Year: 2005
Type: review
Abstract: Liver transplantation (LT) has increasingly been accepted as the standard of care for patients with irreversible advanced liver disease. Due to an expanded list of diseases that are accepted as indications for transplantation, for example, specific criteria for hepatocellular carcinoma (HCC), coupled with a finite number of available organs, the national waiting list of patients has steadily grown. Nonetheless, the supply of donor organs has not kept pace, with currently 16% of patients dying on the waiting list without obtaining a transplant.1 This mortality rate has indicated a need to develop effective selection criteria for the more suitable candidates. Efforts to prepare patients so they are in the optimal state of physical and emotional health to adapt successfully after transplantation remain a priority. Recognizing the potential impact of psychiatric disorders, including addictions, on the liver transplant patient's outcome is essential. The aim of this article is to provide an overview the psychiatric disorders and issues with which the transplant hepatologist must be knowledgeable. In particular, this review evaluates how psychiatric and chemical dependency disorders may interfere with optimal adherence to recommended treatment and social support. In these complicated cases, psychiatric consultation can aid in the determination of the relative importance of a patient's psychiatric history and assist in preparing these individuals for transplantation. LT, liver transplantation; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ALD, alcoholic liver disease; MMT, methadone maintained; PTSD, posttraumatic stress disorder; SSRIs, selective serotonin reuptake inhibiting antidepressants. The objective of the pretransplant evaluation is to ensure that the patient is appropriate for transplantation. The current one- and five-year survival rates after liver transplantation over time has steadily increased to 86% and 72%, respectively.1 Nevertheless, patient compliance with immunosuppressive medication has been directly implicated in acute and chronic rejection episodes in organ transplant patients in general,2-4 with chronic rejection being the leading cause of graft loss for liver transplant recipients.5, 6 In fact for all types of organ transplants, noncompliance is responsible for up to 25% of late deaths posttransplant.2 Although there are no data indicating whether specific psychiatric disorders per se are associated with shorter life expectancy after transplantation, the potential impact of any disease process on survival is in large part amplified or tempered by the patient's success in adhering to treatment recommendations. Nonadherence encompasses many domains, including medication (particularly immunosuppressives), clinic appointments, laboratory tests, self-monitoring (blood pressure, glucose), exercise, and the use of harmful substances (alcohol and drugs).7 The LT literature has primarily focused on medication nonadherence. Medication nonadherence has been observed to be higher in patients with less satisfactory outcomes, for example, those relapsing with alcohol use.8 With advances in clinical research, more effective but often complex treatment plans are in use. Current management of hepatitis C virus (HCV) with interferon and ribavirin serves as an example. For instance, patients with recurrent HCV post-LT will require combination therapy that includes weekly self-administered injections, oral medication, and frequent weekly laboratory testing. Longer life expectancy and improved quality of life than in the past have been attributed to newer regimes of self-administered injections, oral medication, and frequent laboratory testing. Patients who cannot adhere to this program are at risk of increased morbidity and mortality. When a patient has previously demonstrated an inability to conform to the recommendations for one disease process, the possibility of nonadherence with the multifaceted lifelong treatment plan after LT is increased. Thus, how the candidate has adapted to illness and adhered to pre-LT medical directives should be evaluated (Table 2). Given the mortality rate among candidates waiting for LT, the rejection or loss of a transplanted liver due to nonadherence is a tragedy. Many factors contribute to nonadherence, including cognitive impairment, inability to communicate, rebelliousness, arrogance, denial of illness, lack of motivation, hopelessness, and inadequate social support. These traits are more frequently identified in patients with psychiatric or chemical dependency disorders. In a study of heart transplant recipients, Dew et al. described an increased risk of nonadherence depending on the number of psychosocial risk factors (Fig. 1).7 The following sections of this article, subdivided into major categories, will address the influence of a variety of psychiatric and addictive conditions on adherence. An increase of nonadherence is associated with an increased number of psychosocial risk factors in heart transplant recipients. Psychosocial factors include hostility, poor support from caregivers, poor support from friends, failure to use active coping strategies, and use of avoidant coping strategies. Adapted from Dew et al.7 The presence of an enduring social network is required to assist a patient who is otherwise compromised in achieving satisfactory survival and quality of life during the transplant process. The support persons should be capable of providing a combination of basic cares, transportation, medication verification as well as emotional sustenance during a challenging episode of care. Many transplant programs require the well-documented availability of more than one support person in case the identified person becomes unavailable. The primary sources of support are required to be closely involved from the initial stages of assessment, through hospitalization and the postoperative period. More institutions offer a supportive living environment, often called transplant houses, where patients can stay while pursuing medical care. However, since nursing care is not a service provided by these facilities, they mandate that a support person stay with the patient to provide assistance. The availability of a good social support system has been considered to be predictive of lower risk for recidivism and nonadherence, whereas poor or absent social support indicates high risk.9 Marriages and committed relationships have been reported to stay intact throughout the transplant experience.10 Patients who perceive themselves to have social support have been observed to have lower rates of depression.11 A study of diabetic patients undergoing pancreas transplantation found higher rates of social support was correlated with longer graft function.12 Support at the time of LT evaluation is essential for patients with cognitive impairment due to hepatic encephalopathy to comprehend and implement treatment interventions.9 The presence of enduring social support is less common in particular for patients with active personality disorders.13 Features of untreated depressive disorders include social withdrawal, helplessness, and irritability than can seriously strain marriages or committed relationships. Depressed patients can also become estranged from their family of origin and lack involvement in work, faith, or community organizations that can lead to supportive friends. Likewise, patients with active chemical dependency issues can become isolated from family or other networks that have become frustrated with the persistent nature of the patient's alcohol and drug use. Cognitive impairment related to hepatitic encephalopathy can result in unpredictable and provocative behavior that tests the patient's associates. Socially isolated individuals present to transplant programs without awareness that LT is an intensely demanding physical and emotional dependence making total self-sufficiency inadvisable. These patients expect that the transplant team and resources such as supportive transplant housing, where available, will suffice. As a result, transplant teams need to develop consistent guidelines and standards for assessing social support. Social workers and mental health professionals can provide guidance as to how a patient can identify new or enhanced sources of support. However, listing should be deferred until this support is clearly in place. Alcoholic liver disease (ALD) is one of the most common types of liver disease in the U.S. and is more common in males (up to 75% of ALD cases).14 Individuals with end-stage alcoholic liver disease account for 15-27% of LT recipients, making ALD the second most common reason for liver transplantation.1, 15 While more than 12,000 individuals died from alcohol-related chronic liver disease in 2001,14 in that same year less than 900 individuals received a liver transplant for ALD.1 These numbers demonstrate that a substantial proportion of patients with ALD never come to transplantation. This suggests that strong biases still exist in referring such patients for transplantation. Assessment and referral by hepatologists knowledgeable of transplantation could significantly improve this deficiency. While the histopathological stages of ALD are well established, the amount of alcohol consumption necessary to develop the lesion are quite variable and no specific amount reliably predicts the development of ALD. Estimations of the threshold amount of ethanol exposure required to cause ALD have been reported both as a habitual intake (80 gm/day for men and 20 gm/day for women)16 and as a lifetime exposure (600 kg for men and 150-300 kg for women).17 Yet only 20% of those who drank 12 beers (approximately 120 gm) daily for 10 years (approximately 450 kg lifetime exposure) become cirrhotic.16 Thus, only some who drink excessively develop cirrhosis while others who report drinking modestly may develop ALD. Nevertheless ALD typically results from 10 to 20 years of heavy, sustained alcohol consumption. Given this requisite consumption pattern, patients with ALD are commonly referred to as "alcohol abusers." Unfortunately, the terms "alcoholism" and "alcohol abuse" are often misused in the literature. Clear diagnostic criteria exist for alcohol use disorders (both alcohol abuse and alcohol dependence), yet these diagnoses are not commonly reported in the transplant literature most likely because nonpsychiatric physicians are unfamiliar with them. The correct diagnosis of an alcohol use disorder depends on stringent criteria, including physiological, psychological, social, occupational, behavioral, and duration criteria (see Table 1 for criteria of alcohol dependence, the more severe form of these disorders). In general, only 75% of those transplanted for ALD meet psychiatric diagnostic criteria for alcohol dependence.18, 19 A thorough psychiatric assessment can help to gather a comprehensive history of alcohol use and associated problems as well as establish the correct alcohol disorder diagnosis and identify whether addiction treatment is indicated. This is especially important as patients may feel compelled to underreport or minimize their history in order to be accepted as a transplant candidate.20 Although >80% of liver transplant programs have a psychiatrist or addiction medicine specialist routinely see each patient with ALD,21 it is critical for the transplant hepatologist to understand the distinction between ALD and the diagnostic criteria for alcohol use disorders. This has clinical relevance for both treatment recommendations and posttransplant relapse as discussed below. Transplant centers across the nation have very different selection criteria for patients with ALD. Many centers mandate a period of sustained sobriety (commonly defined as ≥6 months sober), adequate and available sober social supports, and previous addiction rehabilitation in order for patients with ALD to be considered as transplant candidates. Although selection criteria are increasingly challenged, a 1992 survey of 14 transplant centers across the nation highlights the enormous range in criteria with one center willing to consider patients with ALD drinking until transplantation, whereas other centers categorically refused all ALD candidates with <6 months' sobriety.22 However, most programs required those with <6 months' sobriety to attend rehabilitation before transplantation and could be considered, and no center would categorically reject a candidate with >6 months' but <1 year's sobriety.22 A 1993 survey of the selection practices of 41 transplant programs around the U.S. showed that current heavy alcohol use (80% of programs) and alcohol abuse within the past 6 months (24% of programs) were viewed as absolute contraindications to transplantation.23 Interestingly, at that time, no LT program felt current tobacco use was an absolute contraindication to liver transplantation23 (see tobacco use below). The belief that a specific length of pre-LT sobriety will guarantee post-LT sobriety is misguided. Alcohol use disorders are chronic medical illnesses often with a relapsing-remitting course. As with any chronic illness, treatment planning should focus on long-term treatment and monitoring. In addition, merely meeting a predetermined length of sobriety, especially in the context of end-stage liver disease, does not mean that an addiction is in remission or that addiction rehabilitation is not needed. For alcohol-dependent patients (not specifically LT patients), stable sobriety is measured in years, not months, with 5 years indicating stable sobriety.24 Thus, the use of a 6-month sobriety requirement for liver transplantation candidacy has most likely been necessitated by the end-stage illness of some ALD candidates at initial presentation who would not survive to achieve longer sobriety. For candidates with short sobriety, addiction counseling is highly recommended to provide education about addictions and the therapeutic tools to maintain abstinence. Addiction counseling can be beneficial at any point during abstinence, yet many ALD LT candidates have had no formal alcohol treatment or ever attended an Alcoholics Anonymous (AA) meeting (<50% at some centers).18, 25 Periodic reassessment of alcohol use is critical during the pretransplant wait period, as relapse rates up to 25% have been reported in wait-listed ADL candidates.26, 27 After transplantation, ALD recipients must be routinely reassessed for any alcohol use and commitment to sobriety with referral for addiction counseling if alcohol use has occurred. Inquiries about any alcohol consumption should be made at each follow-up appointment, and occasional or holiday drinking should not be taken lightly. Complete abstinence is recommended, as few ALD LT recipients can control their drinking or return to "social use",8 and those who drink can quickly redevelop alcohol dependence.28 Even the use of nonalcoholic beers and wines is strongly discouraged because patients may relapse to regular alcohol from exposure to these drinks. In addition, routine monitoring for blood alcohol can aid in the detection of covert alcohol use. The majority of published studies of ALD LT recipients have defined post-LT alcohol use as any use. However, such a definition does not specifically identify an alcohol relapse or provide the ability to determine the contribution of alcohol exposure to medical outcomes. Since alcohol use can occur in a great variety of patterns, a well-designed study should evaluate the quantity, frequency, and duration of use. In addition, of the 21 studies of post-LT alcohol published since 1990, only three have a prospective design.29 Given these limitations, the reported one-year post-LT rate of any alcohol use (i.e., the percentage who used any alcohol by one year post-LT) ranges from 8% to 22%.30 By 5 years after LT, the rates of cumulative alcohol use are estimated from 30% to 50%.31, 32 Although these rates may seem discouraging, they compare favorably with the general population of alcohol-dependent individuals for whom two-year relapse rates of 60% to 80% are common following alcohol treatment.24 In addition, many LT recipients who relapse can be successfully treated in alcohol rehabilitation and do not continue sustained heavy levels of alcohol use. Thus, the rates of alcohol use that result in severe medical complications are estimated at 10% to 15%.33-35 Individual cases and small cohorts have reported the post-LT redevelopment of alcoholic liver disease including steatosis,36-38 histologic changes consistent with alcoholic steatohepatitis,36, 39, 40 and even alcohol-induced fibrosis.39-42 In some reports, pathologic changes are identified as early as 6 to 7 months post-LT.40, 42 In one report, 3 of 6 patients who resumed heavy alcohol use post-LT died from acute alcoholic hepatitis.43 A recent retrospective study of 128 ALD LT recipients stratified their post-LT alcohol consumption into three groups: complete abstainers (69%), occasional drinkers (<14 units/week, 10%), and heavy drinkers (>14 units/week or period of time with >4 units/day, 21%). Surprisingly, there were no differences in survival between the three groups at 8 years post-LT.44 However, alcohol use did contribute to nearly 15% of deaths in the heaviest drinkers.44 In addition, although rejection rates were not different between groups, all rejection episodes in the heavy drinkers were related to poor compliance with immunosuppressive drugs.44 In 81 patients who had liver biopsies, the heavy drinkers had significantly more fatty changes and fibrosis, and 14% had evidence of acute alcoholic hepatitis.44 Those who drank alcohol were significantly more likely also to smoke post-LT (P = 0.02), and although there were no differences between groups with respect to de novo malignancies, all of the oropharyngeal squamous cell carcinomas were in smokers. Given the complexities of the psychological, behavioral, and physiological antecedents to alcohol relapse, it is unlikely that a single pretransplant variable will reliably predict alcohol use. Studies have identified a number of factors predictive of pre-LT alcohol use, including a diagnosis of alcohol dependence,32 short pre-LT sobriety,32 a history of polysubstance use,33, 45, 46 a family history of alcoholism,32, 33, 47 previous addiction rehabilitation,32, 33, 45 and personality disorders.48, 49 Although length of sobriety predicts risk for alcohol use post-LT, <6 months' pre-LT sobriety has not consistently predicted those at risk to drink.8, 33 In one analysis, as the number of risk factors for alcohol use increased, so did the risk of relapse, suggesting that as predictors cumulate the risk to drink rises.28 Hepatitis C is the most common indication for liver transplantation in the U.S., accounting for nearly 2,000 liver transplants in 2004 (including those with co-morbid hepatitis B or alcoholic liver disease).1 The number of new infections with HCV in the U.S. has declined to about 30,000 with the majority of these infections incurred from illegally injected drug use.14 An estimated 2.7 million Americans are chronically infected with HCV, and 70% of these will develop chronic liver disease.14 Surprisingly little research has addressed the risks associated with or drug abuse in alcohol use has the of risks with addictive because the of alcohol has for hepatic In recent the high rate of drug abuse with alcohol abuse has to any study that on patients who abuse Nonetheless, as described abuse or dependence are important that have been implicated as predictors of relapse with alcohol after all drug use example, the same of risk Nonetheless, many transplant programs require abstinence from all drug use in chemical dependency and drug to adherence. challenging is a patient who including and These patients use at a higher or for an indication (i.e., for or that from the standard of care. the definition of appropriate or use in these cases is These patients and their physicians feel that their use of these substances is to or to have the of drug abuse or dependence in LT Likewise, little data exist on how to use of When evidence indicating a patient alcohol in to many LT programs that a candidate in chemical dependency directly these programs potential drug abuse depends on the of the medical or psychiatric disorder the of and the of the treatment programs that patients long-term for management be to With use of oral in the U.S. for chronic a great need to develop effective for and this of LT candidates. practices for patients of include to from one to use a single and to to be by a psychiatrist or addiction In addition, a clinic may provide this and control over and as well as providing for programs have been a primary management in the U.S. for individuals with and LT which is demonstrated by a recent survey that only of U.S. LT programs would even consider such a patient for transplant Even more was the to such patients lack of clinical with A of these programs required patients to their methadone use to transplantation, while only 10% had with more than 5 such In the general not LT there is substantial evidence that methadone in stable can result in relapse to use in up to 80% of candidates to methadone during a time they are with the and of end-stage liver disease and transplantation could increase their risk for relapse they would not be for transplantation. In many programs are highly providing to addiction counseling and patients to come a for methadone and maintain such a high of compliance on the part and can be viewed as evidence of good adherence with medical In addition, in LT recipients have been the LT recipients on MMT, relapse to use of was reported in of While of patients had adherence with immunosuppressive this rate is not different from rates of nonadherence in the general transplant In addition, the transplant programs did not feel the nonadherence outcomes, and the transplant were that only 7 of patients had small of LT recipients at a single center = showed long-term patient and graft survival to other LT recipients, with of the patients posttransplant noncompliance or drug In a = of LT recipients at a single patient and graft survival were to national and only patients reported isolated episodes of use post-LT that were not considered to have in patients should not be to liver transplantation. Those who are stable in an program on adequate of methadone and have social support with objective evidence of good treatment compliance should be considered for However, to maintain of care and of the LT between a of the transplant team and treatment from the patient's methadone clinic cannot be the health of tobacco use, the consumption of tobacco by LT patients has been until A recent survey of LT recipients at a single center of potential found 15% post-LT with the majority <1 of A prospective study of post-LT ALD recipients found tobacco across time up to three years post-LT, with An used with the majority studies the between tobacco use and post-LT have the contribution of pre-LT tobacco use to post-LT medical outcomes. For example, found a higher rate of complications in recipients with a pre-LT history of = However, they also found a beneficial of pre-LT as patients who years to transplantation had a of et al. found an increased rate of late deaths years and in ALD LT recipients with deaths that were primarily by and oropharyngeal and were to be associated with tobacco use. In addition, their rates of and oropharyngeal were and 25 than the general The specific of increased risk are to be due to a system that does not to and coupled with to tobacco and In a heart transplant had higher rates of and and significantly survival with When patients were to levels of tobacco no patient with a higher than of a after years study has been in LT recipients. disorders are common in the LT due to hepatic encephalopathy and other factors has been reported in of by the medical as with respect to nonadherence, is because it may a patient's of the transplant process. The rate of depressive in cirrhosis is reported to be as high as also reported that patients with high on the a common were at increased risk of a poor As a result, referral to of patients with to severe depressive in particular is recommended to Depressed patients typically have more physical quality of and compromised can treatment of in Although not specifically in the LT patients may for they are on the to their or The presence of a disorder is not a contraindication to selection as a LT candidate since effective treatment exist (see and effective for is to improve outcomes. Patients who have from a disorder are more likely to an active in With treatment of nonadherence that was related to or a of may In most cases, disorders, including and are to disorders where and for LT candidates is Patients with a history of or need before the selection process can Patients who have acute hepatic failure as a result of drug or in combination with of cases in one need a thorough psychosocial Unfortunately, the nature of hepatic failure for patients who on often that psychiatric must be In some cases, the patient may require which the for an In these cases, data must be from all
Source: Liver Transplantation
DOI: 10.1002/lt.20578
Authors: Lois E. Krahn, Andrea DiMartini
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2023193852