Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure

Authors

  • Sheldon C. Cooper,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • Roland C. Aldridge,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • Tahir Shah,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • Kerry Webb,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • Peter Nightingale,

    1. Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • Sue Paris,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • Bridget K. Gunson,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • David J. Mutimer,

    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
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  • James M. Neuberger

    Corresponding author
    1. Liver Unit, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service Foundation Trust, Edgbaston, Birmingham, United Kingdom
    • Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH
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    • Telephone: +44 121 627 2414; FAX: +44 121 627 2449


Abstract

Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol-induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated. Liver Transpl 15:1351–1357, 2009. © 2009 AASLD.

Despite changes in legislation that may reduce the likelihood of intentional overdose and the potential for effective treatment, a minority of patients develop overt fulminant hepatic failure (FHF) after an intentional overdose or therapeutic misadventure.1–4 Paracetamol (acetaminophen) hepatotoxicity is one of the most common causes of FHF in the United Kingdom, accounting for around 50% of cases.5 Criteria for transplantation in these patients are well described,6, 7 but in the selection of suitable patients, especially in this era of severe donor shortage, we must recognize that many with paracetamol-associated liver failure will have intentionally self-harmed. In many cases, the trigger is recent emotional trauma, but in others, there is a history of mental illness and previous attempts at self-harm. Follow-up of deliberate self-harm patients shows a markedly increased standardized mortality ratio for all causes, but particularly for suicide. Indeed, 3% to 15% of those presenting to a hospital following parasuicide will subsequently commit suicide.8–11

Survival after liver transplantation (LT) for paracetamol toxicity exceeds 70% at 5 years,12 and this offers an opportunity for survival in those with the poorest prognosis.13, 14 Although the quality of life after transplantation is usually excellent,15 the survivor must learn to cope with the consequences of immunosuppression and the requirement for life-long follow-up. There are concerns that the outcome after transplantation may be adversely affected by persisting psychological and/or psychiatric problems that may persist despite optimal treatment or intolerable social circumstances that may have precipitated the overdose, making adherence unmanageable even with full social support. Under these circumstances, patients might be denied LT despite physical and laboratory characteristics that predict a fatal outcome without transplantation. Denial of potentially life-saving treatment may be justified by the shortage of donors with the inevitable need for rationing.16, 17 Surveys of the general public have indicated little public support for transplantation in this cohort,18 and if scarce organs are used ineffectively in those who will not benefit, donor rates may further decline.

The transplant team must assess the past medical and psychosocial history to determine whether a transplant is in the best interest of the patient. The decision to proceed with transplantation often has to be made with less than adequate information as the patient may be encephalopathic or ventilated and immediate access to medical records may be limited. In addition to the potential adverse impact of premorbid psychosocial issues on posttransplant adherence to management, adherence might also be affected by the inevitable lack of pretransplant counseling.

The aim of our study was to determine if we could identify factors in the past medical history that could suggest a potential recipient is unlikely to benefit fully from the procedure and to examine adherence to posttransplant follow-up of patients transplanted for paracetamol overdose (POD). We also examined the adherence of patients in 2 comparison groups: a cohort of patients transplanted for FHF associated with other indications and a cohort of age-matched and sex-matched patients transplanted for chronic liver disease (CLD).

Abbreviations

CLD, chronic liver disease; FHF, fulminant hepatic failure; FU, follow-up; LT, liver transplantation; OPA, outpatient appointment attendance; POD, paracetamol overdose.

PATIENTS AND METHODS

Patients

A retrospective analysis of prospectively collected data on patients admitted to the Liver Unit (a tertiary referral center) at Queen Elizabeth Hospital (Birmingham, United Kingdom) with POD FHF was undertaken. The King's College Hospital criteria6 were used to identify potential recipients, but those with significant premorbid unresponsive psychopathology, such as repeated self-injurious behavior despite full medical and social support, were excluded from consideration. The usual immunosuppressive regimen following transplantation consisted of a calcineurin inhibitor, azathioprine, and corticosteroids. The patients were weaned off steroids over 3 months. Clinical reviews were performed twice weekly immediately after discharge; the frequency was gradually reduced thereafter, with reviews often performed only annually with a local hospital review between appointments. Episodes of rejection were confirmed histologically.

Observational Study

Demographic and sociological data, including age, gender, occupation, residential and marital status, dependants, and alcohol intake, both at the time of overdose and after transplantation, were noted. Recorded outcomes included death and graft loss, sociological and psychological health, graft function, and unexplained failure to attend appointments.

Comparative Study

Patients transplanted for POD after 2004 were not included in this analysis to allow a substantial follow-up period for analysis. Medical records from 2 comparison groups were also examined: those who had undergone LT for CLD and those with FHF from other causes. The groups were matched for gender, age, and date of transplantation and were selected from the Liver Unit database by an independent analyst. Patients were not matched for severity of illness.

Definitions were established before the notes and database were analyzed.

The premorbid psychiatric history was considered to be significant if a diagnosis of psychiatric illness (such as depression and/or schizophrenia) was made by a psychiatrist or by the patient's general practitioner.

Adherence to outpatient appointment attendance (OPA) was defined as good if a patient attended more than 75% of scheduled outpatient appointments, as fair if the patient attended 50% to 74% of appointments, and as poor if the patient attended fewer than 50% of appointments or was lost to follow-up.

Adherence to immunosuppressive medication was defined as good if it was never mentioned in the clinic notes, fair if there were short periods of poor adherence that did not lead to significant graft damage, and poor if nonadherence led to significant graft damage or graft loss/death.

Statistical analysis was performed with SPSS 12.0.1. To identify differences in age, grade of encephalopathy at presentation to the liver unit, and duration of follow-up, the Kruskal-Wallis test was performed, and Fisher's exact test was used to examine differences in gender, 30-day mortality, use of pre-LT renal support (hemodialysis or continuous venovenous filtration), and other nominal parameters. A Kaplan-Meier survival plot was employed to examine differences in survival after 30 days post-LT. Comparisons of adherence between the 3 arms of the study (following initial discharge after LT) and also comparisons of adherence and key factors in the premorbid psychiatric state among POD patients were performed with Kendall's tau-b. A comparison of severity scores such as the Model for End-Stage Liver Disease score was not performed, as the scores may have been affected by therapies such as hemofiltration and plasma infusions; furthermore, the Model for End-Stage Liver Disease score, while a robust marker of short-term prognosis, is not a measure of disease severity.

RESULTS

Observational Data

Between 1987 and July 2007, 858 patients were admitted with paracetamol-induced hepatotoxicity, of whom 95 were listed for LT; of the 60 who underwent the procedure, 44 (73%) survived to discharge (Fig. 1). The median survival of the 16 who died before discharge was 17 days (range, 0–83 days), and 7 of these died from infection.

Figure 1.

Outcome of admissions to the Liver Unit of Queen Elizabeth Hospital for paracetamol-induced fulminant hepatic failure.

Of the 44 patients who survived to discharge, case notes were obtained for 42; in the remaining 2 cases, the notes had been destroyed. Currently, 35 patients (58%) remain alive at a mean of 9 years post-transplant. Five required a regraft [chronic rejection (2), hepatic artery thrombosis (3), and portal vein thrombosis (1)]. One patient underwent 2 regrafts: the first for portal vein thrombosis and the second for hepatic artery thrombosis. Of the 44, 9 have subsequently died. One patient committed suicide within the first 3 months after transfer to an inpatient psychiatric facility. Three other deaths occurred within the first year [hepatic artery thrombosis (1) and sepsis (2)]. In 2 cases, death was due to sepsis and renal failure associated with calcineurin toxicity. Two deaths (8 years 7 months and 8 years 9 months post-LT) were due to chronic rejection associated with poor compliance. (Although both deaths were outside the follow-up period of the comparative study, the noncompliance was within the time period.) The cause of death of the final patient was not established.

Of the 35 survivors, 27 currently have liver tests within normal limits. Renal impairment (serum creatinine > 120 μmol/L) is present in 10 patients, with 2 of these on dialysis awaiting renal transplantation. Hypertension is present in 14 patients and in the majority is coexistent with renal impairment. Since transplantation, 17 have been engaged in full-time employment, whereas 5 others have returned to part-time posts.

Premorbid Status

Fourteen were married or living with a partner, 17 were single, 5 were divorced, and 4 were separated; the status of 2 was unknown. Recent stressors that may have precipitated overdose were identified in 30 [relationship difficulties (22), financial troubles (5), and recent bereavement (3)]. No cause was identified in 6 patients. All but 2 admitted taking a deliberate overdose, although the intention was not always suicidal; the disclosure of overdose was made following transplantation in 6. Of the 2 patients who denied intentional overdose, 1 maintained the paracetamol had been taken for pain relief, and the other had no recollection of taking an overdose. In 25 cases, admission to the hospital was either by self-referral or after disclosure of the overdose to a friend or relative. In 9 cases, the patient was found unwell and was admitted to the hospital. The referral details of the other cases were not obtained. A definitive postdischarge psychiatric management plan was recorded in 24 (57%), and 8 patients were discharged on psychotropic medication.

Comparative Analysis

During the observation period up to 2004, 55 patients underwent LT for FHF secondary to POD: the median age was 32 (range, 12–57), 17 patients were male, and the median follow-up (for those surviving at least 30 days post-LT) was 53 (range, 1–137) months. Of those patients who underwent LT for non-POD FHF in the same time period, 57 matched subjects were selected for analysis: their median age was 32 years (range, 14–62), 26 were male, and the median follow-up of those surviving at least 30 days post-LT was 41.5 (range, 1–188) months. The matched cohort of 56 patients who underwent LT for CLD had a median age of 34.5 (range, 15–57), 20 were male, and the median follow-up for those surviving at least 30 days post-LT was 67 (range, 1–181) months (Table 1). The 30-day mortality was significantly greater in the POD group (P < 0.0001), but for those who survived 30 days, there was no significant difference between the 3 groups (P = 0.1; Fig. 2). Pre-LT renal support was required more commonly in the POD FHF patients (n = 30) than in the non-POD FHF patients (n = 5; P < 0.0001). POD FHF patients had a significantly greater grade of encephalopathy at the time of presentation in the unit (P = 0.041). There was no difference in the pre-LT rates of alcohol or drug misuse between the groups. Before LT, depression was more frequent in the POD group, although only 3 of the POD patients had required inpatient care for treatment of psychiatric disease.

Table 1. Pretransplant Characteristics by Disease Group
 POD (n = 55)Non-POD FHF (n = 57)CLD (n = 56)
  1. Abbreviations: CLD, chronic liver disease; FHF, fulminant hepatic failure; POD, paracetamol overdose.

Gender: male172620
Median age in years (range)32 (12–57)32 (14–64)34.5 (15–57)
Median follow-up in months (range)53 (1–137)41.5 (1–188)67 (1–181)
30-day mortality (P < 0.0001)14/55 (25%)3/57 (5%)1/56 (2%)
Alcohol misuse12/54 (22%)7/55 (13%)8/55 (15%)
Drug abuse4/54 (7%)8/53 (15%)3/54 (6%)
Psychiatric history (P < 0.0001)23/54 (43%)2/56 (4%)4/56 (7%)
Inpatient psychiatric treatment3/54 (6%)1/56 (2%)0/56
Outpatient psychiatric treatment (P = 0.007)10/54 (19%)3/56 (5%)1/56 (2%)
Depression (P < 0.0001)19/54 (35%)2/56 (4%)2/56 (4%)
Anxiety1/54 (2%)0/561/56 (2%)
Personality disorder1/54 (2%)1/56 (2%)1/56 (2%)
Eating disorder2/54 (4%)0/560/56
Figure 2.

Kaplan-Meier survival plot for POD, FHF, and CLD LT recipients. For those surviving beyond 30 days, there was no significant difference between groups in subsequent survival (P = 0.1). Survival curves were truncated when the number at risk fell below 5. Cases were matched by age, gender, and time of LT but not by severity of liver disease. Abbreviations: CLD, chronic liver disease; FHF, fulminant hepatic failure; FU, follow-up; LT, liver transplantation; POD, paracetamol overdose.

Adherence to post-LT OPA and immunosuppressive medication following initial post-LT discharge are illustrated in Figs. 3 and 4 (full records were unavailable for 3 POD patients and 2 FHF patients). OPA adherence was significantly worse in the POD group in comparison with the non-POD FHF group (P = 0.001) and the CLD group (P = 0.02). Adherence with immunosuppression was significantly worse in the POD patients in comparison with the FHF group (P = 0.025), but no significant difference was seen between the POD and CLD groups.

Figure 3.

Outpatient attendance adherence by indication for LT. Abbreviations: CLD, chronic liver disease; FHF, fulminant hepatic failure; LT, liver transplantation; POD, paracetamol overdose.

Figure 4.

Immunosuppression adherence by indication for LT. Abbreviations: CLD, chronic liver disease; FHF, fulminant hepatic failure; LT, liver transplantation; POD, paracetamol overdose.

In the CLD group, 3 deaths were due to histologically confirmed chronic rejection: 2 had documented poor compliance with immunosuppression, and 1 of these had a fair OPA record. Chronic rejection leading to death was seen in 1 non-POD FHF liver recipient, who was documented as having poor compliance with immunosuppression, despite a good OPA record. In the POD group (up to January 2004), chronic rejection was not observed (outside of the defined follow-up period, 2 deaths from chronic rejection were observed in patients with poor compliance). However, 1 POD patient with previous bipolar disorder, who was the only patient in this series to have received electroconvulsive therapy, committed suicide within 2 months of LT. One POD patient with a pre-LT diagnosis of bulimia and alcohol misuse died 5 years post-LT from alcoholic liver disease.

The POD group was further examined to determine if poor adherence was associated with any identifiable premorbid psychiatric conditions, but adherence to either OPA or immunosuppression was not associated with previous psychiatric disorders or alcohol or drug misuse. There was no association between marital status, residential status (pre-transplant and post-transplant), or the presence or absence of dependants and compliance following transplantation. Further psychiatric input was not associated with significantly improved compliance, 56% being compliant without input and 60% being compliant with such input. Employment after transplantation was found to be associated with compliance [82% of those in full-time employment were compliant versus 44% of those who were not (P < 0.05)], with no deaths recorded in those who returned to work.

DISCUSSION

There are very few published studies that examine the long-term outcome of patients transplanted for POD. For patients with severe paracetamol poisoning, not only is the decision to proceed to LT associated with medical uncertainty that the patient's probability of surviving with a transplant is greater than that without a graft, but there are also ethical dilemmas as unresolved social and psychiatric problems may affect the patient's medium-term and long-term outcomes16, 17 and, with a shortage of donor organs, another potential recipient will be denied this life-saving procedure. The patient is very often unable to give a history for himself, and there is usually a very short window of time to investigate in detail the psychiatric and social background to ensure that the patient would benefit from transplantation.

We found that 30-day mortality was significantly greater for the POD patients in comparison with the non-POD FHF and CLD patients. This probably reflects the pre-LT condition of POD patients selected for LT, although we acknowledge that in this comparative analysis patients were not matched for severity of illness. Of those who did receive a transplant, longer term outcomes were similar, but there was a greater probability of noncompliance and adverse events associated with psychological morbidity; however, on the basis of these relatively small numbers, it was not possible to identify those patients who were at greatest risk of losing their graft from deliberate self-harm or noncompliance with follow-up.

The frequency of pre-LT psychiatric conditions is greater for the POD group than for the comparison cohorts, as would be anticipated, but the relatively favorable long-term outcome observed for the transplanted POD patients will reflect, at least in part, the stringent criteria for patient selection, and thus simple extrapolation to the whole cohort of patients with POD is inappropriate. However, adherence to outpatient follow-up was worse for POD patients than for the patients in the comparison groups. Furthermore, adherence to immunosuppression was significantly worse for the POD group than for the non-POD FHF group but not significantly different from that of those transplanted for CLD. Of those patients with POD who were selected for transplantation, not all had a defined history of psychiatric disorders, and in many cases, the initial diagnosis of depression only briefly antedated the overdose. These patients were selected as it was felt that the patients either had not received full treatment for their depression or would respond to treatment after transplantation. The only suicide in the study occurred in the patient with bipolar disorder, which had been previously treated with lithium and electroconvulsive therapy; however, there were 2 deaths post-transplantation associated with psychiatric disorders, 1 of which was associated with alcohol dependence.

Despite the consequences of poor compliance in some of the recipients, this study demonstrates that transplantation for paracetamol-induced hepatic failure is usually successful and justifies the use of scarce resources in selected patients. The majority of those surviving are well and have normal liver function tests. Employment rates are similar to those reported for those transplanted for other indications.19 Several of those transplanted have experienced successful and wanted pregnancies.

There are limitations to any retrospective study. The failure to identify indicators of poor psychiatric prognosis is perhaps unsurprising given the difficulty in predicting both compliance and further self-injurious behavior in other populations. Psychological studies in the nontransplant situation20, 21 have investigated the risk of both poor compliance and completed suicide following earlier attempts. Few definitive predictors exist for either, and multiple elements may contribute. Furthermore, psychological studies investigating suicide risk have also demonstrated the difficulty of extrapolating results based on cohort studies to the individual. Scores such as the Beck intent score rate the suicidal intent of self-harm and may be used to predict recurrence; although high scores imply a significant risk of further self-harm, low scores do not exclude this. There is a life-long risk of further suicide attempts following drug overdose22; studies of parasuicide and its long-term outcomes have not clearly identified the most effective means to improve outcome. The prolonged susceptibility to self-harm suggests a need for long-term psychological support and monitoring in those undergoing transplantation for POD.

The current shortage of suitable organs for transplantation accentuates the importance of optimizing the selection of transplant candidates. Ideally, selection must be fair and equitable and be based on robust and validated medical and psychological criteria, taking into account that premorbid psychopathology increases the possibility of graft loss due to noncompliance. This study shows that depressive illness and prior overdose were not associated with a significantly greater risk of noncompliance and graft loss, although the numbers are relatively small. There is, therefore, a need to balance the rights of the patient to receive a life-saving organ with the rights of other potential recipients and the need to ensure effective use of scarce livers.

It is of concern to us that some patients who may have returned to a normal life with good graft function were excluded from transplantation and our exclusion criteria were too strict. A measured tolerance of poor compliance must therefore be accepted if the greatest number of patients is to benefit, particularly as this study has demonstrated the limited ability to accurately predict poor psychiatric outcome. The currently used selection criteria exclude severe and unresponsive psychiatric disorders, and this explains why no patients in this study cohort had suffered a previous psychotic illness despite schizophrenia being one of the more common psychiatric diagnoses associated with suicide. However, it must be remembered that noncompliance and other potentially self-injurious behaviors are not limited to this population, and overall estimates of noncompliance suggest rates between 20% and 50%.23, 24

Although episodes of poor compliance could not be predicted prior to transplantation, after grafting, several factors correlated with compliance. There was an association between employment following transplantation and both compliance and survival, and this was in keeping with other studies which have suggested that the greater the impact of transplantation is on the patient (such as an inability to continue working), the poorer the compliance will be.24

This study confirms that there remains a risk of self-injurious behavior following transplantation and establishes that such behavior cannot be reliably predicted prior to transplantation. Importantly, the study has demonstrated that a prior history of depression or even previous overdose does not preclude successful transplantation and that such premorbid psychopathologies are not indicative of poor prognosis. Indeed, with an overall survival rate of 58% at a mean of 9 years following transplantation and with the majority of these patients well, with good graft function and good rates of employment, the use of transplantation is well validated.

In summary, our study shows that the long-term outcome of transplanted POD patients is very good and is little affected by poor adherence to follow-up and immunosuppressive medication in comparison with age-matched and gender-matched FHF and CLD patients undergoing LT. Adherence is slightly inferior to that of age-matched CLD patients and non-POD FHF patients and may be associated with the pre-LT psychological morbidity of POD patients, and it does not simply reflect age at transplantation or a failure to receive adequate pre-LT counseling. LT following POD warrants careful selection of recipients, but with this in place, both excellent relative survival and comparable levels of compliance may be achieved.

Acknowledgements

The authors acknowledge the help provided by S. Benson with data collection.

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