- 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.
- 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
- 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
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
- 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
- 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.
- 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
- 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
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.