January 12, 2013

Liver Transplant—Psychiatric and Psychosocial Aspects

Journal of Clinical & Experimental Hepatology
Volume 2, Issue 4 , Pages 382-392, December 2012

Sandeep Grover, Siddharth Sarkar

Department of Psychiatry, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India

Received 22 May 2012; accepted 17 August 2012. published online 29 August 2012.

Liver transplantation is a life saving surgical procedure that is associated with improved longevity and enhanced quality of life. The number of successful liver transplants is growing worldwide. The procedure requires a dedicated and trained team of experts. A psychiatrist plays an important role in such a team. Psychiatric and psychosocial assessment is considered imperative to evaluate the candidate's suitability as a transplant recipient. Many psychiatric disorders may lead to the need for liver transplant, and if kept unchecked can adversely affect outcomes. Psychiatric problems arising in the post-transplant period may also require intervention of the psychiatrist. The donor too needs to be evaluated adequately to assess for psychological fitness for the procedure. This article provides broad overview of the various psychiatric and psychosocial issues pertaining to liver transplantation.

Keywords: psychiatry, psychosocial, liver transplant

After the advent of potent immunosuppressants, the number of solid organ transplants has increased substantially.1 The organs that are transplanted from one person to another include kidneys, liver, heart, lungs, and pancreas among others. The field of transplant medicine has emerged as a growing specialty and has seen many innovative procedures, surgical techniques, and improved aftercare measures.2 Encouraging results have been obtained, with better patient outcomes and longevity.

Since the conduct of first successful liver transplant in 1967, the number of liver transplants has grown steadily over the decades. It is now being conducted all over the world in increasing counts. Although around 6000 liver transplants are conducted in the United States in a year,3 the number of cases requiring transplant on the waiting list are far more than the number of procedures done in a year. With the live donor liver transplantation, the numbers of liver transplantations conducted has increased significantly.

The procedure of liver transplantation is carried out by a team of experts and specialists, who endeavor to improve outcomes by playing a role before, during and after the surgery. The psychiatrist/mental health professional can have a very important role to play in such a team. There can be mental health issues that lead to the liver transplant in the first place, for example, liver damage due to alcohol dependence or a suicidal attempt in which person intentionally takes overdose of acetaminophen leading to hepatic failure. Once the decision for liver transplant is taken, waiting for transplant may lead to anxieties about survival and availability of the organ.4 Patients may be apprehensive about asking potential donors for help in case of live donor transplantation.5 The transplant procedure as well the conditions leading to it can be quite stressful for the patients and may have psychiatric and psychosocial implications. Post-transplant, patients require regular compliance to lifelong immunosuppressants and modification in lifestyle, including abstinence from alcohol. All these factors challenge the coping of the patients, and increase the likelihood of emergence of psychological symptoms. The psychiatrist/mental health professional with expertise in dealing with such problems, would be placed at a unique position to contribute to enhanced patient care, and improved outcomes. This review provides a broad overview of the various psychiatric and psychosocial issues pertaining to liver transplantation.

Psychiatric disorders in pre-transplant phase

Patients with liver failure requiring liver transplantation can have various psychological and psychiatric problems. Timely identification and treatment of these can lead to improvement in condition of the patient, thereby optimizing the pre-operative fitness. An important aspect of evaluation is the proper documentation of the same. It not only serves the purpose of record keeping, but helps in clearer decision-making regarding management of psychiatric condition and better communication with other members of the treatment team. It is in general suggested that treatment recommendations need to be made, taking into consideration all the pertinent aspects of a particular patient.

The most commonly encountered psychological problems include alcohol use disorders, opioid use disorders, anxiety disorders and depressive disorders. Alcohol liver disease (ALD) is one of the commonest reasons for undergoing liver transplantation.6, 7 In most of such cases of ALD, diagnosis of alcohol dependence is tenable.8 Debate has continued as to whether and when ALD patients should be considered for transplantation. Some argue from a moralistic standpoint that since alcohol had been consumed by a person willfully leading to complications,9 so scarce grafts should not be expended on alcohol users. Others assert that there is no difference in survival of ALD transplant cases as compared to others, and a majority of patients with ALD do abstain from alcohol after transplantation.10, 11, 12 Hence these patients should be considered for transplantation. Currently most centers require some duration of abstinence from alcohol before consideration for transplantation.13 The requisite duration varies from center to center. It has been seen that longer abstinence prior to transplantation reduces the chances of relapse after the transplant.14, 15 However, other studies have shown that early transplant, even during the acute alcoholic hepatitis phase, is also associated with greater survival benefit over 2 years.16 Interestingly, early transplantation has been found as a protective factor against relapse to alcohol when compared to cirrhotic patients on wait list.17 Thus, deserving ALD patients should be offered transplantation.

Apart from pre-transplant abstinence, many other factors have been assessed as predictors of relapse to alcohol use post-transplant. These include a family history of alcohol use,18, 19 personality disorders20, 21 and poly-substance abuse.18, 22 Another important aspect is presence of psychiatric comorbidity in patients with ALD undergoing liver transplant. Studies have shown that presence of antisocial behavior and eating disorder increases the chances of relapse in the post-operative phase.20 In a review of literature, it was found that social stability, older age, good compliance with medical care, absence of repeated alcohol treatment failures, absence of alcohol problems among first-degree relatives, absence of current polydrug misuse, and lack of co-existing severe mental disorder were associated with longer abstinence in the post-operative period.23 Duration of pre-operative abstinence appears to be a poor predictor of abstinence despite extensive research and wide usage.23 Intravenous drug use also has an important relationship with need for liver transplantation. It is an important risk factor for contracting Hepatitis C, which is among commonest reasons for liver transplantation. Hence drug dependence, especially of injectable drugs like opioids and cocaine, needs to be carefully screened. One study suggests that outcome of intravenous drug users with Hepatitis C related liver transplantation is not substantially different from non-drug users.24 Poly-substance use disorder however, has been seen to adversely affect the outcome in ALD. In a study of liver transplant patients it was seen that approximately one third of the transplanted poly-substance users relapsed to substance use.25

Opioid users have been traditionally considered unsuitable for liver transplantation. In a mailed survey of transplant programs,26 it was noted that approximately only half of the programs accepted patients on methadone maintenance. Of those, a significant proportion required that the methadone be tapered off before the transplant. However, some authors have argued against the same.27 Studies done in patients on methadone maintenance treatment (MMT) in general show that tapering off of MMT results in relapse to illicit opiate use in 80% of patients.28 Hence, asking the patients to taper off methadone at the time when they are dealing with the stress and pain of end-stage liver disease and are facing liver transplant may increase the risk of relapse. Further, if a patient relapses, he or she would be removed from the list of those eligible for transplantation. Studies have also shown that in general there is no difference in the MMT liver transplant recipients and general transplant population with regards to adherence to immunosuppressive medications and overall graft survival rates.26, 29, 30 Hence such patients should be evaluated on a case to case basis and methadone can be safely continued in the post-transplant period in the usual doses. Those patients who are on stable adequate doses of methadone, follow other measures of MMT program and have excellent social support should be considered for liver transplant.

Many studies have been conducted to assess depressive symptoms in patients awaiting liver transplantation.31, 32, 33, 34, 35, 36, 37, 38, 39, 40 The sample sizes of such studies have ranged from 20 to 247.31, 32, 33, 34, 35, 36, 37, 38, 39, 40 Various instruments have been used to measure and diagnose depression including self-rating scales like Beck Depression Inventory; clinician rated scale like Hamilton Depression Rating Scale and structured interviews with professionals. The rates of depression have varied from 4.5% 31 to 64%.33 The different measures for assessing depression and different methodologies of assessing (self versus clinician rated) can account for some of the variance in prevalence of depression. In a comparatively large study by Bianchi et al35 with relatively rigorous methodology, significant depressive symptoms were present in approximately 57% of the sample using Beck Depression Inventory. Attempt have also been made to differentiate the rates of depression relating to different etiologies of cirrhosis, with some studies reporting higher, whereas others reporting lower or no difference in the rates of depression in patients with viral etiology for cirrhosis compared to other etiologies.27, 28, 31 Identification of depression in the pre-transplant phase is important, because there is some evidence to suggest that presence of depression in the pre-transplant period is associated with non-adherence with treatment.41

Studies have also delved into the occurrence of anxiety disorders and adjustment disorder in patients awaiting liver transplantation. Different methods have been used to measure anxiety like Beck Anxiety Inventory, Hospital Anxiety Depression Scale, and structured clinical interviews. The results show the prevalence of anxiety symptoms or anxiety disorders varies between 20 and 50% in the patients awaiting transplantation.31, 32, 37, 38, 39, 42, 43 Among the various anxiety disorders, presence of adjustment disorders31, 37, 38 and obsessive symptoms42 have been documented in a significant proportion of patients. A study in which domains of anxiety and depression were combined, reported a diagnosis of adjustment disorder or depression in upto 36% of the patients awaiting liver transplantation.44

Personality characteristics and coping abilities have been evaluated in patients waiting to undergo liver transplant. It has been seen that patients frequently have maladaptive coping styles with poor fighting spirit, anxious preoccupations, hopelessness, negation and fatalism being found frequently.45 Negative coping styles that include acceptance-resignation strategy were associated with a worse perception of physical functioning, general and mental health.46 Others have reported psychological regressive functioning (high control and dependency on medical staff, submissiveness) in patients waiting for liver transplantation, which can be interpreted as defensive responses to upcoming transplant.47

Another common psychiatric entity which has been reported in pre-transplant patients is delirium. It is reported in up to half of patients prior to liver transplantation.31, 48, 49 This may be ascribed to hepatic encephalopathy and other associated medical factors like electrolyte imbalances and infections. It is important to identify delirium as the presence of this condition may impair the ability of the patient to fully comprehend the implications of the transplant and its related commitments.

Concern has been raised about whether psychotic disorders should be considered a contraindication to liver transplantation.50 There have been instances where transplantation has been performed successfully in patients with schizophrenia and other psychoses.51, 52 The common problems encountered before and after the transplant in psychotic patients include non-compliance to psychotropic and immunosuppressant medications, risk of suicide attempts and recurrence of the psychotic symptoms.52 Being homeless or living alone is associated with higher rates of non-compliance to medications in these patients. Hence, it is recommended that due consideration should be given to control the psychotic symptoms in the pre-transplant phase and the symptoms should be closely monitored in the post-transplant period.

Pre-transplant assessment

Pre-transplant evaluation is used to identify psychiatric illnesses and psychological problems in the patients,53, 54 and provides an opportunity to intervene and manage them effectively. This evaluation is a part of the preparatory stage for consideration of liver transplantation. It must be remembered that evaluation for transplant may be required on more than one occasion as there may be a delay in obtaining graft and attaining medical fitness for the surgery. Further, while carrying out the assessment, information must be obtained from all possible sources.

Certain cases, for example, those with acetaminophen toxicity will require urgent psychiatric evaluation. This situation may be complicated by patient being on mechanical ventilation, which compromises detailed psychiatric evaluation of patient. In such situations, information should be collected from other sources including that from caregivers and family members. In many cases, the decision for considering transplant is determined on the basis of the history. In general many transplant teams are more comfortable in listing a patient when the overdose appears to be an outcome of an isolated impulsive act precipitated by a stressful life event, rather than those who have recurrent pattern of self-harming behavior arising due to psychiatric disorders like alcohol dependence, personality disorders or mood disorder.55

Psychiatric evaluation

Identification and management of psychiatric problems in the pre-transplant phase is very important because these have a bearing on the post-transplant outcome. It has been shown that quality of life of candidates waiting for liver transplant is also influenced by psychiatric disorders. In a study which evaluated the quality of life of pre-transplant patients, it was seen that physical and mental wellbeing in liver transplant candidates were influenced far more by psychiatric factors such as depression and coping strategies than by clinical and sociodemographic factors.38 Hence, identification and management of psychiatric disorders is of paramount importance to improve the outcome of patients waiting for the transplant and also in the post-transplant phase.

The protocol for assessment varies from center to center. It has been suggested that active psychiatric illness is a modifiable risk factor for poor outcome in transplant recipients.56 Hence a comprehensive assessment is necessary.

A group of assessment measures encompassing a wide variety of functions can be utilized to obtain a comprehensive understanding of the patient. The assessment protocol can use a structured diagnostic instrument for psychiatric diagnosis,57 instruments to assess depression, anxiety and delirium,58, 59, 60 a structured personality assessment,61 coping inventories,62 neuropsychological batteries,63 and others as deemed necessary. It has been seen that structured interviews lead to better accuracy of psychiatric diagnosis as compared to unstructured traditional diagnostic assessment.64 The presence of psychiatric disorders can be evaluated by the initial use of screening questionnaires followed by detailed psychiatric evaluation. Various screening questionnaires include generic instruments like General Health Questionnaire (GHQ)65 or disorder specific questionnaires like Primary Care Evaluation of Mental Disorders (PRIME-MD)-Patient Health Questionnaire (PHQ).66 These screeners can be followed by detailed relevant self-rated or clinician-rated instruments. GHQ was originally developed as a 60-item questionnaire as a unitary screening measure for psychological problems. Now the 30-, 28- and 12-item versions are in vogue. The 12-item version is a very popular screening measure. Each item is noted on a 2—point scale (better than usual or same as usual is rated as 0, and less than usual or much less than usual is rated as 1). PRIME-MD PHQ is a self-report screening instrument which can be used to screen/diagnose common mental disorders. It includes 8 diagnostic categories, viz. major depressive disorder, panic disorder, other anxiety disorder, bulimia nervosa and other sub threshold disorders such as other depressive disorders, probable alcohol abuse or dependence, somatoform disorder and binge eating disorders. There is high degree of agreement on the presence of psychiatric illness as assessed by PHQ and physicians.

Patients undergoing liver transplantation pose difficulty in diagnosis of depression due to the emergence of somatic symptoms from the underlying medical illnesses and the concomitant medications. Hence alternative approaches to ascertain depression can be utilized as has been done for other medically ill patients.67, 68 Certain items from the substitutive criteria like ‘brooding, self-pity or pessimism’ and ‘cannot be cheered up, doesn't smile, no response to good news or funny situations’ may be useful for detection of mild and severe depression, respectively, as has been found for cancer patients.69 Beck Depression Inventory58 which focuses on the cognitive aspects of depression may be a better suited instrument for assessment of depression in liver transplant candidates. It is a 21-item self-report instrument for measuring the presence and severity of depressive symptoms. It is one of the most widely used instruments for measuring the severity of depression. It can also be used to monitor change in depressive symptoms over time and provide an objective measure for judging improvement.

Other important psychiatric aspects to be considered are antisocial and borderline personality features, history of assault, positive psychotic symptoms such as hallucinations and delusions.53

Psychosocial assessment

Besides core psychiatric disorders, there can be many psychosocial issues which can influence the outcome of liver transplant. Hence, a detailed and comprehensive psychosocial evaluation is imperative in patients undergoing liver transplantation. This would be helpful in understanding the circumstances and the profile of the patient better, allowing requisite changes to be incorporated in the management. In this evaluation, information needs to be gathered from as many sources as possible. The patient's own history, significant other's account, medical records, insurance records, nursing staff's inputs and other sources may give valuable information. At times patients may be motivated to conceal certain information so that they are not excluded from the transplant list. This may happen especially in cases of alcohol use disorders where the patient may minimize or deny recent use of alcohol so that they are considered appropriate candidates for transplant.70

The salient features of the psychiatric and psychosocial evaluation are highlighted in Table 1. The evaluation of the patient typically involves determining the coping skills and other psychological attributes of the patient, gauging the social situation, assessing the patient's capacity to give informed consent, and ascertaining the likely adherence to post-transplant care. Information should be specifically recorded about alcohol and substance use as these often create the need for the transplant, and relapsing to such behavior may worsen the outcome.23

Table 1. Psychosocial evaluation of the patient.

Assessment of psychological attributes of the patient
Coping styles
Adaptation to illness
Illness behavior
Commonly applied defense mechanisms
Motivation for surgery
Past treatment compliance
Quality of life
Evaluation of the social supports
Availability of an identified caregiver
Availability of alternative person(s) in case primary caregiver is not available on a particular day
Assess for the financial condition and supports
Availability of adequate finances/ insurance cover for the transplant procedure
Ability to afford for lifelong immunosuppressant medications
Assess ability to understand the transplant procedure and the associated risks and liabilities, to put the expected benefits in the right perspective, give informed consent
Assess the likely adherence to the treatment

Considering the importance of psychological issues, different instruments have been designed to carry out comprehensive psychosocial assessment of patients to undergo liver transplantation. The Transplant Evaluation Rating Scale (TERS)71 classifies patients' level of adjustment in ten aspects of psychosocial functioning. The scale shows a good inter-rater reliability and has been evaluated in liver transplant recipients. Psychosocial Assessment of Candidates for Transplantation (PACT) is another instrument that has been used in this population.58 PACT has eight subscales, each rated on a 5-point scale, and an initial and final rating independently based on the rater's overall impressions of the candidate's acceptability for transplant. Recently, Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) has been evaluated in transplant candidates.72 The instrument shows good inter-rater reliability, and good correlation with psychosocial outcome. Use of any one or combination of these instruments can help in deciding transplantation candidacy.

The liver transplant is a stressful procedure. The patient requires emotional support, good nursing care, regular follow up, proper medication adherence and monitoring subsequent to the transplantation. These are facilitated by the presence of a support figure. Social supports are required for pragmatic reasons to ensure patients' psychological and medical well being. Hence it is useful to have an identified caregiver who would co-ordinate the care and act on behalf of the patient when in need. He or she may be needed to decide on behalf of the patient if the latter becomes incapacitated. Alternate supports also need to be enlisted for possible situations when the primary caregiver is unavailable to provide care, or takes a vacation. The caregiving process has its own stress and emotional well being of such caregivers also need to be attended to.73, 74

An important aspect of assessment is evaluation of competence to give informed consent. It needs to be ascertained whether the patient is in a condition to fully comprehend the implications of his or her decision. The transplant requires a lifetime commitment and major changes in lifestyle. It is useful to unambiguously provide as much information as possible, before a decision is made.75, 76 In case patient is not deemed to have capacity to give such consent, then the onus falls on the identified legal guardian to make such a decision on his/her behalf. The issue of confidentiality should be treaded carefully. The patient may disclose confidential information to the mental health professional which may have implications in the overall management. For example history of intravenous drug use concealed from others, fearing stigma or rejection from candidacy. It may be prudent to convey to the patient beforehand that requisite information would be shared with the multidisciplinary transplant team members for his or her benefit.

At times, emergency evaluation may be necessary especially in cases of acute hepatic failure.77 Therein limited time may be available to conduct detailed assessments. Moreover, patient's condition may not permit a clinical interview. It may be practical to gather as much information as possible from the collateral sources to generate an impression of the patient's psychological condition. Thus, assessment is expedited and so that a life saving procedure can be conducted in due time.

Psychiatric issues as contraindications for liver transplant

It is important to remember that some of the psychiatric aspects as depicted in Table 2 are considered as relative contraindications for liver transplant. These conditions must be interpreted with caution as mere presence of these does not preclude a patient from being a recipient.

Table 2. Psychiatric and psychosocial contraindications of liver transplantation.

Severe personality disorders
Active substance use
Active psychosis
Severe neuro-cognitive disorders
Absent or inadequate psychosocial supports
Demonstrated poor adherence
Factitious disorder

Psychiatric problems in the post-transplant period

In the immediate post-transplant period, many psychiatric problems can arise which may necessitate the involvement of the psychiatrist/mental health professional. Delirium (also referred to as encephalopathy) is reported to be the most common neuropsychiatric problem after the transplant surgery.78, 79, 80 It is characterized by confusion, disorientation, fluctuation in consciousness and agitation, and poses as a management difficulty in the intensive care unit. Development of encephalopathy has been associated with higher rates of mortality.80 The causes of delirium can be varied in a patient of liver transplantation and may include concurrent brain pathological processes, e.g. infection or bleed; effects of vasoconstriction secondary to immunosuppressive medications (especially cyclosporine and Tacrolimus); and central nervous system pharmacodynamic effects of the immunosuppressive medications.81 Evaluation of delirium during this period of time must include careful medical examination of the patient and a review of the medications and laboratory studies. Neuroimaging, EEG recording, and lumbar puncture can also provide valuable information in evaluating the cause of delirium.82 Delirium can be managed with low dose antipsychotics (oral and injectable) and behavioral interventions, along with addressing the underlying cause.

Apart from delirium, development of catatonia has been reported in the post-operative period.83, 84, 85 Medical complications of the transplant can also present as other psychiatric disorders. Hepatic artery thrombosis has been found to be associated with development of psychosis.86 Hence a careful assessment of the symptoms, and proper psychiatric examination is warranted.

Many psychiatric disorders have been seen to be present subsequent to liver transplantation. The rates of depression have ranged from 5% to 46%.87, 88 In a follow up series, Fukunishi et al89 using interviews by trained professionals in the post-transplant period found psychiatric illnesses to be present in 22 out of 41 (54%) of adult recipients within 3 months post-transplant. The diagnoses included delirium in 7 patients, depression in 5, dysthymia in 4, adjustment disorder in 3, brief psychosis, PTSD and substance related disorder in one patient each. Over longer follow up of 1 and 3 years, lesser numbers of patients had diagnosable psychiatric disorders (7% and 2% respectively).78 Rothenhäusler et al87 studied 75 liver transplant patients post-operatively for psychiatric disorders and found at least one disorder in 17 patients (22.7% of sample). The authors found full PTSD in 2 patients, full PTSD and depression in 2 patients and partial PTSD (having symptoms of PTSD, but not meeting full criteria) and depression in one patient, and partial PTSD in 12 patients. Chiu et al90 reported that upto 70% of the patients had psychiatric disorders in the post-transplant period and anxiety, depression and delirium were the major reasons for referral to a psychiatrist/mental health professional. Pérez-San-Gregorio et al91 noted that depressive symptoms as measured by HADS were more common in the ICU post-transplant, while anxiety was present in the post discharge phase. High levels of post-transplant anxiety resulted in reduced functioning in multiple life domains.91 Russell et al88 showed that the rates of anxiety and depression decrease significantly when compared to the pre-transplant rates.

A ‘paradoxical psychiatric syndrome’ has been described in recipients of liver transplantation.89 It has been termed paradoxical as it develops despite successful transplantation. It develops late after the transplantation and is characterized by recipients having strong guilt feelings toward their donors, not being able to verbalize their inner feelings, and using avoidant coping behaviors to suppress their conflicts. The ‘paradoxical psychiatric syndrome’ has been shown to be associated with pre-transplant alexithymia and abnormal projective drawing in the recipients.92

Management of psychiatric disorders and other psychosocial issues

The psychiatrist/mental health professional have an important role in management of psychiatric disorders detected before and after the transplantation. Besides this the psychiatrist/mental health professional have an important multifaceted role in the continuum of care of transplant recipients (as mentioned in Table 3).

Table 3. Role of the psychiatrist in the management of the patients of liver transplant.
Appropriate treatment of the pre-existing substance use disorders and other psychiatric disorders
Consideration toward possible interaction and side effects with pharmacological agents
Assess for emergence of psychiatric symptoms, institute relevant management measures in case they arise
Conduct psychotherapy when incorporated in management plan
Enhance adherence to treatment
Communicate the expectations of the treatment team to the patient and give patient's feedback to the treatment team
Engage in support groups if available
Develop and monitor occupational and social rehabilitation plan

Many of the psychiatric illnesses can be treated with effective pharmacotherapeutic and psychotherapeutic interventions. Particular consideration needs to be given to pharmacological interactions as these patients may be receiving a variety of medications. Pharmacological options primarily include antipsychotics for management of delirium and psychosis, antidepressants for anxiety and depression, and benzodiazepines for anxiety and sleep problems. When needed mood stabilizers, anticraving agents and deterrent agents can be given. Attention needs to be paid toward possible drug interactions, especially with the immunosuppressants that are prescribed to avoid graft rejection. While reviewing the drugs it is important to look for not only the prescription drugs, but attention also must be paid to over the counter medications. Tacrolimus may potentiate the QTc prolongation with antipsychotics, especially first generation antipsychotics like haloperidol. It can also potentiate nephrotoxicity when co-administered with lithium. Systemic steroids can increase the chances of seizures with bupropion. Carbamazepine may decrease the blood levels of cyclosporine due to induction of hepatic metabolism.93, 94

In patients with history of alcohol use and ALD, relapse to alcohol taking behaviors has been considered as a major challenge. The relapse rates have been found to vary from about 10 to 30%.14, 18, 19, 95, 96 The predictors of relapse to harmful use of alcohol include shorter duration of abstinence, presence of psychiatric comorbidities, younger age, and high scores on scales assessing risk of relapse.95, 96, 97 Different trajectories of alcohol use pattern after transplantation has been reported.12 Preventing lapse and relapse to alcohol use is of significant importance. Even in cases of lapse or relapse, immediate and effective treatment interventions can delay and avert harms of alcohol use.

A major issue in liver transplant recipient is long term adherence to treatment. Poor adherence not only manifests as failure to take prescribed immunosuppressants on a regular basis, but also as missed appointments to the physicians, failure to get required laboratory tests done, and failure to conform to lifestyle changes like avoidance of alcohol and smoking.98 The problem of non-adherence has been found to be present in both children and adult recepients.99, 100 There is no single intervention demonstrated to reliably improve adherence, and it appears that a multifaceted approach involving reminders, enlisting co-operation of significant others, and motivation enhancement may be of use.89

Undergoing liver transplantation may be associated with some improvement in health related quality of life.101, 102 There is improvement in quality of life as compared to pre-transplant period, but quality of life remains poor in most domains when compared to general population.102 In a long term follow up study it has been shown that the improvement in various domains may not be sustained over time, and may differ with etiology of liver failure.103 The occupational and social rehabilitation plan needs to consider these findings. The patient may be able to regain previous activities and vocations. However, not all occupations would be sustainable for transplant recipient, due to the requirement of regular and timely medications and avoidance of sources of infection. Detailed plan of gradual reinstatement of occupational and social roles can be worked out in consultation with the patient.

Besides all the above, a psychiatrist due to his or her expertise is at a better position to communicate the concerns of the patient to the treating team and vice versa. He or she has the opportunity to allay the undue anxieties of the patients and answer queries and doubts. Structured psychotherapy can be done by the psychiatrist when deemed required. This may be especially helpful in abstinence from alcohol and other substances, either pre-transplant or post-transplant.104

Donor related issues

With time, the number of living donors for liver transplant has gradually risen. They are usually a family member of the patient, often a spouse or a parent.75 Most donors consider organ donation as a positive experience and would donate again if needed.105, 106, 107 In a comparison of actual and potential donors, it was seen that actual donors have a higher self-esteem,108 reflecting that donor felt a sense of purpose.

The psychosocial evaluation of the donor may be grounds for disqualification from surgery in many cases and can range from 8 to 20%.109, 110, 111 Careful assessment of the donor would help in reducing the effects of coercion leading to donate, and could possibly reduce the chances of dissatisfaction among the donors.

The psychosocial evaluation of these donors is as important as that of the recipient. The various aspects which need to be covered are detailed in Table 4. Information needs to be gathered about any psychiatric illness in the donors. It has been seen that rates of pre-transplant psychiatric disorders correspond to mental health of the donors after the procedure.112 Nonetheless, having a psychiatric illness of the donor should not be considered a contraindication for organ donation. It is beneficial to institute treatment and optimize mental health of the donor prior to the surgery. Psychiatric symptoms can also arise post-operatively as a consequence of unrealistic expectations or peri-operative complications.113 In a large sample of donors with a median follow up of 6 months,114 the occurrence of post-operative psychiatric complications in donors was 4.1% (16 out of 392 donors). The post-operative illnesses included depression (12 patients), anxiety (2 patients), substance abuse (2 patients), bipolar disorder, accidental overdose, insomnia, crying episodes and worsening of obsessive-compulsive disorder (1 patient each).

Table 4. Psycho-social evaluation of donors.

Evaluation for psychiatric illnesses, past and present
Assessment of psychological strengths and weaknesses
Enquiry about understanding of the transplant procedure and it's implications
Assessment of capacity for informed consent
Relationship with the recipient and closeness
Evidence of coercion or financial motivation for being a donor
Availability of social supports for peri-operative period, especially if the donor is the identified caregiver for longer term

It is important to focus on the informed consent of the donors as they themselves are at significant surgical risks during the procedure. It has been seen that though clinicians explain about risks and benefits, donors report unmet information needs. There are knowledge gaps regarding risks and unanticipated complications.102 At times donors are pressured to give informed consent or may have some concealed internal motive for organ donation.115, 116 One author suggests that decisions about donation were reached before the ‘informed consent process’ was conducted in propriety.117 The process of giving adequate information to the donors and allowing them to choose a course of action is of vital importance.

It is necessary to guard donor against coercion, but situations may not be fully clear at times. There may be entrenched dynamics in the family system which may not be apparent easily. The ‘black sheep syndrome’ in such a situation refers to disrespected family member attempting to gain appreciation by donating the organ.118 Moreover, there may be a combination of elements of coercion as well as sense of genuine affection toward recipient, and the role of each needs to be teased out. It has been seen that donors who were conflicted about the decision and who were pressurized had more anxiety and depression, and a poorer quality of life post-transplant.105 It would be valuable to understand the concerns and feelings of the patient toward the recipient, as well as the closeness, to make a confident impression. Post-transplant concern of the donor about the organ has been described, especially when the recipient had been ill.119 Known as the ‘Siamese twin effect’, such an observation was not robustly found in a study from Japan.120 The donor not only needs psychological support pre-operatively, but also post procedure. Significant others as well as therapists may help in providing such a support.


The numbers of liver transplantation bases has been steadily rising over time, and there is increasing emphasis on psychosocial assessment in order to improve patient outcomes. Such an assessment should be multidimensional covering past and present psychiatric and substance use disorders, psychological strengths and weaknesses, ability to give informed consent, availability of financial and social supports, and so on. The aim of this assessment is a better understanding of the patient. The assessment of donors also needs to be emphasized. All the liver transplant units should have a psychiatrist/mental health professional as a part of the transplant team who should work with the patient, the donor and the family of both to address the psychiatric and psychosocial issues arising in the context of liver transplant.



Conflicts of interest

All authors have none to declare.




Model for End-stage Disease

Journal of Clinical & Experimental Hepatology

Article in Press

Ashwani K. Singal, Patrick S. Kamath

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

Received 2 November 2012; accepted 20 November 2012. published online 03 December 2012.
Corrected Proof

Model for end-stage liver disease (MELD) score, initially developed to predict survival following transjugular intrahepatic portosystemic shunt was subsequently found to be accurate predictor of mortality amongst patents with end-stage liver disease. Since 2002, MELD score using 3 objective variables (serum bilirubin, serum creatinine, and institutional normalized ratio) has been used worldwide for listing and transplanting patients with end-stage liver disease allowing transplanting sicker patients first irrespective of the wait time on the list. MELD score has also been shown to be accurate predictor of survival amongst patients with alcoholic hepatitis, following variceal hemorrhage, infections in cirrhosis, after surgery in patients with cirrhosis including liver resection, trauma, and hepatorenal syndrome (HRS). Although, MELD score is closest to the ideal score, there are some limitations including its inaccuracy in predicting survival in 15–20% cases. Over the last decade, many efforts have been made to further improve and refine MELD score. Until, a better score is developed, liver allocation would continue based on the currently used MELD score.

Keywords: MELD, Liver transplantation, Cirrhosis

Abbreviations: MELD, model for end-stage liver disease, LT, liver transplantation, CTP, Child–Pugh–Turcotte, ESLD, end-stage liver disease, UNOS, United Network for Organ Sharing, TIPS, transjugular intrahepatic portosystemic, GFR, glomerular filtration rate, MDRD, modification of diet in renal disease, FHF, fulminant hepatic failure, QALY, quality adjusted life years, MLP, multi-layer perceptron, SOFA, sequential organ failure assessment, SOFT, survival outcomes following transplantation, BAR, balance risk, EDC, extended donor criteria, UKELD, UK end stage liver disease score, deMELD, drop-out equivalent MELD, SLK, simultaneous liver kidney transplantation, AH, alcoholic hepatitis, DFI, discriminate function index, HVPG, hepatic venous pressure gradient, VH, variceal hemorrhage

Allocation of organs for liver transplantation in the United States in the 1980s and early 1990s was prioritized based on the level of care required by the patient: hospitalized patients in the intensive care unit, hospitalized patients on the regular floor, and outpatient care. This approach had the potential of ‘gaming’ the system by keeping the patients in ICU in order to be transplanted. In 1996, a consensus conference mandating need for minimal criteria for listing the patients for liver transplantation (LT) introduced the Child–Pugh–Turcotte (CTP) score for liver allocation.1 CTP score is based on severity of 3 objective (serum albumin, serum bilirubin, and prothrombin time) and 2 subjective (ascites and encephalopathy) parameters. Subjective parameters vary with use of diuretics or paracenteses for ascites and use of lactulose for encephalopathy. CTP score introduced to some extent the concept of ‘sicker patient first’ with the introduction of status 1A for patients with fulminant hepatic failure, primary non-function or hepatic artery thrombosis within 7 days of transplantation, and decompensated Wilson's disease. Organ allocation for patients with end-stage liver disease (ESLD), however, largely depended on waiting time on the list. In 1998, the Institute of Medicine mandated that patients be allocated organs based on their disease severity and risk of death rather than on waiting time.2

Development of the Model for End-stage Liver Disease Score and Adoption by the United Network for Organ Sharing for Liver Allocation

February 27, 2002 was a historical day when the MELD score was adopted and approved by the United Network for Organ Sharing (UNOS) as a score to allocate organs for patients awaiting liver transplantation (LT) in the United States.3 This score changed the policy of organ allocation not only upholding the concept of “patient comes first” but also “sickest patient comes first”. That is, the patient most at risk for mortality would be at the highest priority for organ allocation.

MELD score was developed by a group of researchers at the Mayo Clinic initially as a model to predict survival following transjugular intrahepatic portosystemic (TIPS) for refractory variceal bleeding or refractory ascites.4 The model was later shown to quite accurately predict 3 months mortality amongst patients with chronic end-stage liver disease awaiting LT.5, 6 As the score was objective and could predict mortality at 3 months with higher accuracy than the CTP score, allocation of livers for transplantation became MELD based, de-emphasizing the concept of waiting time.3, 7

The score was initially named as Mayo model for end-stage liver disease (MELD) score reflecting the institution where the score was developed. With the acceptance of this score by the UNOS for organ allocation, the model was renamed as model for end-stage liver disease. This allowed wider acceptability of the score keeping the same abbreviation of MELD.7, 8 Other changes made to the score by the UNOS were: capping serum creatinine at 4 mg/dl, capping the score at 40, and setting the lower limit for each component of the score to 1 in order to avoid negative scores. Further, etiology of the liver disease as a factor was removed from the model, as this did not impact mortality amongst patients with end-stage liver disease awaiting LT.5

Comparison of Child–Pugh–Turcotte Versus Model for End-stage Liver Disease Score

Mortality and MELD score are linearly correlated amongst patients with end-stage liver disease listed for LT with 3 month mortality estimated to be 4%, 27%, 76%, 83%, and 100% for MELD scores of <10, 10–19, 20–29, 30–39, and 40 or more respectively. Predictive ability of any model or score is given by c-statistic, which ranges between 0 and 1. A ‘c’ statistic of 0.7 is considered clinically useful and a c-statistic of 0.8 or more qualifies for an accurate model. This means that if 2 patients are on the waiting list, a model with a c-statistic of 0.8 would be 80% accurate in predicting death of the patient with the higher score earlier than the patient with the lower score. In the initially developed model, c-statistic for MELD score was 0.87, which was superior to CTP score with c-statistic of 0.84. Other studies including meta-analyses have shown that both CTP and MELD scores are predictive of waitlist mortality.9, 10 However, the MELD score allows finer stratification than CTP score. Further, MELD incorporates serum creatinine, a factor which is important in predicting survival in patients with liver disease.11, 12, 13

Components of the Model for End-stage Liver disease Score and Limitations of Each Component

MELD score is calculated using serum bilirubin, serum creatinine, and International Normalized Ratio (INR) and is given by the formula 9.57 × loge (creatinine) + 3.78 × loge (total bilirubin) + 11.2 × loge (INR) + 6.43. The score can be calculated using online website www.mayoclinicorg./gi-rst/mayomodel5html.

Serum Bilirubin

Problems with using serum bilirubin as a variable are the potential for error in measurement and elevation in the presence of renal failure.14 Further, total bilirubin which is used for calculation of the MELD score may change due to increased indirect bilirubin from hemolysis, blood transfusion, and genetic variability of the bilirubin metabolism. The predictive ability of the MELD score does not change whether direct or total bilirubin is used, and hence the total bilirubin is used for calculating the MELD score in clinical practice.15

Serum Creatinine

For the purposes of organ allocation, serum creatinine is set at a lower limit of 1 mg/dl with a ceiling at 4 mg/dl. Any patient who received dialysis ≥2 times in the previous week irrespective of the serum creatinine value is determined to have a serum creatinine of 4 mg/dl. This ceiling value for serum creatinine is arbitrary and in one study, increasing the upper limit of serum creatinine to 5.5 had a small impact of 2.5% in 3 months mortality amongst wait listed candidates but improved accuracy of the MELD score in predicting 3 months mortality.16 The limitation of inclusion of serum creatinine is variation in its value depending on the method of measurement: colorimetric or enzymatic. Further, in the presence of high serum bilirubin, the colorimetric method is unreliable and underestimates the value of creatinine; the enzymatic method is preferred for measuring the serum creatinine in such situations.17 Another limitation is gender with lower value amongst females compared to men for the same level of renal function.18 A study comparing glomerular filtration rate (GFR) based on Modification of Diet in Renal Disease (MDRD) formula and serum creatinine showed similar results in estimating waitlist mortality.19 Another study using corrected MELD with estimated GFR was unable to predict short-term mortality at 3–6 months but was better in predicting mortality at 9–12 months after listing.20 In contrast, true GFR estimated using iohexol clearance is a better predictor of the renal function compared to MDRD or serum creatinine estimation as the latter methods tend to overestimate true GFR.21


The INR has a sigmoid shape effect on the 3 months mortality of wait listed candidates with maximum effect between INR of 1 and 3. INR measured using thromboplastin obtained from patients on anticoagulant therapy leads to variations in the inter-laboratory readings on the INR values.22, 23 Combined with geographic variation on the MELD threshold for transplantation, this limitation significantly impacts odds of liver allocation.22 Further, INR is prone to be confounded by use of warfarin. Use of liver specific thromboplastin using plasma from patients with cirrhosis instead of plasma from patients on warfarin eliminates this discrepancy and variation across laboratories.24 However, this method is expensive and adds to confusion in ordering the same tests for different indications. In one study amongst patients with cirrhosis on stable anticoagulation, model without INR was less accurate than the original MELD model suggesting that even in anticoagulated patients MELD model should be used for estimation of prognosis.25

Other Variables

Etiology of liver disease was initially included into the model but was later shown to be not predictive of outcomes and was then removed from the model.5 Similarly, complications of cirrhosis and portal hypertension such as ascites, variceal bleeding, or hepatic encephalopathy being components of CTP score did not significantly add to accuracy of MELD score suggesting that these complications usually reflect the status of underlying liver function.26

Impact of Implementing Model for End-stage Liver Disease Score

Impact on Outcomes

Introduction of MELD score for organ allocation in the United States in the very first year resulted in about 12% reduction in waitlist mortality.7 This trend continued in later years with reduction in total number of deaths on waitlist from 2046 in 2001 to 1364 in 2005 with reduction in waiting time from 656 days to 416 days.27 Part of this reduction was due to increase in number of donor livers from 4671 in 2001 to 5160 in 2005. However, in spite of accounting for this, policy of allocating livers based on MELD score was responsible for this reduction as similar reduction in waitlist mortality did not occur amongst patients with fulminant hepatic failure (FHF).28

Studies have shown association of pre-LT MELD score with the hospital resource utilization such as operative time, use of red blood cell transfusions, duration of stay in the intensive care unit and total hospital stay and charges. In one study, MELD score of more than 23 predicted a higher morbidity and prolonged ICU stay.29 In another study, there was about 55% increased cost of transplanting a patient as compared to pre-MELD era.30 However, data on increased resource utilization since the implementation of MELD score are controversial with no such change reported in a large database retrospective study.31 However, there is also significant improvement in quality of life resulting in dynamic improvement in the cost to quality adjusted life years (QALY) ratio especially after 3–5 years of follow up amongst patients with high MELD scores prior to transplantation.32

Impact on Disparities in Liver Transplantation

Ethnic disparities on waitlist mortality and receipt of liver transplant within 3 years of registering have reduced.33, 34 Incorporation of serum creatinine into the model resulted in gender disparities in receipt of transplant and higher waitlist mortality among women by 13% compared to men.35 This is due to the fact that for the given renal function, women tend to have lower serum creatinine compared to men due to lower muscle mass in women.

Model for End-stage Liver Disease and Post-transplant Survival

In spite of transplanting patients with a higher MELD score, post-LT survival did not change in the MELD era. Post-transplant survival is a multidimensional non-linear issue and depends upon multiple recipient and donor factors along with experience of transplant center. In one study, use of multi-layer perceptron (MLP) using 18 different recipient and donor variables was better predictor of post-transplant outcomes as compared to MELD and sequential organ failure assessment (SOFA) scores.36 In another study, 3 months post-transplant mortality was predicted by a SOFT (survival outcomes following transplantation) score incorporating 18 recipient and donor factors in addition to MELD score.37

In order to match graft with the MELD score and other recipient factors, a balance risk (BAR) score has been suggested in order to achieve a balance between waitlist mortality and post-transplant outcomes.38 In one study, combination of 3 extended donor criteria (EDC): age, steatosis >30% and cold ischemia time with MELD >28 predicted graft failure.39 Worsening MELD score or delta-MELD (current MELD-maximum score in the last 3 months) has been shown to impact post-transplant outcome,40 and one should avoid graft with >1 EDC for such patients.41 Similar observations by another study on patients with Hepatitis B virus (HBV) related liver disease and MELD >29 showed that downgrading MELD score using anti-HBV drugs improved outcomes of LT compared to emergency LT.42 In this respect, product of age and delta-MELD less than 1600 may be required for optimal post-transplant outcomes.43

Impact on Liver Allocation

The aims of liver allocation are to reduce wait-list mortality and achieve significant transplant benefit. Although, sickest patients are expected to derive most transplant benefit, disease severity also impacts immediate post-transplant outcomes. Hence, in clinical practice, a balanced approach is needed to optimize liver allocation.44 Etiology of liver disease is not factored into the calculation of MELD score; patients with viral etiology of cirrhosis and MELD >15 had significantly lower survival than alcoholic cirrhosis patients with similar MELD suggesting that viral cirrhosis patients may be disadvantaged in the MELD allocation policy.45 For a given MELD score between 15–17 and 24–40, a patient with higher serum creatinine is shown to have higher waitlist mortality compared to a patient with lower serum creatinine. This factor, if taken into consideration, would affect the liver allocation.12 Laboratory variations of INR and serum creatinine across transplant centers also result in variations in the MELD score. This combined with geographic variation results in a varying MELD threshold for receiving organs.46 In addition, allocation of a specific score for patients with Hepatocellular carcinoma (HCC) and other conditions47 significantly impacts odds of liver allocation.22 In this respect, normalization of MELD score based on corrected value of each variable normalized to the maximal normal value (Vmax) of each laboratory and given as: corrected value = measured value × Vmax of lab 1/Vmax of lab 2 may optimize liver allocation.48

Model for End-stage Liver Disease Exception Points and Liver Allocation

Patients with HCC with lower MELD have a risk of progression of the tumor while waiting for transplant, leading to death or progression of disease which may exclude them from receiving an organ. On the other hand, HCC patients with higher biological MELD have been shown to have poor post-transplant survival compared to comparable MELD in non-HCC patients.49 Therefore, in February 2003, UNOS accepted a policy of awarding MELD exception points for HCC patients within Milan criteria. This change along with the documentation of post-LT outcomes for HCC within Milan criteria to be as good as for any other indication, has resulted in the proportion of transplants performed for HCC increasing from 4.6% in during 1997–2002 to 26% during 2002–2007.49 Therefore, in March 2005, this policy was modified to award 22 MELD exception points instead of 24 points to patients with HCC to more accurately reflect their risk of dying.50 Even with this policy, the odds of a patient with HCC receiving the organ remains substantially higher compared to non-HCC patient.51, 52 On the other hand, about 29% of patients with HCC are dropped from the waiting list due to tumor progression suggesting consideration of other factors such as number of tumors, alphafetoprotein levels, tumor biology, and biological or calculated MELD score for transplanting HCC patients.49, 53 However, many of these factors are also associated with tumor recurrence after transplantation and a higher probability of drop out risk from the waiting list is directly correlated with a higher risk of recurrence of HCC after transplantation.54 Hence a balanced approach is needed to optimize use of livers for transplanting HCC patients aiming at maintaining post-transplant survival as well as optimizing the chance of receiving a transplant. In this regard, the concept of drop-out equivalent MELD (deMELD) points has been introduced taking into consideration the risk of drop out from the waiting list based on MELD score and other HCC characteristics. For example, two patients with similar MELD scores would be given different exception points based on their drop out risk from the waiting list after considering factors such as number of tumors, maximum tumor size, age of the patient, etiology of liver disease, and AFP levels.55

Model for End-stage Liver Disease and Simultaneous Kidney Transplantation

Due to incorporation of serum creatinine into the model, there has been an increase in the proportion of simultaneous liver kidney transplantation (SLK) from 2 to 3% during 1994–2001 to 4–7% during 2002–2010 and increased incidence of post-transplant end-stage renal disease.56, 57 However, post-transplant outcomes have not worsened in the MELD era.57, 58 Increasing use of SLK has raised concern about the shortage of donor kidneys. Guidelines on allocating simultaneous kidney to LT recipients as laid down by a consensus group are not perfect.59 In this respect, there is an unmet need for biomarkers to accurately predict reversibility of the renal function after LT.

Low Model for End-stage Liver Disease Score and Liver Transplantation

Patients with MELD score of less than 15 who receive a transplant do worse than patients with a similar score who do not receive a transplant with 3 month post-LT mortality being about 3.6 times higher with LT for MELD 6–11, and 2.4 times higher for MELD 12–14.60 However, this may not be true for living donor liver transplantation for non-HCC patients as they still derived a significant survival benefit compared to patients waiting for deceased donor due to reduced wait time and better graft quality.61 This was confirmed in a study analyzing the UNOS database where transplant benefit of patients with MELD <16 depended upon the quality of graft they received, and poor survival benefit amongst these patients was due to receipt of grafts with the highest donor risk index.62 Transplants for patients with low MELD score using high risk or marginal grafts are also associated with increased length of stay and cost of transplantation.63

Applications Other than Liver Transplantation for Cirrhosis

Referral for Hospice Care

Hospice care may be useful adjunct to coordinate care of patients awaiting liver transplantation. In addition, patients who are not candidates for liver transplantation and are likely to die within 6 months may be referred for hospice care.64 MELD can accurately guide treating physicians on making such decisions. In one study, median MELD at the time of admission to hospice care program was 21 with median length of stay being 38 days. There was a linear correlation of length of stay and MELD score.65 In another study, MELD >24 could accurately predict mortality at 30 days in about 80% cases.

Fulminant Hepatic Failure

Data on whether MELD score can predict mortality in FHF are controversial. In one study, MELD score was accurate in predicting the 30 day mortality amongst patients receiving LT for non-acetaminophen related FHF.66 Similarly, another study reported on adults with non-acetaminophen FHF showed MELD as good as King's college criteria.67 However, in a US multicenter study on patients with hepatitis A induced FHF, MELD was unable to predict outcome of patients on the LT list with a c-statistic of only 0.7.68 However, there were only 4 deaths and therefore the significance of the study is unclear. The most common cause of mortality amongst FHF patients is cerebral edema and it is likely that other factors including intra cranial pressure are important in predicting waitlist mortality of FHF patients. In a prospective study from Denmark, MELD was an important variable in predicting onset of FHF amongst patients with acetaminophen overdose.69 However, after the onset of FHF, MELD score was no more important in predicting mortality. Whether patients with FHF should be considered status 1A and be prioritized over end-stage liver disease patients irrespective of MELD scores was addressed in a study using Scientific Registry of Transplant Recipients database. The findings showed that patients with end-stage liver disease and MELD score >40 had higher waitlist mortality compared to status 1A patients suggesting that these patients be prioritized over status 1A patients in allocation of livers. However, further studies are needed to confirm these findings before implementing any change in policy.70

Alcoholic Hepatitis

MELD score accurately predicts outcome in patients with alcoholic hepatitis (AH). Studies comparing other scores and MELD score have shown conflicting data. Six studies have compared MELD and discriminate function index (DFI) scores amongst AH patients. MELD was similar to DFI for predicting 30 day mortality in 3 studies (c-statistic of 0.82, 0.73, and 0.89 for MELD >11, 21, and 18 vs. 0.86, 0.69, and 0.81 respectively for DFI >3271, 72, 73); superior to DFI in 2 studies in predicting 30 day mortality (0.83 for MELD >22 vs. 0.74 for DFI >4174 or occurrence of complications of liver disease in one study75); and inferior to DFI in one study.76 Three studies comparing MELD and CTP showed 2 scores to be similar for mortality during the hospital stay72 or at 3 and 6 months6 while in the third study, CTP but not MELD was predictor of 90 day mortality.76 Apart from other limitations of MELD score, specific issue pertaining to AH is variation in MELD score cut off to accurately predict mortality ranging from 11 to 22 in different studies. American Association for Study of Liver Diseases (AASLD) guidelines recommend MELD cut-off of 18 to initiate corticosteroid therapy for patients with AH.77

Cirrhosis with Infections

MELD score and renal failure including type of hepatorenal syndrome (HRS) predict outcome of infected cirrhotics while CTP score was not predictive.78 It is likely that MELD score contributes at both the stages and in patients with higher MELD score there should be a high index for suspecting infection and initiation of antibiotics. For example in a retrospective analysis on 256 Albanian patients with cirrhosis, MELD score was a predictor for occurrence of SBP and mortality.79 In another study on 111 hospitalized cirrhotics MELD was a predictor for SBP, increasing risk by about 11% for every increase in MELD score with 9.7 times higher odds for developing SBP at a MELD cut-off of 15.80 Amongst patients with community acquired pneumonia (CAP) in cirrhotics, a new score (MELD-CAP) incorporating extent of pneumonia and septic shock at admission was a better predictor of severe disease and mortality compared to CAP in patients without cirrhosis (OR 1.33 [1.09–1.52] and 1.21 [1.03–1.42]).81 MELD incorporated with serum sodium (MELD-Na) also accurately predicted mortality in patients with spontaneous bacterial empyema.82

Transjugular Intrahepatic Portosystemic Placement

As mentioned earlier, MELD score was initially developed to predict mortality after TIPS placement to manage patients with variceal bleeding or ascites refractory to routine measures.4 MELD score in predicting mortality after TIPS placement was superior to Emory score in one study and slightly superior or similar to CTP score in another study.83, 84 MELD score <18 is ideal for TIPS placement, and those with MELD scores19–24 are borderline for successful outcome. Patients with MELD >24 are not optimal candidates for TIPS placement; TIPS may be carried out in these patients if they are candidates for liver transplantation.85 These guidelines have also been found to be useful for placement of TIPS amongst post-transplant patients and it is recommended that TIPS be carried out only if the MELD score is <15 in these patients.86

Surgery Apart from Liver Transplantation

Patients with decompensated cirrhosis may require abdominal or extra-abdominal non-transplant surgery in especially in the last 2 years of their life.87 The effect of the surgical procedure, blood loss, hypoxemia due to ascites and/or hydrothorax, and anesthetic agents all make a diseased liver prone to further deterioration with a potential risk for precipitating liver failure.88 Severity of liver disease predicting outcome after surgery has been known for years. Earlier, the risk used to be gauged using the CTP stage with 10%, 30%, and 82% postoperative mortality amongst patients with CTP stages A, B, and C respectively.89 Type of surgery (emergency vs. elective) has been associated with outcome. Amongst patients with CTP class A, B, and C mortality for emergency surgery is 22%, 38%, and 100% respectively.90 Since the introduction of MELD score, retrospective studies have confirmed MELD score to be predictive of outcome following surgery other than LT.91, 92 In the largest retrospective study addressing this issue reported from the Mayo Clinic analyzing 772 patients undergoing various kinds of surgeries, MELD score was an important variable in predicting outcome after surgery for short-term (7, 30, and 90 days) and long-term outcomes at 1 or 5 years. Other important predictors were ASA class and recipient age with addition of 5.5 MELD points for ASA class IV and 3 MELD points for age more than 70 years.92 Emergency surgery was not predictive when the model was also controlled for the MELD score in addition to other variables. Based on MELD score, age, and ASA status one can predict outcomes after surgery using an online model at http://www.mayoclinic.org/meld/mayomodel9.html. This model can help in counseling patients and physicians on the risk of surgery. The association of risk of death after surgery and the MELD score >8 was linear and it is generally believed that patients with MELD score <10 can tolerate surgery, those with 10–15 MELD score may be considered, and patients with MELD score >15 should avoid an elective surgery. This recommendation has been validated in other studies on different populations.93, 94 However, a study from Korea including a large number of patients with hepatitis B related cirrhosis reported that the model tends to overestimate mortality at more than ≥1 year after surgery95 as the long-term outcome may potentially be confounded by comorbidities and other factors.

Comparing Model for End-stage Liver Disease and Child–Pugh–Turcotte for Outcome After Surgery

Many studies have compared MELD with CTP stage in predicting mortality after surgery. In one study, 3 month mortality rates amongst 3 respective CTP stages were 2%, 22%, and 55% and similar rates at MELD of 6–9, 10–14, 15–19, 20–24, and >24 were 3.5%, 8.9%, 14.3%, 12.5%, and 63.6% respectively.96 In yet another study, perioperative mortality rates based on CTP stage were 10%, 17%, and 63% while similar rates at MELD of <10, 10–15, and >15 were 9%, 19%, and 54% respectively.97 Amongst both the studies, CTP stage emerged better predictor of perioperative mortality compared to MELD score. In contrast, integrated MELD score was superior to CTP stage for predicting postoperative mortality.94 In another study, CTP and MELD scores were similar in predicting outcome after elective surgery but only fairly after urgent surgery in cirrhotics.98

Type of Surgery

For the same MELD score, mortality is higher in some studies for intra-abdominal surgery compared to abdominal wall surgeries including surgery for umbilical hernia. Amongst 220 cirrhotics undergoing cholecystectomy, a common surgery in general population including cirrhotics, the procedure was safe with no perioperative mortality across MELD range 8–27. However, a higher postoperative complication rate was noted for patients with MELD >13.99 MELD score remains a powerful predictor of outcomes for head and neck cancer surgery at a cut-off of 9.7 (23% vs. 3% postoperative mortality; P = 0.03).100

Regarding elective cardiac surgery, if possible, least invasive option of angioplasty with or without stent placement should be considered. One should also avoid coated stents, as they require need for anticoagulants and antiplatelet agents such as clopidogrel. Cardiac surgery is safe in CTP stage A, can be considered in select CTP-B stage patients and should be avoided in CTP-C stage.101, 102 MELD score remains a predictor of outcome after tricuspid valve surgery103 and left ventricular assist device placement.104, 105

HCC Resection in Cirrhosis

Patients without underlying cirrhosis and those with stage 1 HCC in the absence of thrombocytopenia (<150,000/cmm) and/or clinically significant portal hypertension are better served by resection.106, 107 MELD score is a powerful predictor of outcomes following liver resection in cirrhotics.108 Post-hepatectomy liver failure (prothrombin time <50% and serum bilirubin >50 mmol/dl) on day 5 after surgery was strong predictors of perioperative mortality.109 In one study, incidence of hepatic failure after hepatic resection was 0% with MELD score of <9, 3.6% with MELD 9–10, and 37.5% with MELD score of >10. In another study, perioperative mortality for minor (3 or less segments) or major (4 or more segments) hepatectomy was 29% amongst patients with MELD score of >8 and 0% with MELD score of 8 or less. Similarly, mortality after liver resection was higher for MELD score >8 compared to lower MELD (4% vs.0.6%; P = 0.004) on analyzing over 1100 HCC patients undergoing resection between 1991 and 2005 at one center in Taiwan.110 In yet another study, perioperative mortality was 19% at MELD >8 vs. 0% for lower MELD.111 Same workers from Italy in another study reported on the concept of conditional survival (sum of the survival from the time of diagnosis and the post-surgical survival) and concluded that a MELD score of <9 achieves best conditional survival. Amongst patients with MELD >9, further risk stratification can be made based on extent of surgery and serum sodium levels.112

Variceal Bleeding

Many variables such as severity of liver disease, severity of bleeding, bleeding in the hospital, receipt of endoscopic treatment, hepatic venous pressure gradient (HVPG), and HCC predict outcome after variceal hemorrhage (VH).113, 114, 115 MELD score has been shown to be an accurate predictor of outcome after VH.83, 116, 117 MELD >18 was a predictor of rebleeding within first 5 days and overall mortality at 6 weeks.117 MELD score is also a powerful predictor for mortality at 6 weeks for patients who develop early rebleeding after endoscopic variceal ligation.118 Comparison of CTP and MELD scores in predicting outcome of VH have shown discrepant data with similar prediction in one study119 while CTP to be better predictor compared to MELD in another study.120

Hepatorenal Syndrome

Outcome depends on type of HRS with extremely poor prognosis for type 1 patients and MELD score of 20 or more. In contrast, patients with type 2 HRS have longer survival if their MELD score is <20 compared to ≥20 (11 vs. 3 months; P < 0.002).78


MELD score is a predictor of death in trauma patients with each unit increase in MELD increasing mortality risk by 18%.121


Since implementation of the MELD score, the number of re-transplants has decreased raising the question as to whether MELD disadvantages patients listed for re-transplantation. This issue was addressed in a study from the Mayo Clinic which showed that current MELD allocation policy serves candidates listed for primary or re-transplantation equitably.122

Is Model for End-stage Liver Disease an Ideal Prognostic Score?

An ideal prognostic score should be accurate, objective, valid on a continuous scale, validated worldwide, should be able to guide treatment, and easy to calculate. MELD score meets most of these criteria with its biggest strength being validation across the world in various liver diseases. However, there are some limitations of the MELD score. Although, the variables needed to calculate the score are readily available, there is need for a computing device or website for calculating the score. The score has also potential for inaccuracy to predict waitlist mortality in 15–20% cases; therefore, further refinements are required before it can be considered an ideal score.

Further Refinements of Model for End-stage Liver Disease

MELD variables can fluctuate with correction of precipitating factor such as control of infection, discontinuation of hepatotoxic drug or diuretics, and correction of renal dysfunction, coagulopathy, or biliary obstruction. When the MELD score was initially developed, the bilirubin, creatinine, and INR were recorded when the acute process has resolved. This issue was later addressed in a study where the serial MELD scores were taken until the MELD stabilized. The data showed that delta-MELD (difference between current MELD score and lowest MELD score within 30 days prior to current MELD) was not significant after controlling for other factors in the model.123 The authors concluded that it is reasonable to take current MELD for predicting survival in daily practice even in recently decompensated patients. However, in another study, delta-MELD was predictive of waitlist as well as post-LT survival with 4.9 odds of dying in the post-transplant period with delta-MELD of >10.40

Model for End-stage Liver Disease-Na

Hyponatremia is a predictor of waitlist mortality amongst patients with end-stage liver disease after controlling for MELD score with increase in mortality by 5% for each mmol decrease in serum sodium between levels of 125–140 mmol/L.124 Serum sodium is a reflection of renal function and hypothetically may improve the accuracy of the model as serum creatinine used for calculating the MELD score may not accurately capture the true renal status. Similar observations about the impact of serum sodium between 125 and 140 mmol/L on the waitlist mortality have been made by other workers.125 Amongst patients with severe hyponatremia (<125 mmol/L), serum sodium was a better predictor of mortality than MELD score amongst patients with refractory ascites.126

Data on the impact of sodium on the accuracy of MELD score are controversial as reported by other studies.127 In a recently reported study, addition of serum sodium into the MELD model very marginally improved the accuracy of the model with increase of c-statistic from 0.865 to 0.878 (P < 0.01) and in the validation data-set, MELD-Na affected only about 12% of listed patients.128 In another study reported from the Mayo Clinic, MELD-Na was better predictor of outcome amongst patients with alcoholic hepatitis who had ascites, but not in those without ascites.129 Lack of significant impact of serum sodium on the MELD score's accuracy could be due to the fact that a small proportion of patients with cirrhosis develop significant hyponatremia. For now, it is unclear whether liver organs should be allocated based on the MELD-Na model. Incorporation of serum sodium is also limited by its potential for ‘manipulating’ the system with change in volume status with free water intake and use of diuretics.

Other Suggested Modifications

Updated MELD (assigning lower weight to creatinine and INR while higher weight to bilirubin based on SRTR analysis of 38,899 patients transplanted between 2001–2006),130 refit MELD (reassigning lower and upper limits of 0.8 and 3.0 for serum creatinine while 1 and 3 for INR respectively),128 integrated MELD including sodium and age,93 MESO (ratio of MELD to serum sodium), Meld-Na (incorporating serum sodium for levels between 125 and 140 mmol/L),124 UK end stage liver disease score (UKELD) which is similar to MELD-Na and is used for listing patients for liver transplantation in the UK,131 and ReFit MELD-Na as for refit MELD but including serum sodium also128 are some of the refinements, which have been tried to improve the accuracy of the MELD score. In one study, comparing these models, UKELD and updated MELD were poor in predicting mortality compared to other 4 models.132

Other factors shown to improve the MELD accuracy are HVPG,133 von Willebrand factor level at a cut-off level of 315%,134 persistent CRP levels of ≥29 mg/L,135 prealbumin levels of >69 mg/L,136 apoptosis marker CK-18.137 Refinements to improve the accuracy of MELD would continue and until we find a better score, livers could continue to be allocated using the current MELD based system.

Conflicts of interest

All authors have none to declare.