dilemma of alcohol use by potential living liver donors, The
Bramstedt, Katrina A
Previous and current alcohol use by potential living liver donors presents ethical challenges for donor selection committees. Discussing these challenges, we offer guidelines for selection and management of these individuals. Donor safety and welfare should be the primary concern, thus relapse potential during the postdonation period for those with a history of alcohol dependence or abuse is of importance, especially because of the potentially severe consequences of mixing pain relievers (eg, acetaminophen) and alcohol during liver regeneration. Psychosocial and chemical dependency evaluations are critical for potential living donors as well as recipients. (Progress in Transplantation. 2006;16:24-27)
Significant alcohol use is well-known to cause adverse effects on the liver; namely, fat accumulation in liver cells (fatty liver), liver inflammation (hepatitis), and cirrhosis (scarred liver) that can lead to the need for a transplant.1 The availability of deceased donor livers for transplantation falls considerably short of the need each year2; therefore, many institutions now offer living liver transplantation as a way to help address the shortfall. Among US transplant centers, there is no uniform set of criteria for living donor selection, especially psychosocial criteria. Further, we found no detailed discussion of alcohol use, abuse, or dependence and living liver donation in either the medical or bioethics literature. This article brings these issues to light and offers ethical guidance for donor selection teams.
A 24-year-old man presented at our institution seeking to be a living liver donor for his mother who had primary biliary cirrhosis. Her Model of End-Stage Liver Disease Score (MELD) score 2 weeks previously was 19. During the evaluation by the transplant bioethicist, the potential donor admitted to “binge drinking” of alcoholic beverages during college, but since graduating and anticipating donation, he had stopped drinking all alcohol 2 weeks previously. He reported that he quit on his own and had not enrolled in an alcohol rehabilitation program, nor was he attending an alcohol cessation support group. In addition, he continued to associate with friends who consumed alcohol. He made multiple comments that seemed to indicate the belief that negative consequences would not happen to him, thus he was advised to seriously reflect on the risks associated with using alcohol after donation. He was also referred for a chemical dependency assessment.
The transplant team’s chemical dependency counselor assessed the potential donor and identified a family history of heavy drinking by his father, maternal grandparents, and uncles. The potential donor began binge drinking early in high school, consuming 6 to 12 beers twice a month, and often ignored his parents’ warnings to not drive after drinking. In college, despite an alcohol-related arrest for sexual assault, his tolerance and consumption increased as he consumed up to a case of beer twice a week, with daily drinking of 12 beers per day during finals weeks. He also made failed attempts to reduce or stop drinking and had loss of control, which resulted in hangovers that caused him to miss scheduled classes. Of further significance was his continued use of alcohol despite a previous warning from our liver transplant team to stop because of elevated liver function tests. He denied use of other substances, and results of a urine toxicology screen were negative.
The assessment data obtained indicated alcohol dependence. In addition to continued abstinence from alcohol, it was recommended that the donor candidate participate in an intensive outpatient chemical dependency program to learn about the disease concept of alcoholism, to become familiar with relapse prevention skills, and to initiate ongoing participation in Alcoholics Anonymous. Despite his mother’s need for part of his liver to sustain her life, he angrily refused the recommendations-insisting that his drinking had never caused problems for him and that he considered himself to be a “normal college kid.”
Although living liver donation can help recipients reduce their transplant waiting time (potentially preventing further decline in clinical status before transplantation), the benefits to recipients must be reflected on in light of the risks to the donors. Because donors undergo an operation that is completely unnecessary and the only benefits to them are of an altruistic nature, the safety of the donor is paramount. Variables that increase donor risk must be both looked for and reflected on when found, regardless of whether the variables are medical, surgical, or psychosocial.
As a point of reference for our discussion, we reviewed the Web site of every US transplant program that conducted at least 1 living liver transplant in 2004 (47 hospitals). Forty-four of 47 centers (93.6%) formally discussed living liver transplantation on their Web site; however, only 7 (15.9%) Web sites explicitly discussed alcohol and substance abuse as a living donor evaluation criterion. Some hospitals may indeed incorporate evaluations for alcohol and substance abuse in their donor selection process, yet not discuss this on their Web sites; however, we find such Internet omissions striking, especially when medical criteria for donors are explicitly mentioned. Although a “psychosocial evaluation” might possibly include a formal chemical dependency assessment, the medical literature only rarely explicitly mentions alcohol and substance abuse evaluation as part of donor screening.3,4 We agree with Walter et al5 that at present, the donor team is “still without cogent criteria for an adequate psychosomatic evaluation and selection of donors.” Even though blood tests on potential donors might reveal alcohol intake (eg, positive ethanol, elevated triglyceride, elevated γ-glutamyltransferase), this does not replace the need for a psychosocial assessment regarding alcohol and substance use.
As mentioned, the effect of alcohol on whole livers is widely known. The effect of alcohol on regenerating livers (after resection), however, is a distinct matter. Preexisting liver disease can alter the regenerative capacity of the liver. Architectural liver abnormalities caused by cirrhosis and fibrosis, for example, impair and limit liver regeneration. Even infection and malnutrition can impair liver regeneration because of increased cell death and delayed mitosis.6 The effect of alcohol on livers that are regenerating in the body of the healthy liver donor is less clear. Because chronic alcohol consumption is toxic to mature liver cells, the same detrimental effects may happen to newly regenerating cells. Both the acute and chronic administration of alcohol decreases the rate of hepatic DNA synthesis in mature liver cells after partial hepatectomy7-9; and without DNA synthesis, there can be no liver cell regeneration. However, recent studies have provided conflicting results as to the effects of alcohol on the regenerative ability of the liver.
In 1982, Duguay et al10 showed that chronic alcohol administration in rats, before partial hepatectomy, resulted in a statistically significant reduction of liver regeneration for up to 72 hours and a delayed peak regenerative activity by 24 hours when compared to livers not exposed to alcohol. These results were later supported by study from Liatsos et al.11 This group showed that alcohol inhibited hepatic regenerative capacity and prolonged the liver regenerative process in rats. Liatsos and colleagues also measured the effects of alcohol upon hepatic stimulator substance, which is a hepatotrophic substance. They found that alcohol causes a delay of 24 hours in the peak of hepatic stimulator substance after partial hepatectomy in rats. Thus, these 2 studies show that previous chronic alcohol use can delay the onset and reduce the amount of liver regeneration. However, similar studies have not been conducted in humans.
A later study by Zhang et al12 provided conflicting results when compared to the previously mentioned data. The study’s aim was to document the effects of daily light, moderate, and heavy alcohol exposure on hepatic regenerative activity in rats. They concluded that light alcohol consumption enhances hepatic regenerative activity after partial hepatectomy. When compared to water-fed rats, the livers from rats fed alcohol in light amounts showed enhanced regenerative activity and the livers from rats fed high amounts of alcohol resulted in impaired hepatic regeneration. Thus, “light” amounts of alcohol may offer a beneficial effect to regenerative liver cells, but much more research needs to be conducted before these results can be clinically applied. Because of conflicting studies, there is no firm answer as to the actual effects (positive and negative) of alcohol on liver regeneration in humans.
While the donor is recuperating after hepatectomy, he or she might ingest acetaminophen for pain relief. This could be problematic for an unrehabilitated alcohol abuser, because several reports have indicated that acetaminophen use with chronic alcohol consumption can be harmful.13,14 In fact, for the past 8 years, the Food and Drug Administration has required warning labels on acetaminophen containers, indicating that chronic use of alcohol while taking pain relievers can result in liver damage.15 Less known are the risks of using acetaminophen in the context of binge drinking, which is so common among young adults like the young man in our case study. McCuskey et al16 found that use of acetaminophen after even a single weekendtype alcohol binge can potentiate hepatotoxicity that can be further compounded by additional alcohol binges.
The issues raised by this case create many questions for the donor selection team: (1) Should current “light drinking” (1-2 alcoholic beverages a day) be an exclusion criterion for potential living liver donors? (2) Should a history of “heavy drinking” (4 or more alcoholic beverages a day) be an exclusion criterion for potential living donors who have acceptable liver biopsy? and (3) Should completion of a formal chemical dependency rehabilitation program be required of potential living donors with a history of alcohol and substance dependence and abuse?
There is one broad solution to all of these questions: at the time of donation, all living liver donors should also meet psychosocial requirements for transplant listing themselves. Further, they should have no medical contraindications to transplantation, because all living liver donors (whether they have a history of alcohol consumption or not) are potentially at risk for undergoing a liver transplant themselves.17 As an example, potential donors should demonstrate the financial capability to have their medical needs met whether through cash, capital, or their own health insurance, because donors can ride on the recipient’s health insurance for only a very limited time. Potential donors with significant mental illness may have impaired functional capacity for decision making and thus be unable to provide voluntary informed consent.3 They may have also reduced coping skills, which could render them unable to deal with surgical complications for themselves and/or the recipient. Also, if potential donors are unable to appreciate the recovery time needed after donation, this could cause personal, family, and financial stress.
Transplant selection criteria exist for both the safety and welfare of transplant recipients, as well as to optimize transplant outcomes in a setting of scarce resources. Individuals evidencing medical exclusions to transplantation (eg, cachexia, obesity) are at significant risk for posttransplant morbidity.18 Similarly, individuals who do not satisfy psychosocial criteria for transplantation are at risk for posttransplant morbidity (or even mortality) because of issues such as mental distress, noncompliance, and alcohol and substance abuse.19 If liver failure necessitating transplantation occurs during the immediate postoperative period, the situation will be stressful for the donor’s family, as well as the physicians involved. The ability to immediately list the donor for a transplant because of him or her meeting medical and psychosocial requirements will be a great advantage to all. It is difficult to conduct a spur-of-the-moment psychosocial evaluation that is thorough and accurate; thus, having the psychosocial evaluation (including alcohol and substance abuse history and rehabilitation, if necessary) completed as part of the donor selection process is an ethically sound approach. Organ allocation to transplant donors must follow processes that foster ethical stewardship of resources.
We argue that potential donors found to have a history of chemical dependence and abuse that is untreated should be required to complete a formal rehabilitation program with a defined period of abstinence before they can be considered suitable living liver donors. The New York State Committee on Quality Improvement in Living Liver Donation recommends that individuals found to have a history of alcohol addiction or substance abuse should evidence “long-term stable abstinence with low risk of exacerbation.”20 The OPTN/UNOS Ad Hoc Living Donor Committee recommends that teams “evaluate potential [liver] donors for the presence of active substance abuse,” but it does not specifically address whether alcohol use (any quantity) should be considered an absolute or relative exclusion criterion.21 From a safety and welfare perspecive, if active substance abuse is detected as part of the potential donor’s evaluation process, there is an ethical obligation to refer the individual to a treatment provider. Although individuals cannot be forced to complete these treatment programs, they should be advised that it would be in their best interests, regardless of whether they participate as living donors.
Requiring potential donors to satisfy abstinence and rehabilitation requirements could indeed put the intended liver tissue recipient in the position of having to seek a new living donor while lingering on the transplant waiting list. This is because, (1) the patient may get sicker the longer he or she waits on the list; and (2) the potential donor may not successfully complete rehabilitation. If living liver donation is their transplant preference, we advise that intended recipients consider an alternate potential donor as a backup. There may, however, be insurance restrictions on the evaluation of multiple potential donors or evaluations that occur concurrently.
There is a medical connection between alcohol and the liver, but there is also a philosophical connection. Potential living donors who fail to acknowledge that their drinking could affect their health (especially during the liver regeneration period) are failing to recognize the inherent connection between alcohol, the liver, and the potential need for a transplant. This disconnect is striking and should not be overlooked or undervalued by donor evaluation teams. Individuals entering the transplant process as donors should not be actively setting themselves up for their own need for transplant.
A question that still remains unanswered is, How long should living donors abstain from alcohol consumption after their donation? This is a valid question because social drinking is a common practice and drinking 1 to 2 alcoholic beverages a day has been promoted by some medical professionals as a means to decrease overall mortality and the incidence of angina, myocardial infarction, and stroke.22,23 Although living donor data do not exist with regard to this matter, we argue for a conservative approach. Specifically, the donor should not do any light drinking until after the liver has been clinically determined to have regenerated within normal limits and is functioning appropriately (eg, imaging studies, laboratory tests).
1. Mandayam S, Jamal MM, Morgan TR. Epidemiology of alcoholic liver disease. Semin Liver Dis. 2004;24:217-232.
2. Department of Health and Human Services, Health Resources and Services Administration, Special Programs Bureau, Division of Transplantation and United Network for Organ Sharing. 2003 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1993-2002. Rockville, MD. Available at: http://www.unos.org. Accessed July 6, 2005.
3. Trotter JF. Selection of donors and recipients for living donor liver transplantation. Liver Transplant. 2000;6(suppl 2):S52-S58.
4. Brown RS Jr. Evaluation of the potential living donor. Transplant Proc. 2003;353:915-916.
5. Walter M, Bronner E, Steinmuller T, Klapp BF, Danzer G. Psychosocial data of potential living donors before living donor liver transplantation. Clin Transplant. 2002; 16:55-59.
6. Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. JAm Coll Surg. 2003;197:634-659.
7. Zhang BH, Gong Y, Minuk GY. Chronic ethanol consumption disrupts complexation between EGF receptor and phospholipase C-gl. Biochem Biophys Res Commun. April 1999;257:89-94.
8. Chen J, Kunos B, Gao B. Ethanol rapidly inhibits I1-6-activated STAT 3 and C/EBP mRNA expression in freshly isolated rat hepatocytes. PEBS Letters. 1999;457:162-168.
9. Yang SQ, Lin HZ, Yin M, Albrecht JH, Diehl AM. Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. Am J Physiol. 1998;275:G696-704.
10. Duguay L, Coutu D, Hetu C, JoIy JG. Inhibition of liver regeneration by chronic alcohol administration. Gut. January 1982;23:8-13.
11. Liatsos GD, Mykoniatis MG, Margeli A, Liakos AA, Theocharis SE. Effect of acute ethanol exposure on hepatic stimulator substance (HSS) levels during liver regeneration: protective function of HSS. Digest Dis Sd. 2003;48:1929-1938.
12. Zhang M, Gong Y, Corbin I, Mellon A, Choy P, Uhanova J, Minuk GY. Light ethanol consumption enhances liver regeneration after partial hepatectomy in rats. Gastroenterology. 2000;119:1333-1339.
13. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology. 1995:22:767-773.
14. Draganov P, Durrence H, Cox C, Reuben A. Alcohol-acetaminophen syndrome. Even moderate social drinkers are at risk. Postgrad Med. 2000:107:189-195.
15. United States Department of Health and Human Services. HHS News. FDA announces new alcohol warnings for pain relievers and fever reducers. 21 October 1998. Press release #P98-31. Available at: http://www.fda.gov/bbs/topics/NEWS /NEW00659.html. Accessed July 6, 2005.
16. McCuskey RS, Bethea NW, Wong J, et al. Ethanol hinging exacerbates sinusoidal endothelial and parenchyma! injury elicited by acetaminophen. / Hepatol. 2005;42:371-377.
17. Akabayashi A, Slingsby BT, Fujita M. The first donor death after living-related liver transplantation in Japan. Transplantation. 2004;77:634.
18. Hade AM, Shine AM, Kennedy NP, McCormick PA. Both under-nutrition and obesity increase morbidity following liver transplantation. Irish Med J. 2003;96:140-142.
19. Bunzel B, Laederach-Hofmann K. Solid organ transplantation: are there predictors for posttransplant noncompliance? A literature overview. Transplantation. 2000;70:711-716.
20. New York State Committee on Quality Improvement in Living Liver Donation. Report to New York State Transplant Council and New York State Department of Health. Revised June 2004. Available at: http://www.health.state.ny.us/nysdoh /liver_donation. Accessed July 6, 2005.
21. OPTN/UNOS Ad Hoc Living Donor Committee. Living Liver Donor Evaluation Guidelines. June 2004. Available at: http://www.unos.org/ContentDocuments/Living_Liver_Donor _Evaluation_Guidelines2(1).pdf. Accessed September 20, 2005.
22. Camargo CA Jr, Stampfer MJ, Glynn RJ, et al. Moderate alcohol consumption and risk for angina pectorts or myocardial infarction in U.S. male physicians. Ann Intern Med. 1997;126:372-375.
23. Mukamal KJ, Ascherio A, Mittleman MA, et al. Alcohol and risk for ischémie stroke in men: the role of drinking patterns and usual beverage. Ann Intern Med. 2005;142:11-19.
Katrina A. Bramstedt, PhD, Judy Stowe, MA, LICDC, Brent Lemberg, MD
Cleveland Clinic Foundation, Cleveland, Ohio
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Katrina A. Bramstedt, PhD
Cleveland Clinic Foundation
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