients were excluded because of biliary complications. Eight patients were excluded because they had no liver biopsies taken more than 2 years after the initiation of the treatment. The remaining 12 patients were classified into the non-SVR-Withdrawal group. Cumulatively, we analysed the long-term histological changes of 40 patients: 11 in the SVR group (27.5% of the total), 17 in the non-SVR-IFN group (42.5% of the total) and 12 in the non-SVR-Withdrawal group (30% of the total).

There were no significant differences in the baseline characteristics among patients in the SVR, non-SVR-IFN, and non-SVR-Withdrawal groups (Table 1). The median age of patients at the beginning of therapy was 56.5 years (range, 15–70 years). The treatment started at a median of 9.5 months (range, 1.1–85.3 months) after LDLT. Thirty-five patients (88%) were infected with HCV genotype 1b. HCV genotypes of the remaining patients were 2a (n = 3), 2b (n = 1) and undetermined (n = 1). Median serum HCV RNA load was 2290 kIU/mL (range, 73.7–5000 kIU/mL); i.e. most patients had an extremely high viral load. Before the treatment, the necroinflammatory activity of all patients was A1 or greater, and 33 patients (83%) had a fibrosis score of F1 or greater. Among patients receiving tacrolimus for immunosuppression, the median serum trough level was 5.95 ng/mL (range, 3.3–10.9).

Effect of Maintenance Interferon Therapy on Liver Histology

To evaluate the efficacy of long-term peginterferon therapy on histological changes, we compared scores between final biopsy samples (median, 44.0 months; range, 24.0–81.3 months) and those taken prior to treatment. Five patients in the non-SVR-IFN group discontinued maintenance therapy between 26.5 and 53.1 months after the initiation of the treatment because of the adverse events. For these patients, the biopsies taken just before or within 3 months after discontinuation of the treatment were analysed as final biopsies. Despite the variation in time between pretreatment and final biopsy sample collection, there were no significant differences in the duration among the three groups (P = 0.547). Median duration from initiation of interferon therapy to final liver biopsy was 41.9 months (range, 24.0–81.3 months) in the SVR group, 41.7 months (range, 26.5–68.4 months) in the non-SVR-IFN group and 46.5 months (range, 30.4–79.6 months) in the non-SVR-Withdrawal group.

There were no significant differences in baseline activity grades or fibrosis stages of patients in the three treatment groups when they were first diagnosed with recurrent hepatitis C (Table 1). However, there were noticeable differences among the three groups by the end of treatment (Fig. 2a). The activity grade of all patients in the SVR and non-SVR-IFN groups improved or remained stable, whereas it deteriorated in 6 (50%) of 12 patients in the non-SVR-Withdrawal group. The fibrosis stage deteriorated in all patients in the non-SVR-Withdrawal group; nine of these patients (75%) deteriorated by more than one stage. In contrast, only four patients (24%) in the non-SVR-IFN group deteriorated, all by only a single stage. Furthermore, three patients actually improved. In the SVR group, fibrosis stage decreased or remained stable in 10 of 11 patients (91%).

Figure 2. Effect of maintenance interferon therapy on liver histology: (a) Changes in activity grade (upper) and fibrosis score (lower) of individual patients before interferon therapy (Pre) and at final biopsy (final). (b) Mean changes of liver activity grade (left) and fibrosis stage (right) between pretreatment liver biopsy and the final liver biopsy in each of the three treatment groups. The error bars represent 2 SEs. (c) Kaplan–Meier estimates of the progression rates among patients whose fibrosis advanced to F3 or F4. The dashed line indicates the sustained virological response (SVR) group, the solid line indicates the non-SVR-IFN group and the dotted line indicates the non-SVR-Withdrawal group

In patients in the SVR and non-SVR-IFN groups, the mean activity grade was markedly reduced in the final biopsy, compared to the pretreatment biopsy (Fig. 2b). In contrast, patients in the non-SVR-Withdrawal group experienced an increase in activity grade. The differences between the non-SVR-Withdrawal group and both the SVR and the non-SVR-IFN groups were statistically significant (P <0.001). The mean changes in fibrosis stage in the SVR and non-SVR-IFN groups were −0.18 and +0.06, respectively, suggesting that fibrosis did not change during the follow-up period. However, there was an obvious increase (+2.2) among patients in the non-SVR-Withdrawal group, indicating marked progression of fibrosis.

The Kaplan–Meier analysis allowed us to investigate whether patients in the three treatment groups experienced different progression rates to late-stage fibrosis (Fig. 2c). No patient in the SVR group and only 1 patient (6%) in the non-SVR-IFN group developed fibrosis stage F3 or F4, whereas nine patients (75%) in the non-SVR-Withdrawal group progressed to these stages. The rates of fibrosis progression were significantly higher in the non-SVR-Withdrawal group than in the non-SVR-IFN and SVR groups (P = 0.0049 and P = 0.0086, respectively). There was no significant difference between the SVR group and the non-SVR-IFN group (P = 0.3980). Five-year progression rates to F3 or F4 were 0% in the SVR group, 14% in the non-SVR-IFN group and 54% in the non-SVR-Withdrawal group.

Safety and Tolerability of Maintenance Interferon Therapy

Five of 17 patients (29%) who received low-dose maintenance peginterferon treatment discontinued interferon therapy because of biliary complications (n = 2), neutropenia (n = 1), anaemia (n = 1) and de novo AIH (n = 1), between 26.5 and 53.1 months after its initiation. The biliary complications were not related to interferon therapy. Patients with neutropenia and anaemia recovered after discontinuing interferon therapy and were able to resume therapy within months (3 and 10, respectively). Steroid therapy alleviated the de novo AIH, but the patients did not resume interferon therapy.

Discussion

Studies have repeatedly shown the benefits of achieving SVR via interferon therapy after liver transplantation. For instance, the durability of the SVR is associated with improvements in hepatic inflammation and histological regression of fibrosis over the long-term.^[18–23] In contrast, efficacy of interferon therapy for non-SVR patients after liver transplantation had not previously been investigated. Here, we have demonstrated that long-term peginterferon maintenance therapy suppresses histological progression of recurrent hepatitis C after LDLT.

Maintenance interferon therapy was recently shown to have no influence on either histological or clinical outcomes in patients with nontransplant hepatitis C.^[24] This conclusion was drawn after observing that the rate of fibrosis progression was similar between treatment and control groups following a 3.5-year randomized controlled trial of low-dose peginterferon. As a large number of patients with advanced fibrosis were enrolled in the randomized controlled trial, it is difficult to compare with our study in which the number of patients studied is much smaller and patients with advanced fibrosis were not enrolled. In the current study after liver transplantation, however, we demonstrated that low-dose maintenance interferon therapy reduced necroinflammatory activity and fibrosis scores in non-SVR patients to levels similar to those in SVR patients. Furthermore, we found that non-SVR patients who discontinued treatment had significantly worse scores once no longer receiving therapy.

Although these results clearly suggest that low-dose peginterferon maintenance therapy is beneficial for non-SVR patients with recurrent hepatitis C after liver transplantation, the mechanism behind this positive response is unknown. Progression of hepatitis C and development of fibrosis after discontinuation of interferon treatment has been shown to proceed more rapidly in patients who have undergone liver transplantation.^[20,21] Our results, indicating that activity grade and fibrosis stage markedly deteriorated in non-SVR patients who discontinued maintenance treatment, support these previous findings. Thus, such a rapid progression of recurrent hepatitis C in patients who discontinued interferon therapy may have highlighted the beneficial effect of the low-dose peginterferon maintenance therapy.

Another issue is the tolerability and safety of long-term peginterferon maintenance treatment. In this study, five patients (29%) discontinued the treatment during the peginterferon maintenance treatment, but only three did so for reasons directly related to the treatment. While two of these patients recovered simply by discontinuing the treatment, the third did require steroid pulse therapy to treat de novo AIH. Overall, however, the maintenance therapy did not result in the incidence of major adverse events, suggesting that it is both a tolerable and a safe treatment method.

Our work shows that long-term, low-dose peginterferon administration is an effective method for inhibiting the progression of liver damage for recurrent hepatitis C after liver transplantation. Unfortunately, this was not a randomized control study, and only a small number of patients were eligible for research. Therefore, we recommend further work to more fully explore the effects of this treatment and to improve the outcomes for patients who do not achieve SVR.

References

1. Berenguer M, Prieto M, San Juan F et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002; 36(1): 202–210.
2. Feray C, Caccamo L, Alexander GJ et al. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group. Gastroenterology 1999; 117(3): 619–625.
3. Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002; 122(4): 889–896.
4. Gane E. The natural history and outcome of liver transplantation in hepatitis C virus-infected recipients. Liver Transpl 2003; 9(11): S28–S34.
5. Prieto M, Berenguer M, Rayon JM et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes. Hepatology 1999; 29(1): 250–256.
6. Sanchez-Fueyo A, Restrepo JC, Quinto L et al. Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft. Transplantation 2002; 73(1): 56–63.
7. Velidedeoglu E, Mange KC, Frank A et al. Factors differentially correlated with the outcome of liver transplantation in hcv+ and HCV- recipients. Transplantation 2004; 77(12): 1834–1842.
8. Gordon FD, Kwo P, Vargas HE. Treatment of hepatitis C in liver transplant recipients. Liver Transpl 2009; 15(2): 126–135.
9. Terrault NA. Hepatitis C therapy before and after liver transplantation. Liver Transpl 2008; 14(Suppl. 2): S58–S66.
10. Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol 2008; 49(2): 274–287.
11. Kuo A, Terrault NA. Antiviral therapy in liver transplant recipients: is SVR the only endpoint that matters? J Hepatol 2007; 46(3): 359–361.
12. Ueda Y, Takada Y, Haga H et al. Limited benefit of biochemical response to combination therapy for patients with recurrent hepatitis C after living-donor liver transplantation. Transplantation 2008; 85(6): 855–862.
13. Ueda Y, Takada Y, Marusawa H, Egawa H, Uemoto S, Chiba T. Individualized extension of pegylated interferon plus ribavirin therapy for recurrent Hepatitis C genotype 1b after living-donor liver transplantation. Transplantation 2010; 90(6): 661–665.
14. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24(2): 289–293.
15. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349(9055): 825–832.
16. Ueda Y, Takada Y, Marusawa H et al. Clinical features of biochemical cholestasis in patients with recurrent hepatitis C after living-donor liver transplantation. J Viral Hepat 2010; 17(7): 481–487.
17. Ohno O, Mizokami M, Wu RR et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol 1997; 35(1): 201–207.
18. Abdelmalek MF, Firpi RJ, Soldevila-Pico C et al. Sustained viral response to interferon and ribavirin in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2004; 10(2): 199–207.
19. Bizollon T, Ahmed SN, Radenne S et al. Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence. Gut 2003; 52(2): 283–287.
20. Bizollon T, Pradat P, Mabrut JY et al. Benefit of sustained virological response to combination therapy on graft survival of liver transplanted patients with recurrent chronic hepatitis C. Am J Transplant 2005; 5(8): 1909–1913.
21. Carrion JA, Navasa M, Garcia-Retortillo M et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007; 132(5): 1746–1756.
22. Fernandez I, Meneu JC, Colina F et al. Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation. Liver Transpl 2006; 12(12): 1805–1812.
23. Toniutto P, Fabris C, Fumo E et al. Pegylated versus standard interferon-alpha in antiviral regimens for post-transplant recurrent hepatitis C: comparison of tolerability and efficacy. J Gastroenterol Hepatol 2005; 20(4): 577–582.
24. Di BisceglieAM,ShiffmanML,Everson GT et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359(23): 2429–2441.

Source

Outcomes Among Living Liver Donors

Gastroenterology
Volume 142, Issue 2 , Pages 207-210, February 2012

James F. Trotter 

James E. Everhart

Baylor University Medical Center, Dallas, Texas

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland

published online 26 December 2011.

See “Estimates of early death, acute liver failure, and long-term mortality among live liver donors,” by Muzaale AD, Dagher NN, Montgomery RA, et al, on page 273.

Management of donor risk is the most important consideration in the decision to perform a living donor liver transplantation (LDLT). Counseling potential donors on operative morbidity and mortality requires a comprehensive understanding of the available data on outcomes. Ideally, an individual potential living donor should be informed of the potential complications based on an objective analysis of a center's own results. At present, this ideal has not been obtained. Instead, potential donors and their physicians must rely on outcome data from numerous single-center and a few multicenter studies. Reports from the three largest series from North America found that 28%–40% of donors developed ≥1 complication.¹, ², ³ Perhaps the most comprehensive of these studies, the 9-center Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL) noted that most complications were minor (27%) and life-threatening problems occurred in only 2% of cases.³ The most common complications were biliary leaks (9%), bacterial infections (12%), and incisional hernia (6%). Early postoperative laboratory abnormalities resolve within a few months of surgery with the exception of low platelet counts. A small minority of donors have sustained thrombocytopenia for >1 year after donation.⁴ Donor mortality is the most significant complication as underscored last year after 2 unexpected fatalities within months of each other at 2 of the largest LDLT programs in the country. The approximate risk of donor death is <1%, but a more precise estimation is difficult to ascertain for a number of reasons. Most important, the total number of LDLTs performed in the United States is small relative to the total number of liver transplants. Between 2000 and 2010, there were 3159 living donor liver transplants, which represented only 5.1% of all liver transplantations performed in the United States.⁵ In addition, unlike transplant recipients, there is no national database to register donor deaths. Consequently, reports of donor deaths are found through the media, case reports, or informal communications. Finally, there is no incentive for centers to report donor deaths owing to the negative repercussions of such disclosure.

In this context, the paper by Muzaale et al helps to provide some clarity regarding mortality following donation.⁶ Through the Organ Procurement and Transplantation Network, the authors acquired the social security numbers of all living liver donors and cross-referenced these with the Social Security Death Master File to determine periprocedural (within 90 days of surgery) and overall mortality rates. Comparisons were made with living kidney donors as well as participants in the third National Health and Nutrition Examination Survey (NHANES–III), 88% of which were excluded owing to comorbidities, which would have precluded living liver donation. These investigators reported that the 90-day mortality risk of living liver donors (1.7 per 1000 donors or 0.17%) was not significantly different compared with living kidney donors (0.05%). The long-term cumulative mortality risk was comparable to that of live kidney donors and NHANES participants (1.2%, 1.2%, and 1.4%, respectively) at 11 years. The authors further describe 4 cases of nonfatal acute liver failure in living liver donors. Three of these patients required deceased-donor liver transplantation. Because the Organ Procurement and Transplantation Network provides the full cohort of living liver donors in the United States and confirmation of mortality through the Social Security Death Master File is absolute, the results of this study are likely the best estimation of donor mortality. Clinicians will no doubt find this information useful as they counsel potential LDLT donors and recipients. In addition, this format of cross-referencing 2 databases provides an important study design for future estimates of donor mortality.

Although this study analyzed the largest cohort to date with the most rigorous methodology, the results are similar to previous reports. One prior analysis of publications in the medical and lay press reported donor mortality “definitely” and “definitely or possibly” related to the donor surgery at 0.15% and 0.20%, respectively.⁷ Another study based on survey data estimated donor mortality risk at 0.2%.⁸ An important distinction of the current paper from earlier reports is the use of comparison groups. However, the identification of an appropriate comparator group for living liver donors is difficult because of their unique characteristics. Living liver donors represent a highly selected group; up to 65% are rejected for the discovery of even a mild medical problem during the evaluation.⁹ Therefore, the use of a general population control group (NHANES) for comparison with the living liver donors is problematic. Living liver donors are likely to be healthier than the NHANES participants, despite the exclusion of 88% of that cohort for comorbidities. Consequently, the long-term health of living liver donors might be expected to be even higher than NHANES participants. The fact that there was no difference in long-term mortality between these 2 groups could potentially reflect a worse outcome for the liver donors. In addition, the nonconcurrent time of selection for the 2 cohorts, 1988–1994 for NHANES and 1994–2011 for the living donors, raises concerns about their true comparability. The use of living kidney donors is perhaps the best comparator group for living liver donors, although the risk of a kidney donor operation (0.05%) is likely much lower than liver donation (0.17%), even if not statistically different. On the other hand, as a result of the large volume of living donor kidney transplantations (approximately 6000 per year), there have been 3 times as many perioperative deaths than after living liver donation (Figure).¹⁰ Interestingly, these kidney donor deaths have received much less media attention. Because perioperative mortality is a rare event, efforts to lower the rates may need to take a safety-systems approach, as is currently being developed among A2ALL sites.¹¹

Figure. Number of living liver and living kidney early (< 90 days) donor deaths.⁶, ¹⁰ While the number of living liver donor deaths per 1000 donors is higher (1.7 vs 0.5 living kidney donors), the total number of deaths for kidney donors per year (1.7) is more than four-fold higher compared with liver donors (0.4), because the number of kidney donors per year (5410) is more than 20-fold higher than liver donors (242).

The finding of living liver donors who died by their own hand is notable. The current analysis discovered 2 such deaths in the early perioperative period. The A2ALL study identified 2 other deaths from donor suicides or drug overdose and another attempted suicide, all of which occurred >90 days after surgery. Although psychiatric complications are uncommon, occurring in about 4% of living liver donors, they may be attributable indirectly to the operation by the stress associated with undergoing the complicated evaluation and surgery.¹² The number of documented donor deaths by suicide and drug overdose (n = 4) rivals the total number of early perioperative deaths by other means (n = 5), highlighting the importance of the mental health of donors and prospective donors. Furthermore, the occurrence of these complications after the early postoperative period emphasizes the possibility that surgical complications may not be immediately evident. In fact, one third of rehospitalizations for living liver donors occur >90 days after donation.¹³

In consideration of health-related quality of life (HRQOL) of donors, a recent review concluded that physical well-being declines after surgery, but returns to predonation levels within 1 year, and mental health status remains about the same as predonation HRQOL.¹⁴ A subsequent study has confirmed these findings.¹⁵ However, these conclusions are drawn from just a handful of studies with both pre- and postoperative results that included about 300 donors in all. In addition, postdonation data were not obtained from all donors, introducing potential biases—donors with worse HRQOL may not respond to requests for information. Most important, long-term information on donor HRQOL is largely absent. Out-of-pocket expenses and lost wages have been estimated to average about $5,000, but the range is substantial.¹⁶ Importantly, the personal economic impact is among the greatest concerns for potential living donors.

Not all outcomes for the donor are negative. Among potential benefits is the intangible benefit of an altruistic act. There is often the direct benefit of having a loved one remain alive and returned to function. This is more likely with living than deceased donation owing to the increased risk of death during the often protracted time that recipients await deceased donor transplantation.¹⁷ There is also a public health benefit: Living donation allows another patient to receive a deceased donor liver, thereby decreasing the demand for deceased donor transplantation.

In summary, the report by Muzaale et al⁶ is the current standard for estimating donor mortality. Because the liver community has been unable to establish a national database for donor outcomes, and there are no real prospects for such, the rigorous methodology utilized in this study will allow the best means of prospectively reporting living liver donor mortality risk in the future. However, much more high-quality information is needed in LDLT, especially regarding long-term outcomes.

Acknowledgments

The opinions expressed herein by Dr. Everhart are those of the author and do not necessarily reflect the views of the National Institutes of Health or the Department of Health and Human Services.

References

Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(11)01700-8

doi:10.1053/j.gastro.2011.12.018

© 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

Live liver donation safer than previously thought

01/26/2012

Major surgery to donate a portion of liver does not interfere with long, healthy life

People who donate a portion of their livers for transplant to a relative or friend whose liver is failing can generally expect to live long, healthy lives and recover safely from the donation surgery, Johns Hopkins researchers have found.

“The donor process is safer than some have previously thought,” says transplant surgeon Dorry L. Segev, M.D., Ph.D., an associate professor of surgery and epidemiology at the Johns Hopkins University School of Medicine and leader of the study published in the February issue of the journal Gastroenterology. “Live liver donation is a serious operation with serious risks. However, in this largest study ever conducted in the United States, we have shown that it is safer than many previously believed, with a risk of death of 1.7 per thousand donors.”

The only treatment for end stage liver disease is transplant. Without a functioning liver, patients in liver failure die. Safe live liver donation is possible because the liver is an organ that regenerates itself relatively quickly, Segev notes, allowing the harvest of a small portion of the organ which, when transplanted, grows into a liver large enough to perform its crucial roles in blood detoxification, digestion and metabolism. The regenerative ability also means donors can survive well with a smaller segment of their own livers until they, too, regrow.

A decade ago, surgeons across the United States performed an estimated 500 live liver transplants a year. In 2002, however, there was a highly publicized death of a live liver donor. Since then, live liver donation may have been perceived as more dangerous than it actually is, Segev says, and now only 200 to 300 of these surgeries are performed annually, compared to 6,000 live kidney donations in the United States each year.

More than 16,000 people are currently on the waiting list for a liver transplant in the United States, while only around 6,000 livers are available from deceased donors. “For many, the risk of dying on the waiting list is higher than the chance of getting a deceased donor transplant," Segev says. "For the right patients, with the right needs and the right donors, live donor transplantation can be the best treatment option, and this study reassures us that the risk of a catastrophic complication remains low.”

To determine the safety of live liver donation, Segev and his colleagues combed data from all 4,111 donors in the United States between April, 1994, and March, 2011, and followed patients for an average of 7.6 years. There were seven donor deaths over the period in the 90 days following surgery, but the researchers say the long-term survival rate for donors was overall equal to the long-term survival of live kidney donors and a healthy control group culled from the National Health and Nutrition Survey.

Although the rate of live liver donor death was relatively low, Segev says it is still five times that of the risk of death for live kidney donors. A study by Segev published in the Journal of the American Medical Association in March, 2010, found that the rate of death in live kidney donation in the United States is 3.1 in 10,000. However, kidney donation is a simpler process, Segev notes. The operation itself is less complicated and kidney donors are left with one completely intact healthy kidney, which is typically able to compensate for the function of the one that is removed. By contrast, if a donor does not have enough healthy liver remaining after donation, he or she may not have enough liver function to get through the regeneration process, and might actually need a transplant to survive.

Segev says he was particularly interested in studying the outcomes for donors because most of those who offer to give up part of an organ come to the process very healthy. “The ideal risk of death from donating an organ is zero and we work as hard as we can to seek that ideal,” says Segev, director of clinical research in transplant surgery at Hopkins. “But in these serious, major operations, it is unlikely the risk will ever be zero.”
Other Hopkins researchers involved in the study include Abimereki D. Muzaale, M.D., M.P.H.; Nabil N. Dagher, M.D.; and Robert A. Montgomery, M.D., D.Phil.

For more information here.

http://www.hopkinsmedicine.org/transplant/

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Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants

JAMA. 2012;307(3):283-293. doi: 10.1001/jama.2011.2014

Sandy Feng, MD, PhD; Udeme D. Ekong, MD; Steven J. Lobritto, MD; Anthony J. Demetris, MD; John P. Roberts, MD; Philip Rosenthal, MD; Estella M. Alonso, MD; Mary C. Philogene, PhD; David Ikle, PhD; Katharine M. Poole, MS; Nancy D. Bridges, MD; Laurence A. Turka, MD; Nadia K. Tchao, MD

Abstract

Context Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality.

Objective To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients.

Design, Setting, and Patients Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months).

Main Outcome Measures The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection.

Results Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03).

Conclusion In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.

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Living donor liver transplantation from a donor previously treated with interferon for hepatitis C virus: a case report

Published on: 2011-07-03

Introduction: Selecting a marginal donor in liver transplantation (LT) remains controversial but is necessary because of the small number of available donors.Case presentationA 46-year-old Japanese woman was a candidate to donate her liver to her brother, who had decompensated liver cirrhosis of unknown origin. Eight years before the donation, she had a mild liver dysfunction that was diagnosed as a hepatitis C virus (HCV) infection (serotype 2).

She had received anti-viral therapy with interferon -2b three times weekly for 24 weeks and had a sustained viral response (SVR). A biopsy of her liver before the donation showed normal findings without any active hepatitis, and her serum was negative for HCV-RNA.

Only 67 patients have undergone LT from a cadaveric donor in Japan. The family in this case decided to have living donor LT.

A careful selection for the liver graft donation was made; however, since she was the only candidate, we approved her as a living donor. She was discharged nine days after the liver donation.

Her liver function recovered immediately. A computed tomography scan showed sufficient liver regeneration one year later.

Her brother also had good liver function after LT and had no HCV infection 48 months after surgery and no de novo malignancy. Neither of the siblings has developed an HCV infection.

Conclusions: A patient with SVR status after interferon therapy might be considered a candidate for living donor LT but only if there are no other possibilities of LT for the recipient.

A careful follow-up of the donor after donation is needed. The recipient also must have a very close follow-up because it is difficult to predict what might happen to the graft with post-transplant immunosuppression.

Author: Masaaki HidakaMitsuhisa TakatsukiAkihiko SoyamaHisamitsu MiyaakiTatsuki IchikawaKazuhiko NakaoTakashi KanematsuSusumu Eguchi

Credits/Source: Journal of Medical Case Reports 2011, 5:276

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