Liver Transplantation for Paracetamol Toxicity

Reviewed and revised 30 April 2016

OVERVIEW

• Paracetamol overdose is the most common cause of fulminant hepatic failure in the USA (39% of cases)
• Paracetamol-induced hepatotoxicity is defined as a peak elevation in hepatic transaminases (ALT or AST) > 1000 IU/L in the context of paracetamol overdose
• Liver transplantation is potentially life-saving in the minority of cases of paracetamol toxicity that result in fulminant hepatic failure
• In patients who are otherwise expected to die, orthotopic liver transplant (OLT) in a specialised centre is currently recommended
• The role of liver transplantation in severe hepatotoxicity is controversial

ISSUES

• Early identification of transplant candidates is important, as patients that become too sick may not be able to undergo transplantation (e.g. due to cerebral herniation or multiple organ failure)
• Accurate early prediction of the need for liver transplantation remains an important challenge, currently the King’s College Criteria (KCC) are widely used for this
• There are concerns that use of the KCC does not lead to long-term benefit (at the population level)
• Incorrectly identifying a patient as appropriate for liver transplantation has significant costs

COSTS OF INCORRECTLY IDENTIFYING A PATIENT AS APPROPRIATE FOR LIVER TRANSPLANTATION

Potential costs include:

• effect on patient’s long term survival, health and quality of life (due to major surgery, immunosuppression, etc)
• substantial short- and long-term monetary costs of treatment
• opportunity cost (donated livers are in short-supply, someone else has to miss out)

WHEN TO TRANSFER PATIENTS TO A LIVER TRANSPLANT CENTRE

High-risk features mandating admission to a liver transplant centre are:

• INR >3.0 at 48 hours or >4.5 at any time
• Oliguria or creatinine > 200 micromol/L
• Acidosis with pH < 7.3 after resuscitation
• Systolic hypotension with BP < 80mmHg
• Hypoglycaemia
• Severe thrombocytopenia
• Encephalopathy of any degree

IDENTIFICATION OF LIVER TRANSPLANT CANDIDATES

King’s College Criteria (KCC) are the most widely used and feature in most textbooks on the topic (see below). Other means include:

• modified King’s College Criteria
  • combines KCC with lactate (see below)
• Schiodt score (time until treatment with NAC, decrease in PT, and early thrombocytopenia)
  • identifies risk of hepatic encephalopathy, not which patients require transplantation per se
• Lactate  (>3.5 mmol/L at a median of 55 hours after APAP ingestion or blood lactate concentration >3.0 mmol/L after fluid resuscitation)
  • both a sensitive and a specific predictor of patient death without transplant
• Acute Physiology and Chronic Health Evaluation (APACHE) II score >15
  • similar performance to King’s College Criteria
  • only useful for isolated paracetamol ingestion as comorbidities and coingestants may alter the APACHE score
• Coag profile
  • markedly abnormal PT that continues to rise on the fourth day after overdose indicates a very poor prognosis
  • any patient with a PT in seconds that exceeds the number of hours since ingestion should be considered at extreme risk
• Serum phosphate concentration at 48 hours (Schmidt and Dalhoff, 2005)
  • >1.2 mmol/L on day 2 (48-72 hours) was both sensitive and specific for predicting patients who either received a transplant or died

KING’S COLLEGE CRITERIA (KCC)

• KCC is the most commonly used prediction model for liver transplantation in paracetamol hepatotoxicity
• KCC was initially based on a retrospective study on 588 patients with acute liver failure (ALF) managed medically during 1973–1985 (O’Grady et al, 1989)
• The model was validated in an independent cohort of 175 ALF patients treated between 1986 and 1987
• KCC forms the basis for emergency liver transplantation (ELT) registration in many countries
• Case series and meta-analyses suggest that KCC has a specificity of ~90%; survival without transplantation of patients meeting KCC being <15% (at King’s — see problems below).
• Sensitivity of KCC has been reported to be as low as ~60%, indicating that KCC may fail to detect patients facing a fatal outcome without ELT

The King’s College Criteria

pH < 7.3

or

In a 24h period, all 3 of:

• INR > 6 (PT > 100s) +
• Cr > 300mmol/L +
• grade III or IV encephalopathy

The modified KCC tries to increase sensitivity (reported to be 91%) by also including lactate (Bernal et al, 2002). Consider liver transplantation if:

• arterial lactate concentration >3.5 mmol/l  after early resuscitation (4 h) [sensitivity 67%, specificity 95%]
• pH < 7.3 OR
  lactate > 3.0 mmol/l [sensitivity 76%, specificity 97%]
  after fluid resuscitation (12 h after admission)

DING AND BUCKLEY 2008 — ANALYSIS OF SURVIVAL BENEFIT FROM USING KCC

Study design

• systematic review of papers published from January 1989 to January 2007
• studies included if data was available on survival rates of patients who met KCC but were not transplanted, to allow chance of survival to be determined in these patients
• there were 15 studies (an additional 10 had temporal overlap resulting in the same data being published twice)
• United Kingdom Transplant Support Service Authority, Liver Transplant Audit 1985–95 data used as a comparison to determine survival of patients who received liver transplants
• modeled outcome of decision to transplant a 20-year-old on their survival over the next 60 years
• quality of life for a transplanted person estimated to be 0.6 compared to a healthy person

Results

• 386 patients met KCC but were not transplanted
• of these 96 (24.9%) survived (95% confidence interval (CI) 20.8–29.4) at 10 years
• liver transplant recipients after acute liver failure by comparison have survival at 10 years of 44% (95% CI 38–50)
• however, the survival advantage becomes increasingly unfavourable with extrapolation beyond 10 years, and even more so when using quality-adjusted life years (QALY)
• the expected survival benefit calculated as area under curve (AUC) for a 20-year-old with the KCC was similar without a transplant (13.4 years) as with a transplant (13.5 years), and the latter corresponded to only 8.1 QALYs

Limitations

• wide variation in survival found in the 15 included studies
• selection bias
  • many of the articles included selected series (i.e. not purely meeting KCC criteria)
  • excluded studies that did not report survival of non-transplanted patients
• extrapolation of survival beyond 10 years is assumed to be constant (less rejection, more immune-suppression complications)
• conversion to QALYs is open to bias and may over-estimate the quality of life of spontaneous survivors (see below)
• model has not been externally validated in a clinical setting

PROBLEMS WITH THE KING’S COLLEGE CRITERIA (KCC)

Based on Ding and Buckley (2008):

• 30% of people who meet KCC in the 12 articles from centres other than King’s College survived without transplant
• reported survival in those not transplanted is much worse in studies originating in the King’s unit (13.8 vs. 30.0%)
  • this may be due to spectrum bias (testing of the validity of a diagnostic or prognostic test in a population that is different from the one in which it most usefully would be applied to in practice)
• those patients with the best prognosis may have been preferentially transplanted in the King’s Unit
  • patients that met KCC but not listed for transplant had 9% survival
  • patients that met KCC that were listed for transplant, but not transplanted, had 17% survival
• KCC may be applied differently by other units (non-explicit criteria? consideration of other factors?)
• overall prognosis of patients with paracetamol-induced hepatotoxicity has improved over the past 20 years (43.9% mortality (pre 1990) to 22.6% in the King’s Unit) — Better use of N-acetylcysteine? Better ICU care?

Gow et al (2007) criticise the lactate component of the modified KCC proposed in Bernal et al (2002):

• Data from Melbourne over 12 years: 40 patients with paracetamol induced fulminant hepatic failure (FHF)
• often no donor available for many days, so early transplantation less likely than at King’s
• 2 deaths – 1/38 non-transplanted patients, 1/2 transplanted patients
• Compared to the King’s data from Bernal et al (2002) survival of non-transplanted patients was 68%, compared to 19% at King’s
• There are essentially 2 groups of paracetamol-induced hepatotoxicity patients:
  • stable haemodynamically and no cerebral oedema -> survive with standard ICU care (but would be transplanted at King’s)
  • shock or cerebral oedema -> die regardless of whether they receive a liver transplant
• The King’s data from Bernal et al (2002) appears to be biased because:
  • numerous stable patients with high lactates who probably would otherwise have survived were transplanted at King’s
  • patients were excluded if they were too ill to be listed or died waiting for liver transplantation

LONG-TERM OUTCOME OF ACUTE LIVER FAILURE DUE TO PARACETAMOL TOXICITY

• The long-term outcome of survivors of acute liver failure due to paracetamol toxicity is not well described
• Spontaneous (untransplanted) survival in acetaminophen overdose has markedly improved over the last 2 decades
  • paracetamol-related ALF and grade 3 or 4 encephalopathy at King’s College Hospital between 1999 and 2008 (Bernal et al, 2013)
    • 66%  overall survival
    • 52% survival in the three-quarters that were spontaneous survivors (those who did not receive liver transplantation)
• Survivors often have lasting morbidity in terms of poor physical and mental health (Rangesekar et al, 2013)
• Spontaneous survivors report more days of poor physical and mental health than liver transplant recipients, especially those that are young or female (Rangesekar et al, 2013)
  • unclear whether this reflects pre-existing psychological morbidity and/or severity of acute liver failure, which may have affected the decision to perform transplantation

CONCLUSION

“…the gap between transplant-free and post-transplant survival has narrowed dramatically and to the point that a fundamental review of the role of liver transplantation is indicated.”
— O’Grady, 2013

• Patients with severe paracetamol-induced hepatoxicity need to be recognised early and early discussion with experts at a liver transplant center is warranted to optimise care
• However, orthotopic liver transplantation for paracetamol-induced hepatoxicity may confer little longterm survival benefit in patients meeting the KCC and is associated with considerable costs
• Auxiliary heterotopic liver transplantation or liver support therapy (with no need for immune-suppression following liver recovery) may be useful future strategies

References and links

LITFL

• CCC — Liver Transplantation
• CCC — Acute Paracetamol Toxicity
• CCC — Fulminant Hepatic Failure
• Toxicology Conundrum 045 — Paracetamol-induced hepatotoxicity

Journal articles and textbooks

• Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003 Jan;31(1):299-305. PMID: 12545033.
• Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet. 2002 Feb 16;359(9306):558-63. PMID: 11867109.
• Bernal W, Hyyrylainen A, Gera A. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. Journal of hepatology. 59(1):74-80. 2013. [pubmed]
• Dargan PI, Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care. 2002 Apr;6(2):108-10. PMC137288.
• Ding GK, Buckley NA. Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity. QJM. 2008 Sep;101(9):723-9. PMID: 18606611.[Free Fulltext]
• Gow PJ, Warrilow S, Lontos S, Lubel J, Wongseelashote S, MacQuillan GC, Jones RM, Bellomo R, Angus PW. Time to review the selection criteria for transplantation in paracetamol-induced fulminant hepatic failure? Liver Transpl. 2007 Dec;13(12):1762-3. PubMed PMID: 18044782.
• Hadem J, Strassburg CP, Manns MP. Prediction of outcome and selection of the liver transplant candidate in acute liver failure. Front Physiol. 2012;3:340. PMC3428778.
• Macquillan GC, Seyam MS, Nightingale P, Neuberger JM, Murphy N. Blood lactate but not serum phosphate levels can predict patient outcome in fulminant hepatic failure. Liver Transpl. 2005 Sep;11(9):1073-9. PMID: 16123967.
• O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439-45. PubMed PMID: 2490426. [Free Full Text]
• O’Grady J. Timing and benefit of liver transplantation in acute liver failure. Journal of hepatology. 60(3):663-70. 2014. [pubmed] [free full text]
• Rhodes R, Aggarwal S, Schiano TD. Overdose with suicidal intent: ethical considerations for liver transplant programs. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 17(9):1111-6. 2011. [pubmed] [free full text]
• Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002 Sep;36(3):659-65. PMID: 12198658.
• Schmidt LE, Dalhoff K. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury. Hepatology. 2005 Jan;41(1):26-31. PMID: 15690478.