Towards Standardizing the Alcoholism Evaluation Of Potential Liver Transplant Recipients

Towards Standardizing the Alcoholism Evaluation Of Potential Liver Transplant Recipients Abstract Aims For teams around the world, alcoholic liver disease patients comprise the largest, and clinically most controversial, group applying for liver transplant. And yet evaluation decisions for them remain highly variable by locale. Methods Targeting standardized assessment, we provide guidelines on what information the transplant team should seek, from what sources, and how best to make use of it. This report focuses on ‘what to do and how to do it’ in providing appropriate assessments for this complex patient group. Results Proper evaluation includes (a) taking the clinical history from the patient and a required, corroborating third person, (b) assessing patient cognition, (c) establishing alcohol/substance use diagnosis to differentiate alcohol dependence, abuse and polysubstance dependence, (d) assessing ambivalence in primary alcohol addiction, (e) measuring social stability and (f) using Vaillant’s factors for abstinence prognosis. Conclusions Properly applied, these six factors will allow standardized selection in most cases taken across programs despite differences in resources, available expertise and decision practices. Short Summary This report focuses on the essentials of the psychiatric/behavioral evaluation for ‘alcoholic’ persons referred for liver transplant. Attention to those essentials offers clinical standardization across transplant programs in different locales. INTRODUCTION: THE NEED FOR STANDARDIZATION Differing fiscal resources Even a cursory reading of the recent liver transplant literature demonstrates the lack of standardized, or even consistently applied, approaches to the clinical evaluation of alcoholics that can inform candidate selection (McCallum and Masterton, 2006; DiMartini et al., 2008; Kotlyar et al., 2008; Heinrich and Marcangelo, 2009; Surman et al., 2009; Rodrigue et al., 2013; Khan et al., 2014; Masson et al., 2014; Egawa et al., 2014a, 2014b; Piano et al., 2014; Dom et al., 2015; Lee and Leggio, 2015; Marroni, 2015; Schieber et al., 2015; Choudhary et al., 2016; Kollmann et al., 2016; Leon et al., 2016; Russ et al., 2016). Operative variables driving the heterogeneity of approaches include available resources, different levels of local expertise and different processes in decision making. In considering alcohol and related diagnoses, for example, funding priorities for expertise differ. In the US, some teams integrate the cost of specialized expertise in billings to third-party payors while others may separate them and leave them to the proclivities of third-party insurers. Available funds from insurers can vary widely. By contrast, some large health systems, such as the National Health Service in the United Kingdom and the Department of Veterans Affairs in the US, include psychiatric and social valuations as part of the process funding them accordingly and requiring them in the application decision. Uneven expertise distribution The supply of expertise available to transplant teams differs across centers. For example, in large academic programs, one would expect readily available local expertise. Ideally, the evaluations will be conducted by well-trained physicians who understand both the medical and the substance use factors in considering an alcoholic patient for transplant. This however may not be the case, as when evaluations may be referred to well-meaning alcohol/drug treatment personnel whose training does not include the subtleties of medical care following transplant. For example, a psychologist or counselor from non-transplant settings may caution the transplant team to expect high relapse rates. In fact, within the transplant setting post-operative relapse rates have been shown to be remarkably low within the first 5 years and abstinence rates concomitantly high (DiMartini et al., 2010; Lucey et al., 1997). At the same time, high abstinence rates may owe at least a partial debt to the circumstance in which any drinking may lead to lost adherence with the anti-immune medication regimen and may quickly result in rejection reaction and death. Sound medical expertise will be aware of these factors whereas substance use training, while valuable in its own right, may not be aware of them. Varying decision practices Even when assessment is complete, decision models may vary in different locales. While most decisions to provide or to refrain from liver grafting involves discussion in a multi-discipline team whose members have seen each candidate, relative decision weights may differ. In a famous report on transplant for alcoholic hepatitis (Mathurin et al., 2011), each discipline appears to carry a veto in any given case and a candidate must receive a positive vote from each of the disciplines represented in order to proceed. In most other teams in our awareness, all the disciplines involved are welcomed in the discussion but the final decision to offer transplant rests with the surgeon. In this model, the surgeons retain the final decision because they are responsible for the invasive procedure itself and its consequences in the patient’s life. The present discussion These large issues require consistent solutions if the field is to move toward standardized assessments and outcome comparability across centers. Our contribution to this discussion remains more limited: we will lay out an assessment approach. Aiming at practical use, this will not contain an exhaustive literature review. As examples, we will review neither the use of alcohol use biomarkers—a field best noted for its current imprecision—nor the beginning literature on post-transplant alcoholism treatment. Likewise we will not review the DSM-5 (APA, 2013) and its spectrum approach to clinical nomenclature for which there is little data from specialized settings. We will retain instead the use of syndrome diagnosis, presently best exemplified in the ICD-10 (WHO, 2010) that is used worldwide. We will focus on what to do in providing expert assessment for alcoholic liver transplant candidates and how to do it. We hope to provide this knowledge for use across disciplines and across centers. FORMAT AND SETTING OF THE CLINICAL HISTORY With the addition of two specific changes derived from providing psychiatric evaluations in this setting, the standard medical history format continues to serve both patient and clinician well. The clinical document begins by listing identifying data and this occasions the first, setting specific, change. Patient and other third party Traditionally, the clinical history derives from the patient and identifies only that person. In the setting of liver transplant, however, the presence of a third party, usually a spouse or significant other person who sees the patient frequently, constitutes an absolute requirement. Until the spouse or significant other attends the evaluation in person with both psychiatrist and patient present, the evaluation remains incomplete. The identifying data then includes mention of the third person, as in ‘John Jones is a 47 y/o male accompanied by his wife, Sally Jones, aged 39 years’. The absolute requirement of a third party serves three purposes. 1) Corroboration: Through the course of gathering information from the candidate the evaluator can then turn to the third party and say ‘Does this match your recollection?’ As one instance, when proceeding through a list of alcohol withdrawal symptoms, a patient may describe only a rare tremor while the spouse remarks, ‘His hands shook every morning’. 2) Social Stability: The spouse or other third party is the key individual in pre- and post-liver graft care. Their participation in the interview allows assessment of how stable and knowledgeable that social setting is for a graft recipient who will likely ever after require attention to immunosuppressant medication. And 3) Alcohol/Drug Use Setting: It is not uncommon for patient-other dyads to share pathological alcohol or other drug use activities. Evaluating this concern generally fits best when the interviewer goes over alcohol and drug use questions with the patient, includes corroboration questions, and then can easily extend them to include the use patterns of the third party. In most cases a screen instrument, such as the CAGE or T-ACE (Beresford et al., 1990a; Sokol et al., 1989) questions asked of the significant other, will introduce the topic along with general questions on nicotine and other drug use in the home. Screen questions eliciting a positive response allow follow-up with more clinical detail and a view of the candidate’s participation in the home environment. Since the third party will serve as the primary distress warning indicator of a return to pathological behavior after transplant, that person’s own health and capabilities become a critical part of the assessment. At the same time, this process allows all three—patient, third party and the evaluator as a representative of the transplant team—to build an alliance in the interest of the patient’s health. Clinically, the above requirement assumes a viable transplant candidate in an outpatient setting. What about the patient who presents in fulminant hepatic failure in the intensive care unit, possibly comatose, and with no hope of leaving the hospital without a liver graft? The same requirement applies: the home setting will serve as the patient’s primary safety net and requires a careful assessment. Interviews with as many adults as possible who live in that setting give the best information in this extreme case on the likelihood of extended abstinence. THE PATIENT’S COGNITION By definition, liver transplant candidates present in various stages of hepatic failure. Some may be well compensated and stable on medical treatment while others may arrive in coma or suffering other forms of mental incapacitation due to liver failure. Whether known as delirium (WHO, 2010), encephalopathy, confusion state, cognitive impairment or any of the other terms used historically, the result is a loss of one or more of the cognitive components needed to think properly, to recall a personal history accurately, to make informed decisions and to carry out future plans in a reliable manner. Optimally, and in the candidate’s best interest, the interview should take place with the patient at his/her best clinical state in the setting of hepatic insufficiency or failure. In the great majority of cases, this indicates an outpatient visit. Most inpatient hospitalizations occur when the liver disease has worsened; some clinicians request evaluation in hospital in the interest of getting it done, but this will not yield the best information if a delirium is present. The evaluator can follow the Identifying Data and Chief Complaint with an assessment of the patient’s cognitive state. ‘Are you thinking clearly today?’, ‘Are you clear headed today?’, ‘Are you thinking like your old self today?’ or another variation on this theme introduces the issue. ‘You appear to have some jaundice, today. How is your thinking doing?’ offers another obvious possibility. The patient answers and the interviewer can turn to the third party and ask, ‘Does he/she seem his/ her usual self today or do you see a change in thinking ability?’ Generally patient and significant other perceive changes concurrently but sometimes the third party may pick them up when the patient is too confused or slowed mentally to do so. Most often, the corroborating party mentions a worsening of forgetfulness especially in recalling recent events or plans. Referred to in cognitive science as working memory, this impairment often presents as a subtle change in recall that may not be obvious in routine medical encounters. If the patient and corroborator say that the patient’s cognition seems to be functioning normally, the evaluator may defer the cognitive exam for a few minutes, adding ‘Later in the interview I will ask you some questions that will let me know how your thinking is today’, most often providing an appropriate transition to the History of the Present Illness (HPI) in well compensated liver cases. Although more frequent in hospital settings, any time either the patient or the third party note changes in mentation, or if the interviewer notices the patient is having difficulty with attention and engagement in the conversation, a careful cognitive examination is best performed at the beginning of the interview. If the candidate suffers from cognitive incapacity, he/she may not provide accurate historical data simply because of memory retrieval, concentration, or other problems. As discussed extensively in neuropsychiatric texts, standard cognition assessment is best considered in two forms: basic and complex (Arciniegas and Beresford, 2001). The Mini-Mental State Exam (MMSE; Folstein et al., 1983), in wide use for cognitive screening, has been standardized by age and offers a reasonable tool for assessing basic cognition. It does not address complex cognitive functions. In the first author’s experience with liver transplant candidates, the MMSE does not offer a sufficient clinical test of working memory defined as the ability to record new memory information and then retrieve it 5 min later. Asking the patient to register (repeat out loud) four unrelated words, rather than the MMSE’s three, and then asking the patient to recall them after 5 min by the clock, rather than after the MMSE’s minute or two of varying elapsed time, offers a better window into the candidate’s working memory capabilities. A patient who can recall 3 or 4 of the words after 5 min can usually give a more reliable history than one who can recall only 2, 1, or none. Impaired working memory performance often indicates a subtle ‘subclinical’ hepatic encephalopathy that often will improve with adding or increasing lactulose treatment—a medicine thought to clear thinking by removing ammonia via the digestive tract. The Frontal Assessment Battery (FAB; Dubois et al., 2000) allows a standardized, scored evaluation of complex cognition. Used in its standard fashion, the examiner should have a printed or electronic copy before him/her and give the standard directions to the patient. The resulting additive score can then be used in a formula that accounts for normal age-related changes. Probably more important clinically, responses to the specific FAB tasks can give specific information on present complex cortical abilities in areas such as judgment, memory, level of involvement and executive/planning. Another standardized instrument, the Verbal Trails B (VTB; Mrazik et al., 2010) test, a spoken form of the original written Trails B test, recognizes the often subtle changes in complex cognition brought on by early hepatic encephalopathy. The interviewer introduces the VTB at the bedside or office by saying, ‘I am going to give you a pattern and I would like you to follow the pattern as far as you can go with it. The pattern is “1-A, 2-B.” What comes next?’ With encouragement but not prompting, the patient continues the sequence of alternating numbers and letters. The standardized norm is set at reaching ‘13-M’ or further with no errors in the space of 1 min. A below normal response usually indicates difficulties in functions mediated through the dorso-lateral pre-frontal cortex that are needed to plan and execute tasks, such as taking medications properly. A beside/clinic test of judgment provides a functional window into the orbito-frontal cortex and its state of health. ‘I am going to give you a situation and I want you to tell me what you would do in that situation. You are feeling well, you go to a movie and you are sitting in a crowded movie theater watching the movie. You are the first one to see a fire break out in the theater. What would you do?’ This standard question asks the patient to attend not only to the fire danger but also to the danger of panic in the theater. An acceptable response is ‘I would inform the theater management that there is a fire’ because it implies understanding of the panic danger, and provides an option for action against the fire while taking the panic danger into account. A frequent answer that may imply orbito-frontal compromise is ‘Yell FIRE!’, an option that does not account for the panic danger. The interviewer can follow-up with ‘What might happen if you did that?’ and listen for the secondary danger. If the patient says ‘It might cause a panic’, the interviewer then asks for other action options, ‘What could you do instead?’, listening for viable alternatives. Clinical practice also indicates a description of the motivation that sustains active attention throughout the interview. This last is an indication of the third major complex cognitive ability, one mediated by the anterior cingulate cortex of the frontal lobe. A patient presenting with a clear indifference to the issues at hand may suffer from a subtle delirium or from anterior cingulate cortex injury requiring evaluation. Attention to these and the basic cognitive functions allow an assessment of (a) the reliability of the patient’s clinical history, (b) his/her abilities to judge, plan and manage pre-transplant care in working with the liver team and (c) baseline cognitive functions that may often be impaired in a post-transplant delirium that may go unrecognized owing to their subtlety. When careful examination raises concern about a candidate’s cognitive ability, one question every transplant team asks is ‘Are the changes permanent?’ since few teams will provide liver grafting for demented patients. In the vast majority of candidates, it is important to consider changes of this nature as most likely indications of delirium—a temporary loss due to pathophysiologic causes from the liver failure—that will reverse with transplant. Improvement in the cognitive functions themselves, with lactulose, rifaximin, or other medical treatment to lower circulating ammonia levels before transplant, provides clinical evidence of a reversible delirium. True dementias, on the other hand, present with gradual lessening of cognitive abilities that do not reverse with treatment and indicate the necessity of an extensive dementia evaluation. Wernicke-Korsakoff’s syndrome, also known as Alcohol Amnestic Syndrome, characterized by a profound working memory deficit in the setting of generally normal cognition—especially of normal registration whereby a patient can recall six or seven or more random order digits spoken as a series by the examiner—indicates a trial of thiamine and the B-complex vitamins in an effort to demonstrate acceptable improvement prior to considering a liver graft procedure. HISTORY OF THE PRESENT ILLNESS The HPI is the work horse of the clinical evaluation and takes up the greatest part of the hour required for a capable assessment in experienced hands. Its specific sections in the liver transplant evaluation include the history and course of (a) the liver disease, (b) alcohol use, (c) other drug use including nicotine, (d) psychiatric disorders and conditions and (e) social stability. Liver history the psychiatric interviewer need not go into extensive detail that repeats the work of the hepatologists. A productive use of the first few minutes of history taking, however, includes meeting the patient and their significant other person on the common ground of concern about the liver disease. This builds a clinical alliance while giving the interviewer useful data. For example, the question ‘When did you first learn about your liver problem?’ provides a beginning point in understanding the course of events. Some report that their liver disease was first discovered from routine laboratory tests well before any symptoms. Others note that they were unaware of any conditions until the onset of a decompensation such as from acute alcoholic hepatitis (Lucey et al., 2009). In the latter condition some follow-up studies describe a window of approximately eighteen months between the first alcoholic hepatitis flare and the onset of more rapidly compensation from cirrhosis. In other cases, however, the alcoholic hepatitis may be more pathophysiologically aggressive and lead to more immediate transplant consideration. If the conclusion of the transplant team’s evaluation is to refer the patient for alcoholism treatment, for example, it is important to know where the patient might be in this relative time window of stable mental and physical functioning. Bearing on the alcohol use history itself, discussing the medical condition offers a useful point at which to ask ‘Did your physician or any other caregiver say that you should stop alcohol use?’ Use of a substance despite clear physical health consequences is one of the hallmarks of addictive disorder. The course of giving up alcohol or substance use may often take many months and include repetitive warnings from health care givers. On the other hand, a patient who minimizes the stated concerns of physicians and others about alcohol or drug use, with clear evidence to the contrary as in clinical records, may suggest an unresolved ambivalence with respect to stopping use. Assessing a history of prior confusion rounds out this section. It includes asking about bleeding episodes with related confusion, any periods of confusion that occurred spontaneously, and treatment for liver-related confusion. The corroborating other person often provides useful information on this topic since the patient may not remember all or part of a confusion episode. Prior occurrences, generally caused by the clinical or sub-clinical delirium due to the liver disease referred to as hepatic encephalopathy, signal that cognitive impairment has occurred in the past and that continues to be an important focus in the present assessment. In alcoholic cases, for example, confusion is sometimes wrongly misinterpreted as alcohol intoxication. A significant other person in the patient’s life who can differentiate the two will be an asset in continuing post-transplant care. Last use One way of transitioning from this part of the history into the next, often more sensitive, section on substance use is to ask the general question ‘When was your last use of alcohol or substances of any kind?’ The clinician may then record the patient’s recollection of last use and seek corroboration from the significant other person. This further introduces the third person’s role in the interview, and gives it a normal, matter of fact, tone that most third persons find helpful in being able to describe the patient’s drinking openly and honestly. It also introduces the focus on drinking and other drug use. Alcohol use history Clinically, two general concepts guide the use assessment of alcohol and other addictive drugs. First, the interviewer is assessing an addiction, or addictive disorder and alcoholism is a form of this phenomenon. Alcoholism, described more specifically below as alcohol dependence (AD; WHO, 2010), is second in prevalence only to nicotine addiction in most general populations. Second, AD and other forms of substance dependence are clinical diagnoses of specific behaviors, rather than quantifications of amounts and frequencies of use. An easily available source, the International Classification of Diseases, Tenth Edition (WHO, 2010) outlines the phenomena common to all addictive disorders. Further, experience in assessing liver transplant candidates suggests using the medical model of addictive disorders as disease states. Other models—such as moral choice, habit and reinforcement, or learned behavior—may make up useful discussions in other arenas but these have far less support from empirical data and offer very limited clinical utility. An empirically based medical model focuses on diagnosis and prognosis. Making a diagnosis The diagnosis of AD, and those of the other drug dependencies, requires specific evidence of phenomena in three clinical domains: physiological dependence—including tolerance and withdrawal, Loss of Control (LOC) of alcohol use—often erroneously referred to as ‘craving’—and decline in either physical or social functioning, or both. Of the dependence criteria listed in ICD-10 (WHO, 2010), for example, tolerance and withdrawal refer to physical dependence, while the LOC phenomenon and social or physical impairment each stand as independent criteria. But for our purpose, the three large symptom domains offer an easy way of remembering and assessing relevant symptoms in the clinic. Physiological dependence: tolerance and withdrawal Tolerance refers to the ability of the central nervous system (CNS) to approximate, or attempt to maintain, normal functioning in the presence of ever increasing doses of ethyl alcohol or any other CNS substance. Clinically, the person reports needing more alcohol to get the same effect once noticed at a much lower dose earlier in the natural history of drinking. To assess this, the physician must establish a baseline effect that has changed over time. This necessitates careful attention to the details of the drinking history. One useful approach may be to ask what the effect of alcohol was when a person first began drinking on his or her own. Results include such things as nausea, feeling high, or other unique descriptors that the patient can provide: what they noticed after one or two standard alcohol drinks. A standard drink, each containing roughly 0.6 ounces (about 14 g) of ethyl alcohol may be approximately defined as 12 ounces of 5% alcohol beer, 5 ounces of 12% alcohol wine, or 1.5 ounces of 40% whiskey or other spirits (HHS, 2015). After establishing a baseline, for example ‘in high school I got high after one or two cans of beer’, the interviewer may then ask how many standard drinks the person notices achieved the same effect at the time when their drinking was at its greatest. Some formal criteria designed to include many drugs of abuse require a 50% increase. In the case of alcohol, most will describe a doubling or more of the amount used for an initial effect. Many AD patients will describe amounts several times greater than those drunk in the state naïve to alcohol, such as ‘I don’t notice anything until after I drink a six pack’. This signals that the CNS has adapted to heavy alcohol use, that is, reached a tolerance. Notice that the interview has focused on the change in alcohol effect, not on the absolute amount of ethanol drunk. Using only the medical approach to understanding health and disease, practitioners often focus on the quantity and frequency of recent alcohol use as they might on how often a fever has spiked or how often and in what amount vomiting has occurred. The alcoholic patient, however, may not provide accurate responses to quantity/frequency questions. In the first place they may not remember how much they drink owing to intoxication itself or to related cognitive disorders. In the second place, alcoholism carries considerable social shame with it that often drives minimizing the reports of drinking quantity and frequency. And in the third, and perhaps most important place, alcoholic persons who have not reached stable remission remain in an ambivalent relationship with alcohol itself. This means that they can agree with their physician or caregiver that drinking is hurting them but have not reached the point of giving up the drinking behavior itself. Sensing that the physician’s role is to take their alcohol away, they may not wish to give their clinician opponent an upper hand in the struggle. This often leads to minimized quantity and frequency reports of alcohol use. For these reasons and others—such as the chronicity of the illness that is best measured in decades rather than weeks, months, or years—quantity/frequency questions offer only secondary data sources. The primary focus of the interview is on ‘how’ the person drinks rather than on ‘how much’. That is, the clinician best attends to the style of alcohol use rather than on quantity and frequency consumed. When focusing on the addictive phenomena themselves quantity and frequency data often arrive on their own, and very often aided by a responsible third party participating in the interview. Alcohol withdrawal defined clinically as an excessive activity of the sympathetic nervous system triggered by a rapid decline in alcohol blood level, withdrawal symptoms accompany tolerance in the great majority of individuals. In those who report no withdrawal symptoms despite a history of clear tolerance to alcohol, the clinician must ask whether the patient is drinking in the morning before withdrawal symptoms manifest themselves, or is regularly taking some other CNS depressant, such as a benzodiazepine or an agent with anticholinergic effects, that covers withdrawal symptoms, especially in the morning. On rare occasions, the physician will encounter patients who have little or no withdrawal symptoms despite clear tolerance. Although relatively infrequent, this recognized clinical phenomenon appears most likely due to a genetically based constitutional invulnerability to withdrawal. Since ethanol is a CNS depressant, its quick removal triggers CNS hyperactivity both centrally, as for example expressed by a subjective sense of jitteriness or impending disaster (anxiety), and peripherally through the symptoms of sympathetic nervous system discharge. Table 1 lists acute withdrawal symptoms that patient’s commonly report. Table 1. Patient reported symptoms of early alcohol withdrawal Anxiety  Palpitations (tachycardia)  Tremor  Rapid breathing  Nausea and vomiting  Low grade fever  Sweating  High blood pressure  Anxiety  Palpitations (tachycardia)  Tremor  Rapid breathing  Nausea and vomiting  Low grade fever  Sweating  High blood pressure  Of note, neither headache nor blackout, are symptoms of alcohol withdrawal. The former, a component of ‘hangover’ (Prat et al., 2009) often may have to do with fluid shifts in the brain that engage the meningeal pain sensors, while the latter is a state-dependent amnesia (Rose and Grant, 2010). Later occurrences, however, such as generalized grand mal seizures on or after the 24–36 h of withdrawal and the Delirium Tremens (DT’s) occurring after 72 h make up the most severe and most dangerous withdrawal phenomena (Schuckit, 2014). The DT’s, characterized by (a) confusion, (b) usually visual or tactile hallucinations and (c) extreme rises and vital signs, such as malignant hypertension or tachycardia, presents a true medical emergency usually resulting in hospitalization. Again, however, because of his/her confusion during the DT’s, the patient may not appreciate the significance of hospitalization for withdrawal. The corroborating third party is again useful in this instance. LOC phenomenon The essence of any addiction, and no less so in AD, is LOC of use. This refers to the inability of the AD person to predict with any degree of certainty how much they will imbibe within any drinking episode. Clinically, once the drinking episode starts, the AD person will be unable to stop in the middle of the drinking/use bout without a very great struggle. Useful questions at interview include the phrasing presented in Table 2. Table 2. Assessing loss of control First state: ‘Some people tell me they notice these things when they drink and I would like to know if you’ve ever notice them.   (1) Some find it very hard to stop drinking, once they start. They feel that they are ‘off to the races’ where drinking is concerned.  (2) Some people find themselves drinking more than they wanted to or had planned to.  (3) Some notice that they try to make rules to control their drinking.  First state: ‘Some people tell me they notice these things when they drink and I would like to know if you’ve ever notice them.   (1) Some find it very hard to stop drinking, once they start. They feel that they are ‘off to the races’ where drinking is concerned.  (2) Some people find themselves drinking more than they wanted to or had planned to.  (3) Some notice that they try to make rules to control their drinking.  While the phrasing may seem indirect, the word structure allies both interviewer and patient in looking at one phenomenon—the patient’s experience—rather than implying an adversarial setting in which the interviewer is examining the patient, as if under a microscope. Experience suggests that an allying approach gains much more detailed, and more useful information. At the same time, it is important to distinguish the LOC phenomenon from ‘craving’. The former has to do with the inability to stop drinking once started. Craving, classically defined, refers to the episodic and often intense desire or compulsion to drink or use between bouts of use. It may also be confused with the search for alcohol to treat withdrawal symptoms. The distinction can be made accurately in the clinical setting by paying attention to what occurs during episodes of use and what occurs between them. LOC during use is a hallmark of addiction while craving between use episodes appears to be a much different phenomenon involving brain/environment interactions. Social or physical decline The combination of physical addiction and LOC usually results in a patient’s expending a large portion of time and effort to sustain heavy drinking or to manage or recover from its effects. To assess this, the clinician asks whether drinking has become a problem with respect to family relationships, legal status, work, friendships or physical health. The physician will be especially attuned to the last of these since the physical illness sequelae of AD and other drug dependencies often result in frequent clinical visits and hospitalizations. The family relationships, however, usually offer the most sensitive indications of social difficulties due to alcohol or drug use. A change in work status is usually one of the last indicators of social difficulty since income provides the basis for continued use. AD, then, may be reliably diagnosed when evidence in all three domains presents. The ICD-10 diagnostic criteria do not require evidence in all three domains and therefore cast a somewhat wider diagnostic net. While either approach is defensible, the transplant team will do well to use both concurrently. The first author generally takes the more conservative approach for the AD diagnosis in the setting of life-threatening illness for which there is only one treatment alternative. Lesser diagnoses, such as Alcohol Abuse, offer better prognoses with respect to post-transplant abstinence. GAUGING PROGNOSIS When liver transplant teams ask for psychiatric or related expertise in evaluating liver graft candidates, they ask primarily for the candidate’s prognosis: Will this person ‘waste’ a liver graft with a return to uncontrolled alcohol, or other drug, use? Post-transplant risk Physically, the risk of graft injury or loss from a return to drinking emanates from two sources principally. The first entails alcohol injury to the new liver graft, a relatively rare occurrence that hepatologic knowledge cannot predict at present. Only about 15% of heavy drinkers acquire potentially fatal cirrhosis to begin with and the molecular mechanisms that trigger the process in some, but not in most other heavy drinking individuals, remain largely unknown. The second risk to graft injury is more ominous: graft rejection due to an inattention to post-transplant immune-suppression. Behaviorally, a return to uncontrolled drinking carries a high risk of non-adherence to the medicine regimen. Missing even a few doses in a twice-daily regimen, for example, can lead to a graft rejection reaction that the patient may not notice until its late stages, potentially irreversible and fatal by that time. This factor, mentioned here in the context of alcohol use, applies to any psychoactive agent used in an uncontrolled setting that may affect memory, planning and judgment functions in the brain. Both risks—direct alcohol liver injury, and graft rejection reaction—deserve mention in the psychiatric interview since they provide candidate and significant other with an important perspective on life following transplant. The first author brings them up near the end of the interview and usually in the context of (a) focusing the previous diagnostic and prognostic information on the risks of life after transplant, and (b) justifying the readiness of the significant other to alert the transplant team to any drinking or other concerning behavior. Positive versus negative How, then, to go about the task of assessing the prognosis for alcohol/drug free living post-transplant? (Beresford and Everson, 2000) While each individual patient and their social network provide unique considerations, a series of general factors, gleaned mostly from research on non-transplant populations of alcohol or drug dependent persons, offer useful windows on prognosis. In the great majority of cases these include (a) the alcohol and substance use diagnoses, (b) an assessment of the patient’s ambivalence towards continuing use, (c) measures of the candidate’s social stability and (d) a series of four empirically based factors that Vaillant (Vaillant, 1995) found in prospective research studies (Hillemacher et al., 2016). In addition, candidates with a co-occurring diagnosis of a major psychiatric disorder require (a) an evaluation of psychoactive medication response to the primary disorder and (b) a medication adherence history in addition to the factors already mentioned. Some liver teams focus more on what they see as predictors of negative prognosis—those that predict a return to drinking or use—rather than positive factors such as those that predict continued abstinence as mentioned above. The negative factors often include mention of (a) alcohol or other drug use in the past six months—the infamous ‘six month rule’ that has not been borne out in prospective research, and (b) counting previous ‘recidivist’ episodes, a term that calls to mind criminal incarceration and punishment rather than a remitting/relapsing medical condition. At the same time, many teams and outcome reports in the literature often ignore one of the primary indicators of relapse—the presence or absence of polydrug dependence, a phenomenon described in clinical subtyping of AD presentations as described below. While negative factors, such as evidence of current drinking in the setting of AD, come into play in the evaluation, focus on the positive factors at present offers a sound approach. Diagnosis is prognosis The diagnostic procedure described in detail above provides the basis for important prognostic distinctions bearing on post-transplant abstinence. One of the most common, and surprisingly least referred to in the published studies on candidate evaluation, is the distinction between AD history as a primary dependence and AD as part of a polysubstance dependence history. AD typology and polydrug dependence AD affects as many as 7–10% of persons in the US. In a great majority of cases it involves alcohol as the primary, and often only, drug of sustained abuse. Research reports refer to this as Type 1 Alcohol Dependence (Babor et al., 1992). By contrast polydrug dependence—that is, addiction to two or more substances, not including nicotine, that may include alcohol as one of the dependence substances—affects about 0.5% of persons in the US. This group refers to Type 2 Alcohol Dependence (Babor et al., 1992) or polydrug dependence (Vaillant, 1995). Although the distinction between the two types and their abstinence prognoses has been known for many years (Hillemacher et al., 2016) remarkably few programs take this distinction into account. For example, transplant programs that separate the two demonstrate high rates of abstinence in the primary AD (Type 1) (Lucey et al., 1997; DiMartini et al., 2010) group after transplant when compared to those that do not make this distinction often report much lower abstinence rates. Prior research on non-transplant samples demonstrates that the much more common primary AD persons will enjoy a far better prognosis than the polydrug dependent group (Vaillant, 1995). Table 3 summarizes the distinctions between the two in brief form. Table 3. Alcohol dependence vs. polydrug dependence (alcoholism Types 1 and 2) Primary alcohol dependence  Polydrug dependence  7–10% US population Alcohol primary dependence Normal childhood No conduct disorder (CD) Regular use: teens, twenties No personality diagnosis Natural remission: 30%/year With treatment: 45%/year  0.5% US population Polysubstance dependence Deprivation/abuse childhood CD symptoms: before age 15 Polydrug use: teens-middle age Adult personality disorder Natural remission: 10%/year With treatment: 10%/year  Primary alcohol dependence  Polydrug dependence  7–10% US population Alcohol primary dependence Normal childhood No conduct disorder (CD) Regular use: teens, twenties No personality diagnosis Natural remission: 30%/year With treatment: 45%/year  0.5% US population Polysubstance dependence Deprivation/abuse childhood CD symptoms: before age 15 Polydrug use: teens-middle age Adult personality disorder Natural remission: 10%/year With treatment: 10%/year  Further evidence for the usefulness of this distinction in transplant candidate selection comes from a recently published long term, prospective study on the outcome histories of liver transplant recipients with respect to return to alcohol use (DiMartini et al., 2010). Of five post-liver transplant groups whose ‘trajectories’ were separated by careful statistical analysis, the group presenting the most frequent and severe relapses were those with pre-transplant histories of abusing multiple substances. These data confirm that the polydrug dependent, or Type 2 AD, population carry the worst post-transplant prognosis. Practically speaking, the psychiatrist must evaluate AD type as a clinical guide to prognosis. While the Six Month Rule has little justification for use in Type 1 AD (DiMartini et al., 2006), a history of recent use of any dependent drug—including alcohol—in a Type 2 AD person constitutes an ominous finding. Empirical data on the polydrug group suggests that continuous, stable abstinence comes only after the emotional growth of many years, often in the person’s late 30s or 40s (Vaillant, 1995). In a person with Type 2 AD, demonstration of a corroborated, sustained, stable abstinence from both drugs and alcohol for a significant period of time—often measured by one or more years rather than by months—affords the liver transplant team the confidence to proceed in providing a scarce resource. Abuse rather than dependence When diagnosing AD or other drug dependence, it is important to establish whether the LOC phenomenon exists in each case. Its absence, even in the face of a clear history of tolerance or alcohol-related social or physical problems for example, strongly suggests the lesser diagnosis of Alcohol Abuse. In a clinical series previously reported (Lucey et al., 1994) about 10% of those applying for a liver transplant for alcoholic cirrhosis did not meet dependence criteria but could clearly be considered in the abuse category. Even though a lesser diagnosis, Alcohol Abuse still indicates asking the patient to cease all alcohol use. In that case, two phenomena often occur: (a) the person achieves and maintains abstinence without a struggle, and (b) the risk of relapse over the long term appears considerably lower. Generally speaking, Alcohol Abuse offers a much better prognosis than does AD and is a more optimistic diagnosis to make. Behavioral versus hepatic diagnosis A significant portion of those candidates referred to as ‘alcoholic’ will not merit the AD diagnosis. As previously published, the two authors compared Hepatology and Psychiatric reports for transplant candidates (Lucey et al., 1994). Only about 75% of those with a tissue diagnosis of alcoholic liver disease fit the behavioral AD diagnosis. Conversely, only about 80% of those referred clinically as ‘alcoholics’ met the AD diagnosis. Of the remaining 20%, half fit the Alcohol Abuse diagnosis and half did not merit either. This was especially true of women who, because of a well-known, if poorly understood, gender specific vulnerability to alcoholic liver disease, that may injure the liver without ever reaching AD. This limited overlap emphasizes the need for diagnostic precision. Continuing LOC risk Clinically, longitudinal studies of abstinence make it clear that once the control of drinking behavior departs, it does not return in the great majority of cases (Vaillant, 1995). Once lost, controlled alcohol or drug use cannot be re-learned or re-constituted. In this sense an AD diagnosis signals a permanent condition—including a permanent risk of uncontrolled drinking or use. This has a critical bearing on life after liver transplant in AD persons since it suggests that any alcohol use will remain, always, a high risk behavior for the new organ and daily use of immunosuppressive agents. Even brief non-compliance with the immunosuppressants can result in the rejection reaction and death. One component of the interview, therefore, requires review of this risk with the patient and third party. Poor understanding, or ambivalent acceptance, of post-transplant drinking/use risk in a patient with normal cognition may indicate an unresolved ambivalence toward AD itself and therefore the need for alcohol or other drug focused behavioral treatment. This can be followed by a return for re-evaluation, prior to transplant. Assessing ambivalence with respect to alcohol use Outside of the transplant setting, the process of reaching sustained abstinence can take months to a few years for those who will be able to achieve it. Studies of transplant recipients, however, report high abstinence rates in most subgroups, with the notable exception of those with a polydrug dependence history who lack long-term abstinence before transplant. For all potential recipients, an assessment of the extent to which the candidate has resolved their alcohol use can be made and will contribute meaningfully to the information at the team’s disposal. This assessment is difficult since it relies on the candidate’s subjective report of their relationship with alcohol with little or no outside corroboration or objective measure. Some have attempted quantifying the so-called change readiness in non-transplant samples but these, likewise, do not offer more objective corroboration. In this setting, one approach follows after the clinician has collected diagnostic data and is in a position to provide the AD diagnosis. This can begin with ‘Do you consider yourself an alcoholic?’ An unambivalent response often heard is ‘Absolutely. I cannot drink alcohol without drinking it excessively. Therefore I cannot drink alcohol at all’. This usually signifies a person who has come to grips with the ongoing risk that any alcohol drinking entails. An ambivalent response may be ‘I’m not alcoholic because I don’t drink anymore because of my liver’. Other examples may be ‘No, because I don’t drink every day’, or ‘Alcoholics drink to get drunk and I don’t do that so I am not an alcoholic’, or ‘Alcoholics drink hard liquor and I only drink beer’. In order, neither liver disease, daily versus binge drinking, intoxication, or beverage choice indicate a lack of AD. Specifically, only a minority of heavy drinkers go on to liver failure, current drinking frequency has little to do with the LOC phenomenon, most AD persons try not to appear either intoxicated or in withdrawal, and a standard 12 ounce can of beer has about the same alcohol content as a shot of spirits. Rather, all of these and others may be heard as examples of unresolved ambivalence towards the drinking disorder itself. In this setting it is crucial that the clinician not take on the role of trying to convince the AD person that they suffer from alcoholism. Because of the subjective nature of that task, it usually only leads to an unproductive struggle between clinician and candidate. A better approach is to review the drinking history obtained earlier in the interview with the patient and third party after hearing their response to ‘Do you consider yourself an alcoholic?’ For example, ‘You have described (a) a tolerance—your brain’s ability to adapt to heavy drinking, (b) your becoming ill with withdrawal when you stop, (c) your difficulty in stopping once you start drinking and (d) your liver disease and your social problems due to drinking despite statements of concern from others. When we find those things in a person’s life, we take them together as a diagnosis of Alcohol Dependence, what most people call alcoholism. We think of AD as an illness that people can get better from. But how about you? How do you think of alcoholism?’ From this, there often follows an understanding of the patient’s own perceptions that may be consistent with an unresolved ambivalence or, in occasional cases, a relief in not being regarded as immoral, sinful or any of the other stigmatizing views of AD. While this clinical area requires more investigation and better ways to link ambivalence with outcome, the results of a conversation along these lines gives the clinician the best data on which to judge the candidate’s own progress in stopping alcohol use. Operationally, the clinician’s lack of comfort with the patient’s responses is often the best indication for referral to focused treatment of AD if cognition permits and for subsequent case re-evaluation if the course of the liver disease will permit. Social stability This assessment tests the foundation upon which ongoing medical adherence and favorable prognosis are built. While several social stability scales exist, the simplest comes from the work of Strauss and Bacon (Straus and Bacon, 1951) who found that the presence of any two of four social factors predicted clinic appointment compliance among AD persons. These included: (a) being married, (b) not living alone, (c) stable employment for 3 years and (d) a stable residence for 2 years. Falling below the cut point suggests, but does not establish, the likelihood of insufficient social resources, such as in social isolation and homelessness, that raise the likelihood of both drinking relapse and medical non-compliance. When present, the specialized involvement of a treatment clinic program aimed at adding or strengthening social resources offers the best next step towards return to the liver team for re-assessment. Vaillant’s four prognostic factors In the best available prospective, longitudinal study of AD prognosis, Vaillant’s 8-year study and follow-up noted four operating factors, any two or more of which, when present, predicted long-term sobriety—defined as 2 years or more—while one or none indicated a return to drinking within 1 year (Vaillant, 1995). A proper prognosis evaluation includes them. Structured time Because AD style drinking requires a lot of time and effort, newly abstinent persons often encounter considerable ‘dead’, or unstructured, time that can itself foster a relapse. Structuring that time corrects this concern and is a frequent ingredient in specialized clinic and self-help group (such as Alcoholics Anonymous) formats. Any setting that fills time with productive and engaging activities—that the person’s ‘heart is in’—fits the need. At interview, a brief assessment of how the candidate spends his/her day addresses whether they engage in active projects that involve other people, or live an isolated existence such as in filling the time with endless television viewing. A rehabilitation relationship Sustained, heavy drinking or drug use serves to isolate the person from others and to create the need in those who come into social contact—such as family members—to ‘fix’ the drinking or use. Direct intervention—such as telling the person not to drink or use—generally results in an interpersonal struggle that works against continued abstinence. Rather, abstinence sets the stage for proper boundaries between person and social network. In brief, a professionally staffed clinic, a self-help network such as Alcoholics Anonymous, or informed family members who have given up the struggle to ‘fix’ the patient, or a combination of all of these, communicate the same approach to the person: ‘You can stay but the drinking has to go’. Assessing the extent to which the significant other person present at the liver transplant evaluation interview understands (a) that they cannot control the patient’s drinking or use, and (b) that they are ready to inform the transplant team when any return to use occurs or appears likely to, is a necessity. This can be done by asking ‘Is it clear to you that neither you nor I have any control over [the candidate’s] drinking?’ And, ‘What would you do if, many months after transplant, you suspected that [the candidate] was drinking?’ The proper answer to the first question is Yes and to the second, Call the transplant team as well as mobilize any local caregivers, such as a specialized treatment clinic. When the significant other person does not understand their own limits, further education on the topic is in order. Most third parties who do not apprehend the need to call for help in a dangerous situation involving alcohol or drug use find relief in a review of whom to call and when, then and there in the interview. Sources of hope or self-esteem Regretful thoughts about having hurt others during drinking days frequently return to most AD people during abstinence periods. Ruminating on them has the effect of lowering hope and self-confidence and thereby promoting a return to drinking or use: ‘I am a terrible person, I may as well drink’. In assessing prognosis, the interviewer inquires after mechanisms that help a person through such periods. These include hope for the future—‘What keeps you going in life? What do you look forward to?’—and sources of accomplishment or self-esteem—‘What helps you to feel good about yourself? What gives you a sense of usefulness or accomplishment?’ The evaluator may also note ‘Most people run into regrets about their drinking days. Does this happen to you?’ If the answer is positive, ‘What helps you get past regretful thoughts without drinking?’ For some it may be religious beliefs, for others the ‘higher power’ without religion—as Alcoholics Anonymous describes it, and for others a concentration on items of hope and accomplishment, such as ‘another day behind me without drinking’. Clinically, the absence of forces that counterbalance regretful ruminations presents an ominous sign and one indicating further specialized treatment focus. A negative behavioral reinforcer ‘Is there something very painful that will happen to you, without doubt, the very next time you drink alcohol?’ Very few circumstances meet these criteria. Severe pancreatic pain and the disulfiram-ethanol reaction are the most frequently encountered. Liver failure does count because of its subtlety and lack of predictability on each occasion. While the others of Vaillant’s factors can be considered positive changes in the path to sustained abstinence, this is the only negative one and is generally the least frequently encountered in the liver transplant setting. Summing up prognosis While none of the factors listed under Prognosis may individually offer absolute certainty in respect to sustained abstinence in each individual case, their combination offers a prognostic pattern that appears useful. Our early algorithm (Beresford et al., 1990b), for example, predicted high rates of abstinence in AD liver transplant recipients who present a series of good prognostic factors. With further experience, the individual factors might be summed clinically in Table 4. The reader will notice that the prognostic factors listed there can be addressed and re-evaluated longitudinally. Table 4. Addressing prognostic factors before transplant Physical diagnosis   Cognitive impairment: lactulose or other treatment and re-evaluate  Substance use diagnosis   (1) Type 1 Dependence: proceed to further prognostic evaluation  (2) Type 2 Dependence: verify either lengthy sustained abstinence and the ‘maturing out’ process or verify continued effective treatment as for example in methadone maintenance for opiate dependence  (3) Abuse: verify cessation and abstinence and proceed to transplant  (4) No diagnosis: proceed to transplant  Substance use prognosis   (1) Unresolved Ambivalence Toward Use: focused treatment on this aspect of abstinence; re-evaluate in 3–6 months.  (2) Unstable Social Adjustment: establish viable social resources; 3–6 month follow-up re-assessment  (3) One or none of Vaillant’s Factors: focused treatment referral; 3–6 month follow-up assessment.  Physical diagnosis   Cognitive impairment: lactulose or other treatment and re-evaluate  Substance use diagnosis   (1) Type 1 Dependence: proceed to further prognostic evaluation  (2) Type 2 Dependence: verify either lengthy sustained abstinence and the ‘maturing out’ process or verify continued effective treatment as for example in methadone maintenance for opiate dependence  (3) Abuse: verify cessation and abstinence and proceed to transplant  (4) No diagnosis: proceed to transplant  Substance use prognosis   (1) Unresolved Ambivalence Toward Use: focused treatment on this aspect of abstinence; re-evaluate in 3–6 months.  (2) Unstable Social Adjustment: establish viable social resources; 3–6 month follow-up re-assessment  (3) One or none of Vaillant’s Factors: focused treatment referral; 3–6 month follow-up assessment.  While this offers liver transplant teams the best option in moving to decision, sometimes the clinical presentation does not allow it, as when a patient’s acute liver decompensation indicates transplantation as the only viable option for leaving hospital. In that situation, the evaluator addresses as many of the above factors as possible, including communication with the patient and family, and presents the clinical data in the discussion with the liver transplant team wherein the various sets of data can be considered and a consensus reached. OTHER PSYCHIATRIC ASSESSMENT The foregoing discussion relates to the great majority of persons with alcohol or substance use histories referred for liver transplantation who do not have other pre-existing psychiatric conditions. One critically important feature of this patient group recalls that AD can mimic all of the major psychiatric disorders including Major Depressive Disorder, Bipolar Disorder, Psychosis, several Anxiety Disorders and Obsessive Compulsive Disorder, as well as other entities such as sleep discontinuity and anorexia. These and others can be assessed through a series of standard screening questions that will not appear here. When addressing them, the evaluator must keep one truly important factor in mind: other psychiatric disorders cannot be established with certainty during periods of heavy drinking and, to some extent, during periods of other drug use. Diagnostic clarity for the listed psychiatric disorders requires evidence during abstinence periods that generally exceed one month. Failing to observe this may lead to misdiagnosis and gratuitous use of treatments, most often psychoactive medications. A WORD OF SUMMARY Liver transplantation remains the only successful treatment for liver failure to the present moment, although new developments in genetic engineering and hepatocellular growth may someday replace allograft procedures. Our own recent work has suggested that some of the immunosuppressants or their analogs may someday have a role to play in treating alcohol use disorders (Beresford et al., 2005, 2012, see also Ronan and Beresford report in this Special Issue). In proceeding to allocate liver grafts that preserve lives, transplant teams have acted fairly and compassionately in considering patients with AD and have done so empirically in the best traditions of clinical medicine (Beresford and Everson, 2000). This discussion raises many questions that deserve addressing at this intersection of medical, surgical and psychiatric knowledge. These include the currently unresolved areas of precision in evaluating polysubstance dependent persons, in assessing the ambivalence concerns in the primary AD setting, and issues involving post-transplant care. This field has the opportunity to grow in these important areas that will derive knowledge widely applicable in other settings and conditions from which many more than the transplant recipient population will benefit. FUNDING No grant funds were expended in writing this report. Dr. Beresford receives salary support from the U.S. Department of Veterans Affairs. CONFLICT OF INTEREST STATEMENT None declared. DISCLAIMER The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. REFERENCES APA. ( 2013) Diagnostic and Statistical Manual of Mental Disorders; DSM–5 , 5th ed.. Arlington, VA: American Psychiatric Association. Arciniegas D, Beresford T. ( 2001) Neuropsychiatry: an Introductory Text . Cambridge, UK: Cambridge University Press. Babor TF, Hofmann M, Delboca FK, et al.  . ( 1992) Types of alcoholics, I. Evidence for an empirically derived typology based on indicators of vulnerability and severity. Arch Gen Psychiatry  49: 599– 608. Google Scholar CrossRef Search ADS PubMed  Beresford HF, Deitrich R, Beresford TP. ( 2005) Cyclosporine-A discourages ethanol intake in C57bl/6j mice: a preliminary study. J Stud Alcohol  66: 658– 62. Google Scholar CrossRef Search ADS PubMed  Beresford T, Fay T, Serkova NJ, et al.  . 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Google Scholar CrossRef Search ADS PubMed  Vaillant GE. ( 1995) The Natural History of Alcoholism, Revisited . Cambridge: Harvard University Press. WHO. ( 2010) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines, Clinical Modification (ICD-10-CM) . Geneva: World Health Organization. Medical Council on Alcohol and Oxford University Press 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Alcohol and Alcoholism Oxford University Press

Towards Standardizing the Alcoholism Evaluation Of Potential Liver Transplant Recipients

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Oxford University Press
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Medical Council on Alcohol and Oxford University Press 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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0735-0414
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1464-3502
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Abstract

Abstract Aims For teams around the world, alcoholic liver disease patients comprise the largest, and clinically most controversial, group applying for liver transplant. And yet evaluation decisions for them remain highly variable by locale. Methods Targeting standardized assessment, we provide guidelines on what information the transplant team should seek, from what sources, and how best to make use of it. This report focuses on ‘what to do and how to do it’ in providing appropriate assessments for this complex patient group. Results Proper evaluation includes (a) taking the clinical history from the patient and a required, corroborating third person, (b) assessing patient cognition, (c) establishing alcohol/substance use diagnosis to differentiate alcohol dependence, abuse and polysubstance dependence, (d) assessing ambivalence in primary alcohol addiction, (e) measuring social stability and (f) using Vaillant’s factors for abstinence prognosis. Conclusions Properly applied, these six factors will allow standardized selection in most cases taken across programs despite differences in resources, available expertise and decision practices. Short Summary This report focuses on the essentials of the psychiatric/behavioral evaluation for ‘alcoholic’ persons referred for liver transplant. Attention to those essentials offers clinical standardization across transplant programs in different locales. INTRODUCTION: THE NEED FOR STANDARDIZATION Differing fiscal resources Even a cursory reading of the recent liver transplant literature demonstrates the lack of standardized, or even consistently applied, approaches to the clinical evaluation of alcoholics that can inform candidate selection (McCallum and Masterton, 2006; DiMartini et al., 2008; Kotlyar et al., 2008; Heinrich and Marcangelo, 2009; Surman et al., 2009; Rodrigue et al., 2013; Khan et al., 2014; Masson et al., 2014; Egawa et al., 2014a, 2014b; Piano et al., 2014; Dom et al., 2015; Lee and Leggio, 2015; Marroni, 2015; Schieber et al., 2015; Choudhary et al., 2016; Kollmann et al., 2016; Leon et al., 2016; Russ et al., 2016). Operative variables driving the heterogeneity of approaches include available resources, different levels of local expertise and different processes in decision making. In considering alcohol and related diagnoses, for example, funding priorities for expertise differ. In the US, some teams integrate the cost of specialized expertise in billings to third-party payors while others may separate them and leave them to the proclivities of third-party insurers. Available funds from insurers can vary widely. By contrast, some large health systems, such as the National Health Service in the United Kingdom and the Department of Veterans Affairs in the US, include psychiatric and social valuations as part of the process funding them accordingly and requiring them in the application decision. Uneven expertise distribution The supply of expertise available to transplant teams differs across centers. For example, in large academic programs, one would expect readily available local expertise. Ideally, the evaluations will be conducted by well-trained physicians who understand both the medical and the substance use factors in considering an alcoholic patient for transplant. This however may not be the case, as when evaluations may be referred to well-meaning alcohol/drug treatment personnel whose training does not include the subtleties of medical care following transplant. For example, a psychologist or counselor from non-transplant settings may caution the transplant team to expect high relapse rates. In fact, within the transplant setting post-operative relapse rates have been shown to be remarkably low within the first 5 years and abstinence rates concomitantly high (DiMartini et al., 2010; Lucey et al., 1997). At the same time, high abstinence rates may owe at least a partial debt to the circumstance in which any drinking may lead to lost adherence with the anti-immune medication regimen and may quickly result in rejection reaction and death. Sound medical expertise will be aware of these factors whereas substance use training, while valuable in its own right, may not be aware of them. Varying decision practices Even when assessment is complete, decision models may vary in different locales. While most decisions to provide or to refrain from liver grafting involves discussion in a multi-discipline team whose members have seen each candidate, relative decision weights may differ. In a famous report on transplant for alcoholic hepatitis (Mathurin et al., 2011), each discipline appears to carry a veto in any given case and a candidate must receive a positive vote from each of the disciplines represented in order to proceed. In most other teams in our awareness, all the disciplines involved are welcomed in the discussion but the final decision to offer transplant rests with the surgeon. In this model, the surgeons retain the final decision because they are responsible for the invasive procedure itself and its consequences in the patient’s life. The present discussion These large issues require consistent solutions if the field is to move toward standardized assessments and outcome comparability across centers. Our contribution to this discussion remains more limited: we will lay out an assessment approach. Aiming at practical use, this will not contain an exhaustive literature review. As examples, we will review neither the use of alcohol use biomarkers—a field best noted for its current imprecision—nor the beginning literature on post-transplant alcoholism treatment. Likewise we will not review the DSM-5 (APA, 2013) and its spectrum approach to clinical nomenclature for which there is little data from specialized settings. We will retain instead the use of syndrome diagnosis, presently best exemplified in the ICD-10 (WHO, 2010) that is used worldwide. We will focus on what to do in providing expert assessment for alcoholic liver transplant candidates and how to do it. We hope to provide this knowledge for use across disciplines and across centers. FORMAT AND SETTING OF THE CLINICAL HISTORY With the addition of two specific changes derived from providing psychiatric evaluations in this setting, the standard medical history format continues to serve both patient and clinician well. The clinical document begins by listing identifying data and this occasions the first, setting specific, change. Patient and other third party Traditionally, the clinical history derives from the patient and identifies only that person. In the setting of liver transplant, however, the presence of a third party, usually a spouse or significant other person who sees the patient frequently, constitutes an absolute requirement. Until the spouse or significant other attends the evaluation in person with both psychiatrist and patient present, the evaluation remains incomplete. The identifying data then includes mention of the third person, as in ‘John Jones is a 47 y/o male accompanied by his wife, Sally Jones, aged 39 years’. The absolute requirement of a third party serves three purposes. 1) Corroboration: Through the course of gathering information from the candidate the evaluator can then turn to the third party and say ‘Does this match your recollection?’ As one instance, when proceeding through a list of alcohol withdrawal symptoms, a patient may describe only a rare tremor while the spouse remarks, ‘His hands shook every morning’. 2) Social Stability: The spouse or other third party is the key individual in pre- and post-liver graft care. Their participation in the interview allows assessment of how stable and knowledgeable that social setting is for a graft recipient who will likely ever after require attention to immunosuppressant medication. And 3) Alcohol/Drug Use Setting: It is not uncommon for patient-other dyads to share pathological alcohol or other drug use activities. Evaluating this concern generally fits best when the interviewer goes over alcohol and drug use questions with the patient, includes corroboration questions, and then can easily extend them to include the use patterns of the third party. In most cases a screen instrument, such as the CAGE or T-ACE (Beresford et al., 1990a; Sokol et al., 1989) questions asked of the significant other, will introduce the topic along with general questions on nicotine and other drug use in the home. Screen questions eliciting a positive response allow follow-up with more clinical detail and a view of the candidate’s participation in the home environment. Since the third party will serve as the primary distress warning indicator of a return to pathological behavior after transplant, that person’s own health and capabilities become a critical part of the assessment. At the same time, this process allows all three—patient, third party and the evaluator as a representative of the transplant team—to build an alliance in the interest of the patient’s health. Clinically, the above requirement assumes a viable transplant candidate in an outpatient setting. What about the patient who presents in fulminant hepatic failure in the intensive care unit, possibly comatose, and with no hope of leaving the hospital without a liver graft? The same requirement applies: the home setting will serve as the patient’s primary safety net and requires a careful assessment. Interviews with as many adults as possible who live in that setting give the best information in this extreme case on the likelihood of extended abstinence. THE PATIENT’S COGNITION By definition, liver transplant candidates present in various stages of hepatic failure. Some may be well compensated and stable on medical treatment while others may arrive in coma or suffering other forms of mental incapacitation due to liver failure. Whether known as delirium (WHO, 2010), encephalopathy, confusion state, cognitive impairment or any of the other terms used historically, the result is a loss of one or more of the cognitive components needed to think properly, to recall a personal history accurately, to make informed decisions and to carry out future plans in a reliable manner. Optimally, and in the candidate’s best interest, the interview should take place with the patient at his/her best clinical state in the setting of hepatic insufficiency or failure. In the great majority of cases, this indicates an outpatient visit. Most inpatient hospitalizations occur when the liver disease has worsened; some clinicians request evaluation in hospital in the interest of getting it done, but this will not yield the best information if a delirium is present. The evaluator can follow the Identifying Data and Chief Complaint with an assessment of the patient’s cognitive state. ‘Are you thinking clearly today?’, ‘Are you clear headed today?’, ‘Are you thinking like your old self today?’ or another variation on this theme introduces the issue. ‘You appear to have some jaundice, today. How is your thinking doing?’ offers another obvious possibility. The patient answers and the interviewer can turn to the third party and ask, ‘Does he/she seem his/ her usual self today or do you see a change in thinking ability?’ Generally patient and significant other perceive changes concurrently but sometimes the third party may pick them up when the patient is too confused or slowed mentally to do so. Most often, the corroborating party mentions a worsening of forgetfulness especially in recalling recent events or plans. Referred to in cognitive science as working memory, this impairment often presents as a subtle change in recall that may not be obvious in routine medical encounters. If the patient and corroborator say that the patient’s cognition seems to be functioning normally, the evaluator may defer the cognitive exam for a few minutes, adding ‘Later in the interview I will ask you some questions that will let me know how your thinking is today’, most often providing an appropriate transition to the History of the Present Illness (HPI) in well compensated liver cases. Although more frequent in hospital settings, any time either the patient or the third party note changes in mentation, or if the interviewer notices the patient is having difficulty with attention and engagement in the conversation, a careful cognitive examination is best performed at the beginning of the interview. If the candidate suffers from cognitive incapacity, he/she may not provide accurate historical data simply because of memory retrieval, concentration, or other problems. As discussed extensively in neuropsychiatric texts, standard cognition assessment is best considered in two forms: basic and complex (Arciniegas and Beresford, 2001). The Mini-Mental State Exam (MMSE; Folstein et al., 1983), in wide use for cognitive screening, has been standardized by age and offers a reasonable tool for assessing basic cognition. It does not address complex cognitive functions. In the first author’s experience with liver transplant candidates, the MMSE does not offer a sufficient clinical test of working memory defined as the ability to record new memory information and then retrieve it 5 min later. Asking the patient to register (repeat out loud) four unrelated words, rather than the MMSE’s three, and then asking the patient to recall them after 5 min by the clock, rather than after the MMSE’s minute or two of varying elapsed time, offers a better window into the candidate’s working memory capabilities. A patient who can recall 3 or 4 of the words after 5 min can usually give a more reliable history than one who can recall only 2, 1, or none. Impaired working memory performance often indicates a subtle ‘subclinical’ hepatic encephalopathy that often will improve with adding or increasing lactulose treatment—a medicine thought to clear thinking by removing ammonia via the digestive tract. The Frontal Assessment Battery (FAB; Dubois et al., 2000) allows a standardized, scored evaluation of complex cognition. Used in its standard fashion, the examiner should have a printed or electronic copy before him/her and give the standard directions to the patient. The resulting additive score can then be used in a formula that accounts for normal age-related changes. Probably more important clinically, responses to the specific FAB tasks can give specific information on present complex cortical abilities in areas such as judgment, memory, level of involvement and executive/planning. Another standardized instrument, the Verbal Trails B (VTB; Mrazik et al., 2010) test, a spoken form of the original written Trails B test, recognizes the often subtle changes in complex cognition brought on by early hepatic encephalopathy. The interviewer introduces the VTB at the bedside or office by saying, ‘I am going to give you a pattern and I would like you to follow the pattern as far as you can go with it. The pattern is “1-A, 2-B.” What comes next?’ With encouragement but not prompting, the patient continues the sequence of alternating numbers and letters. The standardized norm is set at reaching ‘13-M’ or further with no errors in the space of 1 min. A below normal response usually indicates difficulties in functions mediated through the dorso-lateral pre-frontal cortex that are needed to plan and execute tasks, such as taking medications properly. A beside/clinic test of judgment provides a functional window into the orbito-frontal cortex and its state of health. ‘I am going to give you a situation and I want you to tell me what you would do in that situation. You are feeling well, you go to a movie and you are sitting in a crowded movie theater watching the movie. You are the first one to see a fire break out in the theater. What would you do?’ This standard question asks the patient to attend not only to the fire danger but also to the danger of panic in the theater. An acceptable response is ‘I would inform the theater management that there is a fire’ because it implies understanding of the panic danger, and provides an option for action against the fire while taking the panic danger into account. A frequent answer that may imply orbito-frontal compromise is ‘Yell FIRE!’, an option that does not account for the panic danger. The interviewer can follow-up with ‘What might happen if you did that?’ and listen for the secondary danger. If the patient says ‘It might cause a panic’, the interviewer then asks for other action options, ‘What could you do instead?’, listening for viable alternatives. Clinical practice also indicates a description of the motivation that sustains active attention throughout the interview. This last is an indication of the third major complex cognitive ability, one mediated by the anterior cingulate cortex of the frontal lobe. A patient presenting with a clear indifference to the issues at hand may suffer from a subtle delirium or from anterior cingulate cortex injury requiring evaluation. Attention to these and the basic cognitive functions allow an assessment of (a) the reliability of the patient’s clinical history, (b) his/her abilities to judge, plan and manage pre-transplant care in working with the liver team and (c) baseline cognitive functions that may often be impaired in a post-transplant delirium that may go unrecognized owing to their subtlety. When careful examination raises concern about a candidate’s cognitive ability, one question every transplant team asks is ‘Are the changes permanent?’ since few teams will provide liver grafting for demented patients. In the vast majority of candidates, it is important to consider changes of this nature as most likely indications of delirium—a temporary loss due to pathophysiologic causes from the liver failure—that will reverse with transplant. Improvement in the cognitive functions themselves, with lactulose, rifaximin, or other medical treatment to lower circulating ammonia levels before transplant, provides clinical evidence of a reversible delirium. True dementias, on the other hand, present with gradual lessening of cognitive abilities that do not reverse with treatment and indicate the necessity of an extensive dementia evaluation. Wernicke-Korsakoff’s syndrome, also known as Alcohol Amnestic Syndrome, characterized by a profound working memory deficit in the setting of generally normal cognition—especially of normal registration whereby a patient can recall six or seven or more random order digits spoken as a series by the examiner—indicates a trial of thiamine and the B-complex vitamins in an effort to demonstrate acceptable improvement prior to considering a liver graft procedure. HISTORY OF THE PRESENT ILLNESS The HPI is the work horse of the clinical evaluation and takes up the greatest part of the hour required for a capable assessment in experienced hands. Its specific sections in the liver transplant evaluation include the history and course of (a) the liver disease, (b) alcohol use, (c) other drug use including nicotine, (d) psychiatric disorders and conditions and (e) social stability. Liver history the psychiatric interviewer need not go into extensive detail that repeats the work of the hepatologists. A productive use of the first few minutes of history taking, however, includes meeting the patient and their significant other person on the common ground of concern about the liver disease. This builds a clinical alliance while giving the interviewer useful data. For example, the question ‘When did you first learn about your liver problem?’ provides a beginning point in understanding the course of events. Some report that their liver disease was first discovered from routine laboratory tests well before any symptoms. Others note that they were unaware of any conditions until the onset of a decompensation such as from acute alcoholic hepatitis (Lucey et al., 2009). In the latter condition some follow-up studies describe a window of approximately eighteen months between the first alcoholic hepatitis flare and the onset of more rapidly compensation from cirrhosis. In other cases, however, the alcoholic hepatitis may be more pathophysiologically aggressive and lead to more immediate transplant consideration. If the conclusion of the transplant team’s evaluation is to refer the patient for alcoholism treatment, for example, it is important to know where the patient might be in this relative time window of stable mental and physical functioning. Bearing on the alcohol use history itself, discussing the medical condition offers a useful point at which to ask ‘Did your physician or any other caregiver say that you should stop alcohol use?’ Use of a substance despite clear physical health consequences is one of the hallmarks of addictive disorder. The course of giving up alcohol or substance use may often take many months and include repetitive warnings from health care givers. On the other hand, a patient who minimizes the stated concerns of physicians and others about alcohol or drug use, with clear evidence to the contrary as in clinical records, may suggest an unresolved ambivalence with respect to stopping use. Assessing a history of prior confusion rounds out this section. It includes asking about bleeding episodes with related confusion, any periods of confusion that occurred spontaneously, and treatment for liver-related confusion. The corroborating other person often provides useful information on this topic since the patient may not remember all or part of a confusion episode. Prior occurrences, generally caused by the clinical or sub-clinical delirium due to the liver disease referred to as hepatic encephalopathy, signal that cognitive impairment has occurred in the past and that continues to be an important focus in the present assessment. In alcoholic cases, for example, confusion is sometimes wrongly misinterpreted as alcohol intoxication. A significant other person in the patient’s life who can differentiate the two will be an asset in continuing post-transplant care. Last use One way of transitioning from this part of the history into the next, often more sensitive, section on substance use is to ask the general question ‘When was your last use of alcohol or substances of any kind?’ The clinician may then record the patient’s recollection of last use and seek corroboration from the significant other person. This further introduces the third person’s role in the interview, and gives it a normal, matter of fact, tone that most third persons find helpful in being able to describe the patient’s drinking openly and honestly. It also introduces the focus on drinking and other drug use. Alcohol use history Clinically, two general concepts guide the use assessment of alcohol and other addictive drugs. First, the interviewer is assessing an addiction, or addictive disorder and alcoholism is a form of this phenomenon. Alcoholism, described more specifically below as alcohol dependence (AD; WHO, 2010), is second in prevalence only to nicotine addiction in most general populations. Second, AD and other forms of substance dependence are clinical diagnoses of specific behaviors, rather than quantifications of amounts and frequencies of use. An easily available source, the International Classification of Diseases, Tenth Edition (WHO, 2010) outlines the phenomena common to all addictive disorders. Further, experience in assessing liver transplant candidates suggests using the medical model of addictive disorders as disease states. Other models—such as moral choice, habit and reinforcement, or learned behavior—may make up useful discussions in other arenas but these have far less support from empirical data and offer very limited clinical utility. An empirically based medical model focuses on diagnosis and prognosis. Making a diagnosis The diagnosis of AD, and those of the other drug dependencies, requires specific evidence of phenomena in three clinical domains: physiological dependence—including tolerance and withdrawal, Loss of Control (LOC) of alcohol use—often erroneously referred to as ‘craving’—and decline in either physical or social functioning, or both. Of the dependence criteria listed in ICD-10 (WHO, 2010), for example, tolerance and withdrawal refer to physical dependence, while the LOC phenomenon and social or physical impairment each stand as independent criteria. But for our purpose, the three large symptom domains offer an easy way of remembering and assessing relevant symptoms in the clinic. Physiological dependence: tolerance and withdrawal Tolerance refers to the ability of the central nervous system (CNS) to approximate, or attempt to maintain, normal functioning in the presence of ever increasing doses of ethyl alcohol or any other CNS substance. Clinically, the person reports needing more alcohol to get the same effect once noticed at a much lower dose earlier in the natural history of drinking. To assess this, the physician must establish a baseline effect that has changed over time. This necessitates careful attention to the details of the drinking history. One useful approach may be to ask what the effect of alcohol was when a person first began drinking on his or her own. Results include such things as nausea, feeling high, or other unique descriptors that the patient can provide: what they noticed after one or two standard alcohol drinks. A standard drink, each containing roughly 0.6 ounces (about 14 g) of ethyl alcohol may be approximately defined as 12 ounces of 5% alcohol beer, 5 ounces of 12% alcohol wine, or 1.5 ounces of 40% whiskey or other spirits (HHS, 2015). After establishing a baseline, for example ‘in high school I got high after one or two cans of beer’, the interviewer may then ask how many standard drinks the person notices achieved the same effect at the time when their drinking was at its greatest. Some formal criteria designed to include many drugs of abuse require a 50% increase. In the case of alcohol, most will describe a doubling or more of the amount used for an initial effect. Many AD patients will describe amounts several times greater than those drunk in the state naïve to alcohol, such as ‘I don’t notice anything until after I drink a six pack’. This signals that the CNS has adapted to heavy alcohol use, that is, reached a tolerance. Notice that the interview has focused on the change in alcohol effect, not on the absolute amount of ethanol drunk. Using only the medical approach to understanding health and disease, practitioners often focus on the quantity and frequency of recent alcohol use as they might on how often a fever has spiked or how often and in what amount vomiting has occurred. The alcoholic patient, however, may not provide accurate responses to quantity/frequency questions. In the first place they may not remember how much they drink owing to intoxication itself or to related cognitive disorders. In the second place, alcoholism carries considerable social shame with it that often drives minimizing the reports of drinking quantity and frequency. And in the third, and perhaps most important place, alcoholic persons who have not reached stable remission remain in an ambivalent relationship with alcohol itself. This means that they can agree with their physician or caregiver that drinking is hurting them but have not reached the point of giving up the drinking behavior itself. Sensing that the physician’s role is to take their alcohol away, they may not wish to give their clinician opponent an upper hand in the struggle. This often leads to minimized quantity and frequency reports of alcohol use. For these reasons and others—such as the chronicity of the illness that is best measured in decades rather than weeks, months, or years—quantity/frequency questions offer only secondary data sources. The primary focus of the interview is on ‘how’ the person drinks rather than on ‘how much’. That is, the clinician best attends to the style of alcohol use rather than on quantity and frequency consumed. When focusing on the addictive phenomena themselves quantity and frequency data often arrive on their own, and very often aided by a responsible third party participating in the interview. Alcohol withdrawal defined clinically as an excessive activity of the sympathetic nervous system triggered by a rapid decline in alcohol blood level, withdrawal symptoms accompany tolerance in the great majority of individuals. In those who report no withdrawal symptoms despite a history of clear tolerance to alcohol, the clinician must ask whether the patient is drinking in the morning before withdrawal symptoms manifest themselves, or is regularly taking some other CNS depressant, such as a benzodiazepine or an agent with anticholinergic effects, that covers withdrawal symptoms, especially in the morning. On rare occasions, the physician will encounter patients who have little or no withdrawal symptoms despite clear tolerance. Although relatively infrequent, this recognized clinical phenomenon appears most likely due to a genetically based constitutional invulnerability to withdrawal. Since ethanol is a CNS depressant, its quick removal triggers CNS hyperactivity both centrally, as for example expressed by a subjective sense of jitteriness or impending disaster (anxiety), and peripherally through the symptoms of sympathetic nervous system discharge. Table 1 lists acute withdrawal symptoms that patient’s commonly report. Table 1. Patient reported symptoms of early alcohol withdrawal Anxiety  Palpitations (tachycardia)  Tremor  Rapid breathing  Nausea and vomiting  Low grade fever  Sweating  High blood pressure  Anxiety  Palpitations (tachycardia)  Tremor  Rapid breathing  Nausea and vomiting  Low grade fever  Sweating  High blood pressure  Of note, neither headache nor blackout, are symptoms of alcohol withdrawal. The former, a component of ‘hangover’ (Prat et al., 2009) often may have to do with fluid shifts in the brain that engage the meningeal pain sensors, while the latter is a state-dependent amnesia (Rose and Grant, 2010). Later occurrences, however, such as generalized grand mal seizures on or after the 24–36 h of withdrawal and the Delirium Tremens (DT’s) occurring after 72 h make up the most severe and most dangerous withdrawal phenomena (Schuckit, 2014). The DT’s, characterized by (a) confusion, (b) usually visual or tactile hallucinations and (c) extreme rises and vital signs, such as malignant hypertension or tachycardia, presents a true medical emergency usually resulting in hospitalization. Again, however, because of his/her confusion during the DT’s, the patient may not appreciate the significance of hospitalization for withdrawal. The corroborating third party is again useful in this instance. LOC phenomenon The essence of any addiction, and no less so in AD, is LOC of use. This refers to the inability of the AD person to predict with any degree of certainty how much they will imbibe within any drinking episode. Clinically, once the drinking episode starts, the AD person will be unable to stop in the middle of the drinking/use bout without a very great struggle. Useful questions at interview include the phrasing presented in Table 2. Table 2. Assessing loss of control First state: ‘Some people tell me they notice these things when they drink and I would like to know if you’ve ever notice them.   (1) Some find it very hard to stop drinking, once they start. They feel that they are ‘off to the races’ where drinking is concerned.  (2) Some people find themselves drinking more than they wanted to or had planned to.  (3) Some notice that they try to make rules to control their drinking.  First state: ‘Some people tell me they notice these things when they drink and I would like to know if you’ve ever notice them.   (1) Some find it very hard to stop drinking, once they start. They feel that they are ‘off to the races’ where drinking is concerned.  (2) Some people find themselves drinking more than they wanted to or had planned to.  (3) Some notice that they try to make rules to control their drinking.  While the phrasing may seem indirect, the word structure allies both interviewer and patient in looking at one phenomenon—the patient’s experience—rather than implying an adversarial setting in which the interviewer is examining the patient, as if under a microscope. Experience suggests that an allying approach gains much more detailed, and more useful information. At the same time, it is important to distinguish the LOC phenomenon from ‘craving’. The former has to do with the inability to stop drinking once started. Craving, classically defined, refers to the episodic and often intense desire or compulsion to drink or use between bouts of use. It may also be confused with the search for alcohol to treat withdrawal symptoms. The distinction can be made accurately in the clinical setting by paying attention to what occurs during episodes of use and what occurs between them. LOC during use is a hallmark of addiction while craving between use episodes appears to be a much different phenomenon involving brain/environment interactions. Social or physical decline The combination of physical addiction and LOC usually results in a patient’s expending a large portion of time and effort to sustain heavy drinking or to manage or recover from its effects. To assess this, the clinician asks whether drinking has become a problem with respect to family relationships, legal status, work, friendships or physical health. The physician will be especially attuned to the last of these since the physical illness sequelae of AD and other drug dependencies often result in frequent clinical visits and hospitalizations. The family relationships, however, usually offer the most sensitive indications of social difficulties due to alcohol or drug use. A change in work status is usually one of the last indicators of social difficulty since income provides the basis for continued use. AD, then, may be reliably diagnosed when evidence in all three domains presents. The ICD-10 diagnostic criteria do not require evidence in all three domains and therefore cast a somewhat wider diagnostic net. While either approach is defensible, the transplant team will do well to use both concurrently. The first author generally takes the more conservative approach for the AD diagnosis in the setting of life-threatening illness for which there is only one treatment alternative. Lesser diagnoses, such as Alcohol Abuse, offer better prognoses with respect to post-transplant abstinence. GAUGING PROGNOSIS When liver transplant teams ask for psychiatric or related expertise in evaluating liver graft candidates, they ask primarily for the candidate’s prognosis: Will this person ‘waste’ a liver graft with a return to uncontrolled alcohol, or other drug, use? Post-transplant risk Physically, the risk of graft injury or loss from a return to drinking emanates from two sources principally. The first entails alcohol injury to the new liver graft, a relatively rare occurrence that hepatologic knowledge cannot predict at present. Only about 15% of heavy drinkers acquire potentially fatal cirrhosis to begin with and the molecular mechanisms that trigger the process in some, but not in most other heavy drinking individuals, remain largely unknown. The second risk to graft injury is more ominous: graft rejection due to an inattention to post-transplant immune-suppression. Behaviorally, a return to uncontrolled drinking carries a high risk of non-adherence to the medicine regimen. Missing even a few doses in a twice-daily regimen, for example, can lead to a graft rejection reaction that the patient may not notice until its late stages, potentially irreversible and fatal by that time. This factor, mentioned here in the context of alcohol use, applies to any psychoactive agent used in an uncontrolled setting that may affect memory, planning and judgment functions in the brain. Both risks—direct alcohol liver injury, and graft rejection reaction—deserve mention in the psychiatric interview since they provide candidate and significant other with an important perspective on life following transplant. The first author brings them up near the end of the interview and usually in the context of (a) focusing the previous diagnostic and prognostic information on the risks of life after transplant, and (b) justifying the readiness of the significant other to alert the transplant team to any drinking or other concerning behavior. Positive versus negative How, then, to go about the task of assessing the prognosis for alcohol/drug free living post-transplant? (Beresford and Everson, 2000) While each individual patient and their social network provide unique considerations, a series of general factors, gleaned mostly from research on non-transplant populations of alcohol or drug dependent persons, offer useful windows on prognosis. In the great majority of cases these include (a) the alcohol and substance use diagnoses, (b) an assessment of the patient’s ambivalence towards continuing use, (c) measures of the candidate’s social stability and (d) a series of four empirically based factors that Vaillant (Vaillant, 1995) found in prospective research studies (Hillemacher et al., 2016). In addition, candidates with a co-occurring diagnosis of a major psychiatric disorder require (a) an evaluation of psychoactive medication response to the primary disorder and (b) a medication adherence history in addition to the factors already mentioned. Some liver teams focus more on what they see as predictors of negative prognosis—those that predict a return to drinking or use—rather than positive factors such as those that predict continued abstinence as mentioned above. The negative factors often include mention of (a) alcohol or other drug use in the past six months—the infamous ‘six month rule’ that has not been borne out in prospective research, and (b) counting previous ‘recidivist’ episodes, a term that calls to mind criminal incarceration and punishment rather than a remitting/relapsing medical condition. At the same time, many teams and outcome reports in the literature often ignore one of the primary indicators of relapse—the presence or absence of polydrug dependence, a phenomenon described in clinical subtyping of AD presentations as described below. While negative factors, such as evidence of current drinking in the setting of AD, come into play in the evaluation, focus on the positive factors at present offers a sound approach. Diagnosis is prognosis The diagnostic procedure described in detail above provides the basis for important prognostic distinctions bearing on post-transplant abstinence. One of the most common, and surprisingly least referred to in the published studies on candidate evaluation, is the distinction between AD history as a primary dependence and AD as part of a polysubstance dependence history. AD typology and polydrug dependence AD affects as many as 7–10% of persons in the US. In a great majority of cases it involves alcohol as the primary, and often only, drug of sustained abuse. Research reports refer to this as Type 1 Alcohol Dependence (Babor et al., 1992). By contrast polydrug dependence—that is, addiction to two or more substances, not including nicotine, that may include alcohol as one of the dependence substances—affects about 0.5% of persons in the US. This group refers to Type 2 Alcohol Dependence (Babor et al., 1992) or polydrug dependence (Vaillant, 1995). Although the distinction between the two types and their abstinence prognoses has been known for many years (Hillemacher et al., 2016) remarkably few programs take this distinction into account. For example, transplant programs that separate the two demonstrate high rates of abstinence in the primary AD (Type 1) (Lucey et al., 1997; DiMartini et al., 2010) group after transplant when compared to those that do not make this distinction often report much lower abstinence rates. Prior research on non-transplant samples demonstrates that the much more common primary AD persons will enjoy a far better prognosis than the polydrug dependent group (Vaillant, 1995). Table 3 summarizes the distinctions between the two in brief form. Table 3. Alcohol dependence vs. polydrug dependence (alcoholism Types 1 and 2) Primary alcohol dependence  Polydrug dependence  7–10% US population Alcohol primary dependence Normal childhood No conduct disorder (CD) Regular use: teens, twenties No personality diagnosis Natural remission: 30%/year With treatment: 45%/year  0.5% US population Polysubstance dependence Deprivation/abuse childhood CD symptoms: before age 15 Polydrug use: teens-middle age Adult personality disorder Natural remission: 10%/year With treatment: 10%/year  Primary alcohol dependence  Polydrug dependence  7–10% US population Alcohol primary dependence Normal childhood No conduct disorder (CD) Regular use: teens, twenties No personality diagnosis Natural remission: 30%/year With treatment: 45%/year  0.5% US population Polysubstance dependence Deprivation/abuse childhood CD symptoms: before age 15 Polydrug use: teens-middle age Adult personality disorder Natural remission: 10%/year With treatment: 10%/year  Further evidence for the usefulness of this distinction in transplant candidate selection comes from a recently published long term, prospective study on the outcome histories of liver transplant recipients with respect to return to alcohol use (DiMartini et al., 2010). Of five post-liver transplant groups whose ‘trajectories’ were separated by careful statistical analysis, the group presenting the most frequent and severe relapses were those with pre-transplant histories of abusing multiple substances. These data confirm that the polydrug dependent, or Type 2 AD, population carry the worst post-transplant prognosis. Practically speaking, the psychiatrist must evaluate AD type as a clinical guide to prognosis. While the Six Month Rule has little justification for use in Type 1 AD (DiMartini et al., 2006), a history of recent use of any dependent drug—including alcohol—in a Type 2 AD person constitutes an ominous finding. Empirical data on the polydrug group suggests that continuous, stable abstinence comes only after the emotional growth of many years, often in the person’s late 30s or 40s (Vaillant, 1995). In a person with Type 2 AD, demonstration of a corroborated, sustained, stable abstinence from both drugs and alcohol for a significant period of time—often measured by one or more years rather than by months—affords the liver transplant team the confidence to proceed in providing a scarce resource. Abuse rather than dependence When diagnosing AD or other drug dependence, it is important to establish whether the LOC phenomenon exists in each case. Its absence, even in the face of a clear history of tolerance or alcohol-related social or physical problems for example, strongly suggests the lesser diagnosis of Alcohol Abuse. In a clinical series previously reported (Lucey et al., 1994) about 10% of those applying for a liver transplant for alcoholic cirrhosis did not meet dependence criteria but could clearly be considered in the abuse category. Even though a lesser diagnosis, Alcohol Abuse still indicates asking the patient to cease all alcohol use. In that case, two phenomena often occur: (a) the person achieves and maintains abstinence without a struggle, and (b) the risk of relapse over the long term appears considerably lower. Generally speaking, Alcohol Abuse offers a much better prognosis than does AD and is a more optimistic diagnosis to make. Behavioral versus hepatic diagnosis A significant portion of those candidates referred to as ‘alcoholic’ will not merit the AD diagnosis. As previously published, the two authors compared Hepatology and Psychiatric reports for transplant candidates (Lucey et al., 1994). Only about 75% of those with a tissue diagnosis of alcoholic liver disease fit the behavioral AD diagnosis. Conversely, only about 80% of those referred clinically as ‘alcoholics’ met the AD diagnosis. Of the remaining 20%, half fit the Alcohol Abuse diagnosis and half did not merit either. This was especially true of women who, because of a well-known, if poorly understood, gender specific vulnerability to alcoholic liver disease, that may injure the liver without ever reaching AD. This limited overlap emphasizes the need for diagnostic precision. Continuing LOC risk Clinically, longitudinal studies of abstinence make it clear that once the control of drinking behavior departs, it does not return in the great majority of cases (Vaillant, 1995). Once lost, controlled alcohol or drug use cannot be re-learned or re-constituted. In this sense an AD diagnosis signals a permanent condition—including a permanent risk of uncontrolled drinking or use. This has a critical bearing on life after liver transplant in AD persons since it suggests that any alcohol use will remain, always, a high risk behavior for the new organ and daily use of immunosuppressive agents. Even brief non-compliance with the immunosuppressants can result in the rejection reaction and death. One component of the interview, therefore, requires review of this risk with the patient and third party. Poor understanding, or ambivalent acceptance, of post-transplant drinking/use risk in a patient with normal cognition may indicate an unresolved ambivalence toward AD itself and therefore the need for alcohol or other drug focused behavioral treatment. This can be followed by a return for re-evaluation, prior to transplant. Assessing ambivalence with respect to alcohol use Outside of the transplant setting, the process of reaching sustained abstinence can take months to a few years for those who will be able to achieve it. Studies of transplant recipients, however, report high abstinence rates in most subgroups, with the notable exception of those with a polydrug dependence history who lack long-term abstinence before transplant. For all potential recipients, an assessment of the extent to which the candidate has resolved their alcohol use can be made and will contribute meaningfully to the information at the team’s disposal. This assessment is difficult since it relies on the candidate’s subjective report of their relationship with alcohol with little or no outside corroboration or objective measure. Some have attempted quantifying the so-called change readiness in non-transplant samples but these, likewise, do not offer more objective corroboration. In this setting, one approach follows after the clinician has collected diagnostic data and is in a position to provide the AD diagnosis. This can begin with ‘Do you consider yourself an alcoholic?’ An unambivalent response often heard is ‘Absolutely. I cannot drink alcohol without drinking it excessively. Therefore I cannot drink alcohol at all’. This usually signifies a person who has come to grips with the ongoing risk that any alcohol drinking entails. An ambivalent response may be ‘I’m not alcoholic because I don’t drink anymore because of my liver’. Other examples may be ‘No, because I don’t drink every day’, or ‘Alcoholics drink to get drunk and I don’t do that so I am not an alcoholic’, or ‘Alcoholics drink hard liquor and I only drink beer’. In order, neither liver disease, daily versus binge drinking, intoxication, or beverage choice indicate a lack of AD. Specifically, only a minority of heavy drinkers go on to liver failure, current drinking frequency has little to do with the LOC phenomenon, most AD persons try not to appear either intoxicated or in withdrawal, and a standard 12 ounce can of beer has about the same alcohol content as a shot of spirits. Rather, all of these and others may be heard as examples of unresolved ambivalence towards the drinking disorder itself. In this setting it is crucial that the clinician not take on the role of trying to convince the AD person that they suffer from alcoholism. Because of the subjective nature of that task, it usually only leads to an unproductive struggle between clinician and candidate. A better approach is to review the drinking history obtained earlier in the interview with the patient and third party after hearing their response to ‘Do you consider yourself an alcoholic?’ For example, ‘You have described (a) a tolerance—your brain’s ability to adapt to heavy drinking, (b) your becoming ill with withdrawal when you stop, (c) your difficulty in stopping once you start drinking and (d) your liver disease and your social problems due to drinking despite statements of concern from others. When we find those things in a person’s life, we take them together as a diagnosis of Alcohol Dependence, what most people call alcoholism. We think of AD as an illness that people can get better from. But how about you? How do you think of alcoholism?’ From this, there often follows an understanding of the patient’s own perceptions that may be consistent with an unresolved ambivalence or, in occasional cases, a relief in not being regarded as immoral, sinful or any of the other stigmatizing views of AD. While this clinical area requires more investigation and better ways to link ambivalence with outcome, the results of a conversation along these lines gives the clinician the best data on which to judge the candidate’s own progress in stopping alcohol use. Operationally, the clinician’s lack of comfort with the patient’s responses is often the best indication for referral to focused treatment of AD if cognition permits and for subsequent case re-evaluation if the course of the liver disease will permit. Social stability This assessment tests the foundation upon which ongoing medical adherence and favorable prognosis are built. While several social stability scales exist, the simplest comes from the work of Strauss and Bacon (Straus and Bacon, 1951) who found that the presence of any two of four social factors predicted clinic appointment compliance among AD persons. These included: (a) being married, (b) not living alone, (c) stable employment for 3 years and (d) a stable residence for 2 years. Falling below the cut point suggests, but does not establish, the likelihood of insufficient social resources, such as in social isolation and homelessness, that raise the likelihood of both drinking relapse and medical non-compliance. When present, the specialized involvement of a treatment clinic program aimed at adding or strengthening social resources offers the best next step towards return to the liver team for re-assessment. Vaillant’s four prognostic factors In the best available prospective, longitudinal study of AD prognosis, Vaillant’s 8-year study and follow-up noted four operating factors, any two or more of which, when present, predicted long-term sobriety—defined as 2 years or more—while one or none indicated a return to drinking within 1 year (Vaillant, 1995). A proper prognosis evaluation includes them. Structured time Because AD style drinking requires a lot of time and effort, newly abstinent persons often encounter considerable ‘dead’, or unstructured, time that can itself foster a relapse. Structuring that time corrects this concern and is a frequent ingredient in specialized clinic and self-help group (such as Alcoholics Anonymous) formats. Any setting that fills time with productive and engaging activities—that the person’s ‘heart is in’—fits the need. At interview, a brief assessment of how the candidate spends his/her day addresses whether they engage in active projects that involve other people, or live an isolated existence such as in filling the time with endless television viewing. A rehabilitation relationship Sustained, heavy drinking or drug use serves to isolate the person from others and to create the need in those who come into social contact—such as family members—to ‘fix’ the drinking or use. Direct intervention—such as telling the person not to drink or use—generally results in an interpersonal struggle that works against continued abstinence. Rather, abstinence sets the stage for proper boundaries between person and social network. In brief, a professionally staffed clinic, a self-help network such as Alcoholics Anonymous, or informed family members who have given up the struggle to ‘fix’ the patient, or a combination of all of these, communicate the same approach to the person: ‘You can stay but the drinking has to go’. Assessing the extent to which the significant other person present at the liver transplant evaluation interview understands (a) that they cannot control the patient’s drinking or use, and (b) that they are ready to inform the transplant team when any return to use occurs or appears likely to, is a necessity. This can be done by asking ‘Is it clear to you that neither you nor I have any control over [the candidate’s] drinking?’ And, ‘What would you do if, many months after transplant, you suspected that [the candidate] was drinking?’ The proper answer to the first question is Yes and to the second, Call the transplant team as well as mobilize any local caregivers, such as a specialized treatment clinic. When the significant other person does not understand their own limits, further education on the topic is in order. Most third parties who do not apprehend the need to call for help in a dangerous situation involving alcohol or drug use find relief in a review of whom to call and when, then and there in the interview. Sources of hope or self-esteem Regretful thoughts about having hurt others during drinking days frequently return to most AD people during abstinence periods. Ruminating on them has the effect of lowering hope and self-confidence and thereby promoting a return to drinking or use: ‘I am a terrible person, I may as well drink’. In assessing prognosis, the interviewer inquires after mechanisms that help a person through such periods. These include hope for the future—‘What keeps you going in life? What do you look forward to?’—and sources of accomplishment or self-esteem—‘What helps you to feel good about yourself? What gives you a sense of usefulness or accomplishment?’ The evaluator may also note ‘Most people run into regrets about their drinking days. Does this happen to you?’ If the answer is positive, ‘What helps you get past regretful thoughts without drinking?’ For some it may be religious beliefs, for others the ‘higher power’ without religion—as Alcoholics Anonymous describes it, and for others a concentration on items of hope and accomplishment, such as ‘another day behind me without drinking’. Clinically, the absence of forces that counterbalance regretful ruminations presents an ominous sign and one indicating further specialized treatment focus. A negative behavioral reinforcer ‘Is there something very painful that will happen to you, without doubt, the very next time you drink alcohol?’ Very few circumstances meet these criteria. Severe pancreatic pain and the disulfiram-ethanol reaction are the most frequently encountered. Liver failure does count because of its subtlety and lack of predictability on each occasion. While the others of Vaillant’s factors can be considered positive changes in the path to sustained abstinence, this is the only negative one and is generally the least frequently encountered in the liver transplant setting. Summing up prognosis While none of the factors listed under Prognosis may individually offer absolute certainty in respect to sustained abstinence in each individual case, their combination offers a prognostic pattern that appears useful. Our early algorithm (Beresford et al., 1990b), for example, predicted high rates of abstinence in AD liver transplant recipients who present a series of good prognostic factors. With further experience, the individual factors might be summed clinically in Table 4. The reader will notice that the prognostic factors listed there can be addressed and re-evaluated longitudinally. Table 4. Addressing prognostic factors before transplant Physical diagnosis   Cognitive impairment: lactulose or other treatment and re-evaluate  Substance use diagnosis   (1) Type 1 Dependence: proceed to further prognostic evaluation  (2) Type 2 Dependence: verify either lengthy sustained abstinence and the ‘maturing out’ process or verify continued effective treatment as for example in methadone maintenance for opiate dependence  (3) Abuse: verify cessation and abstinence and proceed to transplant  (4) No diagnosis: proceed to transplant  Substance use prognosis   (1) Unresolved Ambivalence Toward Use: focused treatment on this aspect of abstinence; re-evaluate in 3–6 months.  (2) Unstable Social Adjustment: establish viable social resources; 3–6 month follow-up re-assessment  (3) One or none of Vaillant’s Factors: focused treatment referral; 3–6 month follow-up assessment.  Physical diagnosis   Cognitive impairment: lactulose or other treatment and re-evaluate  Substance use diagnosis   (1) Type 1 Dependence: proceed to further prognostic evaluation  (2) Type 2 Dependence: verify either lengthy sustained abstinence and the ‘maturing out’ process or verify continued effective treatment as for example in methadone maintenance for opiate dependence  (3) Abuse: verify cessation and abstinence and proceed to transplant  (4) No diagnosis: proceed to transplant  Substance use prognosis   (1) Unresolved Ambivalence Toward Use: focused treatment on this aspect of abstinence; re-evaluate in 3–6 months.  (2) Unstable Social Adjustment: establish viable social resources; 3–6 month follow-up re-assessment  (3) One or none of Vaillant’s Factors: focused treatment referral; 3–6 month follow-up assessment.  While this offers liver transplant teams the best option in moving to decision, sometimes the clinical presentation does not allow it, as when a patient’s acute liver decompensation indicates transplantation as the only viable option for leaving hospital. In that situation, the evaluator addresses as many of the above factors as possible, including communication with the patient and family, and presents the clinical data in the discussion with the liver transplant team wherein the various sets of data can be considered and a consensus reached. OTHER PSYCHIATRIC ASSESSMENT The foregoing discussion relates to the great majority of persons with alcohol or substance use histories referred for liver transplantation who do not have other pre-existing psychiatric conditions. One critically important feature of this patient group recalls that AD can mimic all of the major psychiatric disorders including Major Depressive Disorder, Bipolar Disorder, Psychosis, several Anxiety Disorders and Obsessive Compulsive Disorder, as well as other entities such as sleep discontinuity and anorexia. These and others can be assessed through a series of standard screening questions that will not appear here. When addressing them, the evaluator must keep one truly important factor in mind: other psychiatric disorders cannot be established with certainty during periods of heavy drinking and, to some extent, during periods of other drug use. Diagnostic clarity for the listed psychiatric disorders requires evidence during abstinence periods that generally exceed one month. Failing to observe this may lead to misdiagnosis and gratuitous use of treatments, most often psychoactive medications. A WORD OF SUMMARY Liver transplantation remains the only successful treatment for liver failure to the present moment, although new developments in genetic engineering and hepatocellular growth may someday replace allograft procedures. Our own recent work has suggested that some of the immunosuppressants or their analogs may someday have a role to play in treating alcohol use disorders (Beresford et al., 2005, 2012, see also Ronan and Beresford report in this Special Issue). In proceeding to allocate liver grafts that preserve lives, transplant teams have acted fairly and compassionately in considering patients with AD and have done so empirically in the best traditions of clinical medicine (Beresford and Everson, 2000). This discussion raises many questions that deserve addressing at this intersection of medical, surgical and psychiatric knowledge. These include the currently unresolved areas of precision in evaluating polysubstance dependent persons, in assessing the ambivalence concerns in the primary AD setting, and issues involving post-transplant care. This field has the opportunity to grow in these important areas that will derive knowledge widely applicable in other settings and conditions from which many more than the transplant recipient population will benefit. FUNDING No grant funds were expended in writing this report. Dr. Beresford receives salary support from the U.S. Department of Veterans Affairs. 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Alcohol and AlcoholismOxford University Press

Published: Mar 1, 2018

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