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.
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.
Ability to form working alliance with liver transplantation team
Ability to detect and report on emotional/physical symptoms
Current living situation
Quality and strength of supports
Availability of transportation—both for scheduled appointments and emergencies
Ability of support to develop working alliance with liver transplantation team
Ability of support to detect and report on patient's symptoms
Financial resources (including medical insurance)
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.
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.
Alcoholic Liver Disease Vs. Alcohol Dependence
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
Table 1. DSM-IV Alcohol and Substance Dependence Criteria (Three or More Factors Recurring Within a 12-Month Period)*
Abbreviation: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-IV.
An individual can meet alcohol-dependence criteria without having physiological dependence (tolerance or withdrawal).
Tolerance to substance
Larger amounts over a longer time than intended
Persistent desire or unsuccessful efforts to cut down
Excessive time spent using the substance
Important activities given up or reduced due to substance use
Substance use continues despite knowledge of a physical or psychological problem
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.
Criteria for Transplant Listing
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).
Alcohol Dependence as a Chronic Medical Illness
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.
Alcohol Use After Transplantation for ALD
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
Medical Consequences of Alcohol Use Post-LT
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.
Predictors of Alcohol Use Post-LT
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 street or prescription drug abuse in LT. Conceivably, alcohol use has dominated the examination of risks linked with addictive behaviors because the metabolic pathway of alcohol has direct consequences for hepatic tissue. In recent decades, the high rate of drug abuse coexisting with alcohol abuse presumably has created logistical challenges to any study that focuses on patients who exclusively abuse drugs. Nonetheless, as described earlier, substance abuse or dependence are important variables that have been implicated as predictors of relapse with alcohol after LT.33 Whether all street drug use (for example, marijuana vs. methamphetamine abuse) conveys the same degree of risk remains unclear. Nonetheless, many transplant programs require abstinence from all street drug use in chemical dependency contracts and utilize random drug screening to verify adherence.
One challenging area is a patient who abuses prescription medications, including opioids, benzodiazepines, and stimulants. These patients use medications at a higher dose or for an unusual indication (i.e., opioids for anxiety or sleep) that deviates from the standard of care. Reaching consensus regarding the definition of appropriate or excessive use in these cases is difficult. These patients and sometimes their prescribing physicians feel that their use of these substances is justified to treat pain, sleep, anxiety, or attention deficit disorder. No surveys to date have examined the prevalence of prescription drug abuse or dependence in LT populations. Likewise, little data exist on how best to manage problematic use of prescription medications. When evidence exists indicating a patient abuses alcohol and/or street drugs in addition to prescription agents, many LT programs stipulate that a candidate engage in chemical dependency treatment. How directly these programs confront potential prescription drug abuse depends on the documentation of the medical or psychiatric disorder warranting treatment, the option of nonhabituating alternatives, and the philosophy of the treatment program. Some programs request that patients requiring long-term uploads for pain management be converted to methadone. With increasing use of longer-acting, high-potency oral opioids in the U.S. for chronic pain, a great need exists to develop effective protocols for identifying and managing this subset of LT candidates. Best practices for patients suspected of abusing prescription medications include requiring them to obtain controlled agents from one prescriber only, to use a single pharmacy, and to agree to be followed by a psychiatrist or addiction specialist. In addition, a pain-management clinic may provide this structure and regimented control over opioid dispensing and monitoring, as well as providing nonpharmacologic treatments for pain.
Methadone Maintained Candidates
Methadone maintenance programs have been a primary management option in the U.S. for individuals with heroin addiction. Significant disagreement and controversy surrounds methadone-maintained (MMT) LT candidates, which is demonstrated by a recent survey showing that only 56% of U.S. LT programs would even consider such a patient for transplant evaluation.50 Even more concerning was the approach to such patients despite lack of clinical experience with MMT patients. A surprising 32% of these programs required patients to discontinue their methadone use prior to transplantation, while only 10% had experience with more than 5 such patients.50 In the general MMT population, not LT candidates, there is substantial evidence demonstrating that tapering methadone in stable methadone-maintained opioid addicts can result in relapse to illicit opiate use in up to 80% of patients.51 Requesting MMT candidates to taper off methadone during a time when they are dealing with the stresses and pain of end-stage liver disease and facing transplantation could increase their risk for relapse. If relapse occurred, they would not be eligible for transplantation. In fact, many MMT programs are highly structured, providing access to addiction counseling and requiring patients to come several times a week for methadone and perform random toxicological screening. To maintain such participation demonstrates a high degree of compliance on the MMT patients' part and can be viewed as evidence of good adherence with medical directives.
In addition, outcomes in MMT LT recipients have been good. Of the approximately 180 LT recipients on MMT, relapse to use of illicit opiates was reported in <10% of patients.50 While approximately 26% of MMT patients had adherence difficulties with immunosuppressive medications,50 this rate is not different from rates of nonadherence in the general transplant population. In addition, the transplant programs did not feel the nonadherence necessarily affected outcomes, and the transplant coordinator's impressions were that only 7 of 180 patients had worse outcomes.50 One small series of MMT LT recipients at a single center (n = 5) showed overall long-term patient and graft survival comparable to other LT recipients, with none of the MMT patients evidencing posttransplant noncompliance or illicit drug use.52 In a larger cohort (n = 36) of MMT LT recipients at a single center, patient and graft survival were comparable to national averages, and only 4 patients (11%) reported isolated episodes of heroin use post-LT that were not considered to have resulted in poorer outcomes.53
MMT patients should not be denied access to liver transplantation. Those who are stable in an MMT program on adequate doses of methadone and have excellent social support combined with objective evidence of good treatment compliance should be considered for LT. However, to maintain continuity of care and continued stability of the MMT LT patient, close coordination between a member of the transplant team and treatment personnel from the patient's methadone clinic cannot be overemphasized.
Despite the well-established negative health consequences of tobacco use, the consumption of tobacco products by LT patients has been surprisingly ignored until recently. A recent cross-sectional telephone survey of LT recipients at a single center (42% of potential subjects) found 15% smoking post-LT with the majority smoking <1 pack of cigarettes/day.54 A prospective study of post-LT ALD recipients found 39-58% using tobacco across time points up to three years post-LT, with 90% smoking daily.55 An additional 5% used smokeless tobacco, with the majority chewing daily.
Most studies investigating the association between tobacco use and post-LT outcomes have assessed the contribution of pre-LT tobacco use to post-LT medical outcomes. For example, Pungpapong found a higher rate of vascular complications in recipients with a pre-LT history of smoking (17.8% vs. 8%, P = 0.02).56 However, they also found a significant beneficial effect of pre-LT smoking cessation, as patients who quit smoking two years prior to transplantation had a 58% reduced incidence of vascular complications.56
Jain et al. found an increased rate of late deaths (5 years and beyond) in ALD LT recipients compared with others, deaths that were primarily caused by lung and oropharyngeal cancers57 and were presumed to be associated with tobacco use. In addition, their rates of lung cancer and oropharyngeal cancers were 4 and 25 times higher, respectively, than the general nontransplanted population.57 The specific causes of increased risk are hypothesized to be due to a suppressed immune system that does not react normally to carcinogens and precancerous cells coupled with ongoing exposures to carcinogens (e.g., tobacco and possibly alcohol).
In a heart transplant cohort, smokers had higher rates of vasculopathy and malignancies (mostly lung) and significantly worse survival compared with nonsmokers. When patients were grouped according to carboxy-hemoglobin levels (a biologic marker of tobacco exposure), no patient with a level higher than 2.5% (average of 11 cigarettes a day) survived after 4 years posttransplant.58 No comparable study has been performed in LT recipients.
Coexisting Psychiatric Disorders
Psychiatric disorders are common in the LT population. Delirium due to hepatic encephalopathy and other factors has been reported in 56% of candidates.9 Typically best managed by optimizing the underlying medical disorder, as mentioned earlier with respect to nonadherence, delirium is significant because it may limit a patient's understanding of the transplant process.
Pretransplant Psychiatric Disorders
The rate of significant depressive symptoms in cirrhosis is reported to be as high as 63%.59 Singh also reported that patients with high scores on the Beck Depression Inventory, a common rating scale, were at increased risk of a poor outcome. As a result, prompt referral to psychiatry of patients with moderate to severe depressive symptoms in particular is recommended to facilitate treatment. Depressed patients typically have more physical complaints, reduced quality of life, and compromised coping. Depressive symptoms can complicate treatment of pain in particular. Although not specifically studied in the LT population, undertreated depressed patients may request dose escalation for pain relief when they actually are relying on the opioids to modify their mood or anxiety.60 The presence of a mood disorder is not a contraindication to selection as a LT candidate since effective treatment options exist (see prescription guidelines). Prompt recognition and effective intervention for depression is thought to improve outcomes. Patients who have recovered from a mood disorder are more likely to play an active role in healthcare. With treatment of depression, nonadherence that was related to helplessness or a sense of futility may improve. In most cases, anxiety disorders, including generalized anxiety and panic disorder, are similar to mood disorders where prompt recognition and intervention for LT candidates is desirable.
Patients with a history of suicidal ideation, plans, or attempts need intervention before the selection process can proceed. Patients who have developed acute hepatic failure as a result of drug hepatotoxicity, acetaminophen alone, or in combination with another drug, comprising 49% of cases in one series,61 need a thorough psychosocial evaluation.62 Unfortunately, the rapidly progressive nature of hepatic failure for patients who overdosed on acetaminophen often means that psychiatric assessments must be conducted emergently. In some cases, the patient may require mechanical ventilation, which compromises the opportunity for an in-depth interview. In these cases, data must be collected from all available sources including caregivers and family members. In many cases, the decision to proceed with transplantation on an emergency basis is determined by history. Many transplant teams are more comfortable listing a patient when the overdose appears to be an isolated, impulsive act precipitated by a specific loss or stressful event rather than a recurring pattern of self-destructive behavior in the context of a treatment refractory alcohol, personality, or mood disorder.23
Suitability of patients with a major mental illness is more controversial. In general, a patient with schizophrenia, schizoaffective disorder, bipolar disorder, or a severe personality disorder should not be automatically discounted because of their psychiatric illness. Several studies have reported successful outcome in carefully selected patients with schizophrenia following liver63 and kidney transplantation.64 Coffman published a case series summarizing the experience of several transplant psychiatrists with patients with a primary psychotic disorder.65 In essence, the critical issues are whether the patient's psychiatric disorder has been stabilized, whether they adhere to medical and psychiatric follow-up, and whether they have an appropriate level of stable social support.
Personality disorders are recognized to have a high prevalence rate in patients with chemical dependency issues. In alcoholics, antisocial personality disorder has been described as the most common and consistently present in alcoholic patients who relapse after transplantation.9 Yates conducted a study of 73 candidates with ALD and personality disorder of which 27% had a severe personality disorder.66 Severe personality disorder was associated with higher rates of divorce, more drug abuse, lower IQ, and more emotional impairment. Of this sample, 29 subjects were listed for LT (40%). The three subjects (5%) who received a liver transplant did well and did not have a higher rate of relapse with alcohol. At times personality disorders can be difficult to diagnose unless the examiner has longitudinal contact with the patient. When deciding how much weight to place on a personality disorder in the context of the decision to list for LT, the candidate's ability to work with the transplant team, patterns of nonadherence, and quality of social support should all be considered.
Posttransplant Psychiatric Disorders
The literature on LT recipients developing psychiatric disorders is limited. Overall, there is agreement that many psychiatric conditions are recurrent; for example, bipolar disorder patients have repeated episodes of mania or depression throughout their lifetimes unless treated. When a preoperative psychiatric disorder is detected, the psychiatrist or psychologist should be asked to recommend appropriate monitoring, follow-up, and potentially maintenance treatment after transplantation.
Rothenhauser examined a cohort of 75 patients who had undergone orthotropic LT a median of 3.8 years earlier. They observed that 23% of patients at the time of follow-up had a psychiatric disorder, which was consistent with the 18% and 27% rates found in earlier studies using different methodology.67–69 Of note, the rate of psychiatric morbidity in the general population is in the same range. Rothenhauser reported LT-related full posttraumatic stress disorder (PTSD) (5.3%) and partial PTSD (17.3%). Patients with PTSD had longer duration in the ICU, more medical complications, and the occurrence of acute rejection. The concern was raised that patients with this condition may have increased nonadherence and avoid medical care. Of the patients with PTSD, 50% had coexisting major depression. The recommended approach is periodic screening of post-LT patients for emotional distress and provide appropriate treatment with psychotherapy or medications.
The safe prescription of psychotropic medications in LT candidates or recipients merits consultation with a psychiatrist knowledgeable of the pharmacokinetic changes resulting from end-stage liver disease and the drug-drug interactions with immunosuppressive medications.
Medications for Preventing Relapse With Alcohol
Patients with alcohol-use disorders who drink alcohol pre- or posttransplantation will benefit most from a thorough assessment and treatment by addiction specialists. The use of medications in this population should only be considered in consultation with a psychiatrist to avoid the misuse by the patient of other medications (e.g., benzodiazepines). In addition, other medications designed to reduce cravings and potentially diminish relapse risk for alcohol (e.g., acamprosate, ondansetron, or naltrexone) or opioids (naltrexone) have not been evaluated in transplant patients. The only published study of naltrexone prescribed for actively alcohol-relapsing LT recipients found patients were reluctant to use naltrexone due to its potential, albeit small, risk of hepatotoxicity.25 In addition, a case report of a liver transplant recipient who was prescribed naltrexone to prevent alcohol relapse reported that the patient developed a significant pain syndrome believed to be an unmasking or exacerbation of chronic pain.70 Naltrexone is not recommended for patients with active hepatitis or liver failure and can be a direct hepatotoxin at dosages higher than recommended (≥300 mg/day); however, there are no reports of naltrexone-induced liver failure and amino transferase elevations if caused by naltrexone reverse on discontinuation.70 Acamprosate has been demonstrated to reduce cravings and alcohol consumption in relapsing nontransplant populations.71 Since acamprosate is renally excreted and not hepatically metabolized, it may be useful for patients with liver insufficiency without concomitant renal insufficiency. Disulfiram (Antabuse) is not recommended in transplant populations because it blocks the oxidation of alcohol at the acetaldehyde stage and can create severe nausea, vomiting, and hemodynamic instability. In addition, a metabolite of disulfiram is an inhibitor of CYP450 3A472 and may cause immunosuppressive medication toxicity in transplant recipients.
Since many tobacco users resume use post-LT, the cessation of tobacco use (both smoked and smokeless) is highly recommended prior to transplantation and has become a requirement of transplant listing at some LT programs. Treatments for smoking cessation include behavioral therapies augmented with bupropion and/or nicotine replacement (patches, gum, lozenges, and aerosolized/inhaled).73, 74 Due to the small risk of seizures (1%), bupropion should not be used in patients with a history of seizures and should be more carefully considered in transplant recipients who are already at increased risk of seizure from immunosuppressive medications, especially early posttransplant when immunosuppressive levels are higher.
Selective serotonin reuptake inhibiting antidepressants (SSRIs) are often used in LT candidates and recipients due to their minimal side effects profile, once-a-day dosing, and few drug-drug interactions. Fluoxetine (Prozac) is an exception being a strong inhibitor of CYP4503A4 that can potentially cause immunosuppressive medication toxicity. A recent review of the literature identified a potential increased risk of bleeding for patients on SSRIs (specifically but not exclusively upper gastrointestinal bleeds), and these medications were not recommended in the context of portal hypertension or cirrhosis.75 In addition, medications that could promote spontaneous bleeding (e.g., aspirin, nonsteroidal antiinflammatory drugs) also were not recommended in combination with SSRIs.75 This is especially important in the population of LT recipients on interferon for whom SSRIs are often used to treat depressive symptoms resulting as a side effect of interferon therapy. The authors recommended caution when using SSRIs in this context.75
The evaluation of the transplant candidate seeks to identify the factors that place the patient at higher risk for diminished posttransplantation life expectancy or quality of life. Whether the evaluation is completed by a psychiatrist, psychologist, advanced practice nurse, or social worker depends on the experience of the provider and their ability to work with the transplant selection committee and the institution.76 The evaluation at minimum needs to screen for the issues listed in Table 2 and on a case-by-case basis consider the relative contraindications listed in Table 3. According to the United Network for Organ Sharing (UNOS), there are not any absolute contraindications of a psychiatric nature.1 However, the presence of one or more of these features should prompt the selection committee to carefully consider this patient's eligibility.
Table 3. Relative Psychiatric Contraindications to Liver Transplantation (Especially if Intervention Has Been Attempted and Was Unsuccessful)
Ongoing non-adherence with treatment plans
Inadequate social support
Current alcohol or other substance use
Ongoing suicidal ideation or self-destructive behaviors
Primary psychotic disorders
Factitious behavior with physical symptoms (patient motivated to be ill)
Irreversible severe cognitive impairment (particularly in the context of inadequate social support)
Inability to collaborate effectively with the transplant treatment team
Furthermore, the patient's behavior during the evaluation is a valuable indicator of ability to collaborate with the treatment team and adhere to treatment recommendations.9 When a patient misses an excessive number of appointments, refuses to sign an abstinence contract, or has interpersonal conflicts with multiple team members, these observations can be taken as signs of persistent challenging behaviors that may put the patient at higher risk for an unsatisfactory outcome.
Patients presenting in an emergency situation with less than one week expected survival need decisions to be made based the available historical data without any opportunity for additional chemical dependence or psychiatric treatment. Depending on the circumstances, listing can be contingent upon successful completion of treatment or a patient deferred and reevaluated at a future date. This is a controversial area. Psychosocial factors need to be used as much as possible to help with the decision, especially when the patient cannot be interviewed due to coma.
Treatment recommendations should be well documented and clearly communicated to the patient and his support person. Several authors advocate the use of a written contract presumably to improve compliance and reduce ambiguity.9, 77 This step avoids future scenarios where a patient maintains that he did not realize that listing for transplant was contingent on successfully completing treatment. Especially for patients with recurrent disorders such as alcohol or opioid dependence, a relapse prevention program should be required. Depending on the patient's circumstances, ongoing participation in 12-step recovery programs, individual therapy, medication, or random urine/blood screening should be stipulated. This behavior demonstrates a propensity not to comply with the transplant team's recommendations that mandates reassessment of the candidate's readiness for transplantation in a periodic fashion.
Living Donor Evaluations
Since 1998, the emergence of adult living liver donation presents new challenges in the psychosocial realm. Consensus exists that the standards used for recipients by LT selection committees should not be different. A candidate must go through a similar selection process and be viewed as an acceptable recipient for a cadaveric organ before being listed.1 However, once a candidate is listed, the selection team can evaluate family members and friends who are offering to donate a portion of their liver. Whether a particular transplant program will accept donors who lack a preexisting relationship with the candidate varies.
The psychosocial evaluation of the donor is the most critical part of any living liver donor program. Whenever a person agrees to undergo elective surgery from which his medical condition will not improve but faces a risk of death, a careful assessment of the donor is warranted. Coercion and financial incentives are not considered acceptable. Individuals who have been physically or sexually abused may have personality structures that predispose them to being subtly coerced by family members or friends. Nonetheless, because of the very nature of these pressures, donors may be reticent to reveal these factors. An evaluator must interview the donor without the candidate or family members present to have the best chance of detecting questionable circumstances. In particular, younger adults, who while most likely to be in good physical health, should be closely assessed to determine that they have the maturity to decide whether they wish to put themselves at risk to assist a sibling, parent, or other potentially influential person.
Prospective donors must have a thorough understanding of the risks inherent in hepatic lobectomy. Without a comprehensive discussion of the potential adverse medical and psychological outcomes, a donor cannot make an informed decision without knowing the risks. One option is to schedule the psychosocial evaluation after discussion with the surgeons and patient education sessions. This allows the psychiatrist or other evaluator to verify that the patient both comprehends the possible risks and has factored these into the decision to proceed. Another approach is to have the psychosocial evaluation take place earlier in the sequence of the donor evaluation, allowing earlier detection of concerning psychiatric or chemical dependency issues. However, a team member who has not worked with the potential recipient must assess the donor's ability to make a decision that takes into account the appropriate risks. To avoid conflict of interest, the medical and psychosocial team members working with the donor should recognize that they are the donor's advocates. They must promote the welfare of the donor insulated from the needs of the transplant candidate.
In addition to coercion and lack of capacity to make an informed decision, there is less agreement as to what psychosocial factors predict successful living liver donation. Although the episode of recovery for a donor is expected to be time limited and not require long-term collaboration with a treatment plan, in general, adherence and adequate social support remain necessary. Since the donor is not in a life-threatening situation, arguably, the standards for donor selection in the case of problematic alcohol use or poor social support, if anything, should be higher. Meriting special attention are patients who seem very eager to undergo invasive tests and surgery. If a donor has expectations that donating a hepatic lobe will alter his relationship with the recipient, family, or community, these beliefs need to be as well understood as possible. Conceivably, patients with features suggestive of factitious disorder (also called Munchausen's or polysurgical syndrome) could be willing to take on the patient role to realize their unconscious dependency needs. These individuals could be expected to have a more prolonged recovery before returning to their presurgical functioning. Objective measures of the motivating psychological issues that are less psychologically healthy are lacking, making it impossible to reliably predict donors at risk for poor coping perioperatively.
The presence of an undertreated mood or anxiety disorder pre-donation may complicate recovery or pain management in a fashion similar to the LT recipient. Psychiatric disorders may develop in donors during the postoperative period. A Japanese study reported a 3% rate, all cases of major depression, within one year of donation. These authors speculate that any inability to openly express feelings, a trait common in Japanese culture, may contribute to the development of postoperative psychiatric disorders for donors.78 This study reported a higher rate of post-LT psychiatric disorders (34%) in the 31 recipients that they attribute to the same process. The most frequent psychiatric disorders in LT recipients were postoperative delirium (n = 6), mood disorders (n = 9), and PTSD (n = 2). The donors and recipients at risk did not have higher rates of medical complications. The author suggests a thorough psychiatric assessment of both donors and recipients looking carefully for unexpressed emotional distress.
In the United States, more than 50% of LT candidates have alcohol dependence and psychiatric disorders.79 To date, the outcomes of these patients are generally good, indicating that including these subpopulations is advisable. What remains unclear is the necessary degree of rigor regarding screening processes, definitions of high-risk behaviors, and consensus regarding successful intervention. No truly randomized clinical trials have been conducted examining the effectiveness of screening or treatment methodology for psychiatric factors. Using a control group is viewed as unethical since the UNOS standard of care requires a psychosocial assessment of all patients who are transplant candidates. The shortage of available organs and reality that many transplant candidates die of liver disease while waiting ironically make randomized studies impossible. Yet these circumstances indicate a critical need for continuing efforts to improve psychosocial methodology so that patients undergo this life-saving procedure at the point when they have the best prospects for long-term survival.