Liver Transplantation for Paracetamol Toxicity

OVERVIEW

  • 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 may be 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 center is currently recommended.

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 are widely used for this.
  • There are concerns that use of the KCC does not lead to longterm benefit, especially 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 costs (donated livers are in short-supply, someone else has to miss out)

WHEN TO TRANSFER PATIENTS TO A LIVER TRANSPLANT CENTER

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 (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, but 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
    — >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 ALF managed medically during 1973–1985
  • The model was validated in an independent cohort of 175 ALF patients treated between 1986 and 1987
  • KCC forms the basis for 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 -> determine chance of survival 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 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 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 was only 8.1 QALYs.

Limitations

  • wide variation in survival found in the 15 included studies
  • many of the articles included selected series (i.e. not purely meeting KCC criteria)
  • extrapolation of survival beyond 10 years is assumed to be constant (less rejection, more immune-suppression complications)

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 -> 9% survival
    — patients that met KCC  that were listed for transplant but not transplanted -> 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% (pre 1990) to 22.6% in the King’s Unit) — Better use of NAC? 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 pateints was 68%, compared to 19% at King’s
  • There are essentially 2 groups of paracetamol-induced hepatotoxicity patients:
    — stable hemodynamically and no cerebral edema -> survive with standard ICU care (but would be transplanted at King’s)
    — shock or cerebral edema -> 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

CONCLUSION

  • orthotopic liver transplantation for paracetamol-induced hepatoxicity may confer little longterm survival benefit in patients meeting the KCC and is associated with considerable costs
  • based on the model by Ding and Buckley, if a KCC patient is younger and/ or is fitter for surgery the gain from liver transplantation is less!
  • auxillary heterotopic liver transplantation or liver support therapy (with no need for immune-suppression following liver recovery) may be future strategies

References and links

Lifeinthefastlane.com

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. Review. PubMed 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. PubMed PMID: 11867109.
  • Dargan PI, Jones AL. Acetaminophen poisoning: an update for the intensivist. Crit Care. 2002 Apr;6(2):108-10. Epub 2002 Mar 14. Review. PubMed PMID: 11983032; PubMed Central PMCID: 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. doi: 10.1093/qjmed/hcn077. Epub 2008 Jul 7. Review. PubMed 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. [Free Full Text]
  • 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. doi: 10.3389/fphys.2012.00340. Epub 2012 Aug 28. PubMed PMID: 22973230; PubMed Central PMCID: 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. PubMed PMID: 16123967. [Free Full Text]
  • 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]
  • Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002 Sep;36(3):659-65. PubMed 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. PubMed PMID: 15690478.
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