liver transplantation for alcoholic liver disease

Journal of Hepatology 1995; 23: 474479 Printed in Denmark AN rights reserved

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Journal of Hepatology

ISSN 0168-8278

Editorial

Liver for 2tkmlmk liver disease

David Sherman and Roger Williams

F m SUBJECTS in the field of liver transplantation give rise to controversy as readily as that of al-

coholic liver disease (ALD). Although ALD is the most common cause of chronic liver disease in Europe and the United States, very few patients received transplants for this indication until relatively recently. The reasons for this apparent paradox included the patients’ underlying alcohol problem, the varying natural history and outcome of ALD, the improvement that often but not invariably accompanies abstinence, the effect of alcohol on other organ systems, and the perceived impact of performing transplants for ALD on the public profile of liver transplantation. In the early days of transplantation patients with ALD were rarely considered, as a poor outcome was expected and the risks of a return to alcohol abuse were thought to be too great.

It was not until the NIH Consensus Conference of 1983 (1) that ALD became an accepted indication, although it was anticipated that only a “small number of patients” would merit consideration. For this reason the first published results of transplantation for ALD did not appear in the literature until 1988 (2). At King’s College Hospital only 24 patients with ALD were transplanted from 1980 to 1989, which consti- tuted less than 5% of the total patients transplanted (3). Results from several centres have now shown that l-year survival figures compare favourably with transplantation for other chronic liver disease (34), although indications for transplant and selection criteria varied considerably between centres.

In 1989, ALD became the commonest indication for OLT in the United States (7,8), although in Europe the proportion of the total number of transplants per-

Correspondence: David Sherman, Institute of Liver Studies, King’s College Hospital and King’s College School of Medicine & Dentistry, Bessemer Road, London SE5 9PJ, U.K.

formed for ALD between 1989 and 1991 varied from 4% in the United Kingdom to 18% in Spain (9). There seems little doubt that in the future increasing numbers of patients with end-stage liver disease due to alcohol will be referred to hepatology units (already with over- subscribed transplant programmes) for consideration for transplantation. The issue for the 1990s is therefore not whether such patients should receive a transplant but which patients should go forward onto the waiting list. As with other liver diseases, the assessment in- volves consideration of a) the severity and prognosis of the underlying liver disease; b) the absence of medical and/or surgical contraindications to the transplant operation; and c) the patient’s psychological and social suitability for the ordeal of a transplant and its subsequent demands. Whereas most hepatologists may agree on medical suitability for OLT, a number of dif- fering views have been expressed on the stringency of psychosocial criteria that should be applied. One of the more extreme views was proposed by Moss & Seigl- er (lo), who argued that the number of OLTs for ALD should be strictly limited on the ethical grounds that the condition is largely self-inflicted.

Demand for ‘Ransplantation in ALD Estimates from mortality statistics suggest that at least 1,300 and 36,000 deaths occur from ALD in the UK and USA respectively each year. In contrast, the an- nual respective numbers of transplants for all age groups are currently 550 and 3000. Even if as few as 10% of these cases fulfilled the criteria for transplantation, the demand would greatly exceed the capacity of the system to cope with it. As orthotopic liver transplantation has become almost a routine procedure in many cases over recent years, demand has grown so much that it is not uncommon for patients to remain on waiting lists for between 3 and 6 months. Increasing awareness of improved results among physicians has led to an increase in referrals to transplant centres. A

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consequence is that a greater proportion of suitable patients will be assessed and considered for transplantation. Thus, the situation with regard to ALD serves to illustrate the whole question of the imbalance between demand for and supply of donor organs.

Assessment (Medical and Psychiatric) The principal aims of the initial evaluation are to establish that the patient is medically suitable for transplantation, i.e. that the liver disease is sufficiently severe to warrant the operation and that no major contraindications are present. Most centres also per- form a psycho-social assessment to establish the likeli- hood of long-term abstinence.

Medical assessment There is general agreement on the medical indications for transplantation in ALD, which are similar to those for other chronic liver diseases. Namely, a failure of medical supportive measures for the consequences of end-stage liver disease - portal hypertension and hepatocellular failure. The most common symptoms are recurrent bleeding from oesophageal and/or gastric var- ices, diuretic-resistant ascites resulting in spontaneous bacterial peritonitis and requiring paracentesis, dis- ability due to chronic encephalopathy or liver failure, small hepatocellular carcinomas (less than 4 cm) aris- ing in cirrhotic livers and, rarely, severe intrapulmona- ry shunting. The majority of patients are of Child’s grade B and C. However, in some patients who have become abstinent a remarkable improvement may still be seen over a period of 6 months, particularly in those with active alcoholic hepatitis. Histological proof of di- agnosis is advisable, as occasionally other causes con- tributing to liver damage may be found. Despite the advent of new therapies, such as transjugular in- trahepatic porto-systemic shunts for variceal bleeding and ascites, there is no evidence to date that they pro- vide more than temporary relief.

Contra-indications to transplantation include the presence of alcohol-induced damage to other organs, such as dilated cardiomyopathy (sometimes only de- tectable by echocardiogram and/or right heart cath- eterization), central nervous system damage, chronic pancreatitis, myopathy and gross malnutrition.

Psychiatric assessment Most patients who are referred will already have attempted to give up alcohol, with varying success. It is common practice to involve psychiatrists and social workers in the assessment to help determine the prognosis for future abstinence, as suggested by Lucey et al. (5). Emphasis is placed on the severity of prior alcohol

dependence, the acceptance of the alcohol problem by the patient and his family, the presence of substitute activities, the absence of concomitant psychiatric disease, and a stable work and family environment. Other centres have relied on an arbitrary 6-month abstinence rule, and one centre has utilised a signed ‘contract’ committing the patient to compliance prior to acceptance into the transplant programme (11). At present, no firm evidence exists to favour any of these ap- proaches, which remain as guidelines to assist physicians in a difficult task.

Medical Outcome Initial results from Pittsburgh (2) and King’s College (3) showed that the medical outcome of transplantation for ALD compared favourably with results for other chronic liver diseases. Subsequent published results from a number of centres in Europe and the United States have now confirmed that excellent results may be achieved, with patient survival rates of between 66 and 100% at 1 year (12-14) (Table 1). It should be emphasised that medical and psychiatric selection criteria varied widely between centres, and that improved survival may have been achieved in some cases by transplanting patients with less severe liver disease. The small numbers in some series, such as those from Chicago and Montpelier, suggest strict selection criteria (15,16).

No controlled trials of transplantation have been performed to date in ALD, so that it is difficult to assess the resulting survival benefit. In the study from Michigan (5), follow up of 19 patients (18 of whom were Child’s grade C) considered unsuitable for transplantation because of sepsis, malignancy, cardiac or renal failure revealed that only 35% survived to 3 months and none was alive at 12 months. In contrast, only one out of 17 patients (12 Child’s B or C) who were ‘too well’ for a transplant had died at 18 months. These results illustrate that the prognosis may vary considerably among patients with severe ALD as judged by conventional criteria.

Recent evidence from a large case-control study using combined results from 12 French transplant centres (17) may help to resolve the question as to which patients benefit most from transplantation. The outcome of transplantation in 169 patients with varying clinical severity of liver dysfunction was compared to that of matched controls who were of similar age, Child’s grade and bleeding history to the transplant cohort, and who also did not have contraindications to surgery. Thus, the control group was also ‘suitable’ for transplantation. In addition, a ‘simulated’ control group derived by statistical modelling of a database of

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TABLE 1

Published rates of l-year survival and recidivism in liver transplantation for ALD

Author (date) Centre Number of pts.

Kumar (1989) Pittsburgh 13 Bird (1990) King’s College 24

Lucey (1992) Michigan 45 Stevens (1991) Chicago 10 Knetchle (1992) Madison, 41

Wisconsin Doffoel (1992) Strasbourg 75 Goldstein (1993) Dallas 41

Osorio (1993) San Francisco 43 Pageaux (1993) Montpelier 22 Poynard (1994) French 169

multi-centre Krom (1994) Mayo Clinic 30

% of pts. 12-month Abstinence Recidivism Method Childs’ C survival (5) pre-op. (“~)

64 14 62 (s6/12) 12 Telephone survey 75 66 21 (2302) 22 Clinic/

questionnaire 13 78 11 Clinic/interview - 90 (10 mth) (?6/12 in most) 0 Clinic 95 83 27 (?6/12) 28 Interview+

DSM-III 53 80 42 (~3/12) 33 _ 86 41 (?6/12) 14 Retrospective

case records _ 100 43 (?6/12) 19 Questionnaire

100 73 13 (?6/12) 9 Clinic 40 “high risk” 73 (24 mth) 168 (?6/12) 9 Case records

_ 88 13

nearly 800 patients with alcoholic cirrhosis was used. The results of a 2-year follow up showed that transplantation only conferred significant benefit in the 40 ‘high-risk’ patients with severe liver disease, with a 2- year survival of 64% compared to 41% in matched controls and 23% in the simulated control group. In contrast, there was little difference in outcome in 59 ‘medium-risk’ and 70 ‘low-risk’ patients. The authors dis- counted any effect of increased alcohol consumption in the control groups on outcome, and concluded that survival was increased only in severely ill patients. The increased survival of the “high-risk” matched control group in the French study compared to the simulated group (and those who were ‘too ill’ to transplant in the study from Michigan) reflects the fact that the former did not have contraindications to transplantation.

The Issue of Recidivism Post-Transplant A return to alcohol consumption after a liver transplant is a highly emotive issue and is perceived as a treatment failure. It has a negative impact not only for the patient but also for the transplant team of doctors, nurses and co-ordinators (18). Although most published studies have monitored the rate of recidivism, the definitions have varied considerably (Table l), and methods employed to monitor patients have ranged from telephone survey (4) to the use of structured in- terviews (5,6). For this reason the results are difficult to interpret, but most studies have reported rates between 9 and 33%, albeit for rather short follow-up periods. Furthermore, there is relatively little information on the crucial question of whether drinking post-transplant actually damages the graft.

Little work has been done on the psychological outcome in transplantation for ALD, although Be-

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resford et al. (19) found no increase in depression or non-compliance in comparison with non-alcoholic re- cipients. In a recent study from King’s College, the psychiatric as well as the medical outcome in a cohort of 20 patients transplanted between 1987 and 1992 was examined by an independent investigator who was not a member of the transplant team (20). Results were compared with a control group of 54 patients who received transplants consecutively for other indications. All patients, who were at least 12 months post-transplant, underwent a semi-structured interview and completed self-rating questionnaires to assess physical and psychiatric morbidity, depression and neurosis, social functioning and alcohol dependence. In addition, corroborative information was ob- tained from relatives and general practitioners, the patient having been reassured that all information would be treated with strict confidentiality.

All but two patients had been abstinent pre-transplant for a mean period of 26 months, and the majority of patients fulfilled most of the Ann Arbor criteria (19). All managed to achieve abstinent periods post-transplant for a mean of 10 months. However, at interview 19 admitted to having consumed alcohol since the transplant. Sixteen consumed alcohol regu- larly, with a mean consumption of 3.4 units per day, and three were drinking heavily (in excess of 20 units per day). Forty per cent were drinking above the re- commended safe limits for the general population. Im- portantly, all ALD patients were otherwise compliant and the majority did not have increased levels of physical or psychiatric morbidity in comparison with the controls. Moreover, no correlation between pre-transplant periods of abstinence or severity of dependence on alcohol and long-term post transplant drinking


levels was found. Despite the significantly increased alcohol consumption in the ALD group, only two patients out of 20 exhibited graft damage.

This study suggests that the long-term incidence of recidivism in ALD patients undergoing transplantation may have been underestimated, particularly in studies with only a short follow-up period, and that recurrent drinking is not necessarily accompanied by a worse outcome. Furthermore, the results support the sugges- tion by Vaillant (21) that the ability to maintain an arbitrary 6-month pre-operative abstinence period is not a good predictor of long-term outcome. These results challenge the previously accepted emphasis that has been placed during the assessment period on pre- diction of relapse into alcoholism, and also the belief that any level of drinking after transplantation will ad- versely affect the transplanted liver.

Ethical Issues The denial of a potentially life-saving medical therapy to a particular group of patients is an extremely emotive issue, and has given rise to strong arguments both for (22) and against (10) transplantation for ALD. The traditional view in the early 1980s was that alcoholic liver disease was a self-inflicted problem and that the patient bore a moral responsibility for his illness, particularly if no attempt had been made to seek help. In addition, there were concerns regarding compliance with therapy and attendance for follow up in the post- transplant period, as well as the potential damage to the graft from alcohol. It was also felt that public knowledge that alcoholics were undergoing liver transplantation for cirrhosis would eventually lead to a de- crease in the willingness of the general population to donate organs.

More balanced views have argued for selection criteria based upon an accurate assessment of the prognosis of the alcoholism post-transplant (7,23-25). However, recent evidence suggests that the ability (even of experts) to select individuals who are likely to ab- stain long term may have been greatly overestimated in the past. A return to low levels of alcohol intake after transplantation has previously been regarded as morally unacceptable, despite the fact that the long- term effect of ethanol on the transplantated liver is un- known. The results of the study from King’s College suggest that drinking at or below the government’s re- commended drinking limits in the first 2 to 3 years is not associated with significant graft dysfunction, nor with increased morbidity. In fact, one study from Pitts- burgh (published in abstract form only) has suggested that alcohol use by transplanted ALD patients actually protects against the development of both acute and

chronic rejection (26). Therefore the main reason for insisting on complete abstinence post-transplantation remains the concern that patients will return to uncon- trolled or dependent drinking.

Further arguments may be made to challenge the perception of ALD as a self-inflicted, inevitable consequence of alcoholism and to support the concept of transplantation. Only l&30% of chronic alcohol abusers develop cirrhosis (27), and it is well known that women may develop cirrhosis at lower levels of intake (28). There is increasing evidence for an inherited com- ponent in individual susceptibility, and other environ- mental influences may be important (29). It is often not appreciated that ALD is relatively heterogeneous in presentation and that some patients continue to de- teriorate despite abstinence. It has also been argued that the physician’s role is as an advocate for the patient’s best interests, and that it is inappropriate for him to restrict access to a limited resource on anything other than medical grounds. Finally, the cost of transplantation compares favourably with that of long-term medical care of chronic ALD (16).

Alcoholic Hepatitis The question of transplantation for acute alcoholic hepatitis remains controversial. In its most severe form, which is accompanied by encephalopathy, hepatorenal syndrome and systemic sepsis, mortality may be as high as 60% (30). If multi-organ failure supervenes and haemodialysis is required, most patients will die, although a successful outcome after transplantation has been described in selected cases (31) and this is also the experience at King’s. The majority of patients would be unsuitable because of their inability to survive the operation and the fact that there is insufficient time to assess previous drinking behaviour and family background. Clearly an abstinent period does not apply in this situation. Even if the criteria for surgery are satisfied, many of the patients would not survive even the relatively short waiting period prior to transplantation as in this country. However, this question and the overall value of the procedure in such highly selected cases could only be answered by a controlled trial.

Conclusion The issue of transplantation for ALD is perhaps unique in that psycho-social and ethical selection criteria were established before the optimal medical indications for the procedure could be properly evaluated in long-term studies - witness the small number of transplants performed for ALD in the 1980s. Recent evidence has shown that the risk of recidivism is not eliminated by ensuring a 6-month abstinent period

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prior to transplantation. Whether a more sophisticated assessment of the patient and his family by a multi- disciplinary team (as in Ann Arbor) will reduce drinking by patients transplanted for ALD remains to be seen. In any case, the significance of low levels of alcohol intake post-transplant may have been overestimated.

Understandably, transplant programmes have hith- erto selected cases extremely carefully in their initial stages to ensure optimal results. However, it is possible that these results have been achieved in part by transplanting patients of mostly low or medium risk, as described by Poynard et al. (17). It is possible to envisage a situation within the next few years where patients with ALD will constitute the largest group undergoing assessment (32). As the supply of donor organs is un- likely to increase substantially, the reality is that only a minority of patients referred with end-stage alcohol- induced cirrhosis will undergo transplantation, even if patients with obvious medical and psychiatric contraindications are excluded. The scarcity of organs avail- able for the remaining patients dictates that those who are likely to benefit most medically should be put forward, particularly in view of the evidence that severely ill Child’s grade C patients have the greatest improvement in survival after a transplant. Paradoxically, these patients have the most to lose from a compulsory period of abstinence pre-transplant, i.e. they may not survive the time.

To some extent each transplant centre will determine its own policy towards ALD patients, unless some form of health ‘rationing’ is imposed by central government. Evaluation of individual patients and post-operative psychological support both demand close co-operation between hepatologists and psychiatrists with an interest in addiction. Prospective long-term studies are needed to evaluate the optimal psychosocial assessment and post-transplant management of ALD patients as this is currently unclear. Early referral to transplant centres should be encour- aged, or at least the chance of assessment should not be denied. In reality, alcoholics will probably never ‘compete equally’ for liver transplantation, as suggested by Moss & Siegler (lo), but further studies are needed to clarify the medical selection criteria for transplantation in ALD. Only then can those patients who will benefit most be allocated the precious and limited resource of a donor liver.

References 1. NIH (1984) National Institute of Health Consensus Develop-

ment Conference statement. Liver transplantation - June 2% 23. Hepatology 1983; 4: 107S1OS.

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2. Starzl TE, van Thiel D, Tzakis AG, Iwatsuki S, Todo S, Marsh JW, Koneru B, Staschak S, Steiber A, Gordon RD. Orthotopic liver transplantation for alcoholic cirrhosis. JAMA 1988; 260: 25424.

3. Bird GLA, O’Grady JG, Harvey FH, Calne RY, Williams R. Liver transplantation in patients with alcoholic cirrhosis: selection criteria and rates of survival and relapse. Br Med J 1990; 301: 15-7.

4

5.

6.

7.

8.

9. 10.

11.

12.

13.

14.

15.

Kumar S, Stauber RE, Gavaler JS, Basista MH, Dindzans VJ, Schade RR, Rabinowitz M, Tarter RE, Gordon R, Starzl TE, van Thiel DH. Orthotopic liver transplantation for alcoholic liver disease. Hepatology 1990; 11: 159-64. Lucey MR, Merion RM, Henley KS, Campbell DA, Turcotte JG, Nostrant TT, Blow FC, Beresford TP Selection for and outcome of liver transplantation in alcoholic liver disease. Gastroenterology 1992; 102: 173641. Knechtle SJ, Fleming MF, Barry KL, Steen D, Pirsch JD, Hafez GR, D’Alessandro AM, Reed A, Sollinger HW, Kalay- oglu M, Belzer FO. Liver transplantation for alcoholic liver disease. Surgery 1992; 112: 694703. Sorrel1 MF, Donovan JP Shaw BW. Transplantation in the alcoholic: a stalking horse for a larger problem. Gastroenter- ology 1992; 102: 1806-8. Belle SH, Detre KM. Report from the Pitt-UNOS liver transplant registry. Transpl Proc 1993; 25: 1137-42. European Transplant Registry; 1989-1991. Moss AH, Siegler M. Should alcoholics compete equally for liver transplantation? JAMA 1991; 265: 1295-8. Goldstein R, Tripp L, Clemmons J, Husberg B, Gonwa TA, Potter D, Klintmalm G. Liver transplantation for alcoholic cirrhosis - do they mix? Transplant Proc 1993; 25: 1131-2. Doffoel M, Fratte S, Vanlemmens C, Boudjema K, Ellero B, Woehl-jaegle ML, Altieri M, Duclos B, Wolff P Vetter D, Mantion G, Jaeck D, Gillet M, Hillon P Miguet JP, Cinqual- bre J. Results of liver transplantation (LT) in 75 French patients with alcoholic cirrhosis (AC). Comparison with a non- alcoholic group [Abstract]. Hepatology 1992; 16: 50A18. Krom RA. Liver transplantation and alcohol: who should get transplants? Hepatology 1994; 20 Pt 2: 28S-32s. Osorio R, Freise C, Ascher N, Roberts J, Avery M, Lake JR. Orthotopic liver transplantation for end-stage alcoholic liver disease. Transplant Proc 1993; 25: 11334 Stevens L, Piper J, Emond T, Heffron A, Baker A, Broelsch C. Liver transplantation for controversial indications: alcoholic liver disease, hepatic cancers, and viral hepatitis. Transplant Proc 1991; 23: 19156.

16. Pageaux G, Souche B, Perney P Calvet B, Delande G, Fabre JM, Domergue J, Larrey D, Michel H. Results and cost of orthotopic liver transplantation for alcoholic cirrhosis. Transplant Proc 1993; 25: 1135-6.

17. Poynard T, Barthelemy P Fratte S, Boudjema K, Doffoel M, Vanlemmens C, Miguet JP Mantion G, Messner M, Launois B, Naveau S, Chaput JC, and a Multi-Centre Group. Evalu- ation of efficacy of liver transplantation in alcoholic cirrhosis by a case control study and simulated controls. Lancet 1994; 344: 502-7.

18. Lucey MR. Liver transplantation in alcoholic liver disease. In: Hayes PC, ed. Bailhere’s Clinical Gastroenterology: alcoholic liver disease. London; Bailliere Tindall, 1993: 717-28.

19. Beresford TP Turcotte JG, Merion R, Burtch G, Blow FC, Campbell D, Brower KJ, Coffman K, Lucey MR. A rational approach to liver transplantation for the alcoholic. Psycho- somatics 1990; 31: 241-54.


20. Howard L, Fahy T, Wong P, Sherman D, Gane E, Williams R. The psychiatric outcome of alcoholic liver transplant patients. Q J Med 1994; 87: 731-6.

21. Vaillant GE. What can long-term follow-up teach us about relapse and prevention of relapse in addiction? Br J Addict 1998; 83: 1147-57.

22. Cohen C, Benjamin M. Ethics and social impact committee of the transplant and health policy center, A. A., Michigan. Alcoholics and liver transplantation. JAMA 1991; 265: 1299- 301.

23. Flavin DK, Niven RG, Kelsey JE. Alcoholism and orthotopic liver transplantation. JAMA 1988; 259: 15467.

24. Neuberger JM. Transplantation for alcoholic liver disease. Br Med J 1989; 299: 6934.

25. Schenker S, Perkins HS, Sorrel1 ME Should patients with end-stage alcoholic liver disease have a new liver? Hepatology 1990; 11: 314-9.

26. Bonet H, Gavaler JS, Wright HI, Fagiuoli S, Gurakar A. The effect of continued alcohol use on allograft rejection fol-

lowing liver transplantation for alcoholic liver disease (Ab- stract). Gastroenterology 1993; 104 (4 Pt 2): A878.

27. Grant BF, Dufour MC, Harford TC. Epidemiology of alcoholic liver disease. Sem Liv Dis 1988; 8: 12-25.

28. Pequignot G, Tuyns AG, Berta JL. Ascitic cirrhosis in re- lation to alcohol consumption. Int J Epidemiol 1978; 7: 113- 20.

29. Sherman D, Williams R. Liver damage: mechanisms and management. Br Med Bull 1994; 50: 12438.

30. Theodossi A, Eddleston AWLF Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis. Gut 1982; 23: 75-9.

3 1. Mutimer D, Burra P Neuberger JM, Hubscher S, Buckels J, Mayer AD, McMaster P Elias E. Managing severe alcoholic hepatitis complicated by renal failure. QJM 1993; 86: 649- 56.

32. Davies M, Langman MJS, Elias E, Neuberger JM. Liver disease in a district hospital remote from a transplant centre: a study of admission and deaths. Gut 1992; 33: 1397-9.

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