The predictive value of serum alanine transaminase activity on first presentation to hospital in patients with paracetamol poisoning Khalid Al-Hourani, Rachel Mansi, Janice Pettie, Margaret Dow, Nick Bateman & James Dear NPIS Edinburgh Royal Infirmary of Edinburgh, UK
Introduction Paracetamol poisoning represents a large workload for health services - 38,000 hospital admissions in England 2010-2011 1 Commonest agent that induces to drug-induced liver injury (DILI) - leading cause of acute liver failure in UK and USA 2 - of significant interest to pharma Distinct to idiosyncratic DILI as patients often present before liver injury develops - latent period when management decisions are difficult Need for new biomarkers that can individualize therapy 1. NHS Information Centre, Hospital Episode Statistics for England 2. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42(6):1364-72.
Introduction new markers: microrna Hepatology (2011) 54:1767-76
Introduction new markers: cell death In patients with hepatotoxicity Journal of Hepatology (2012) 56: 1070 1079
Introduction what about existing markers? Study of 94 patients who developed hepatotoxicity (AT > 1000) after single OD First AT concentration Hepatotoxicity - median 211 IU/L (IQR 77 511 IU/L) No hepatotoxicty 19 (14 27) On first presentation serum transaminase activity is already increased in patients who develop hepatotoxicity.
Objective Following paracetamol overdose, determine the value of serum ALT activity at first presentation as a predictor of hepatotoxicity 1. Does a raised ALT diagnose paracetamol-induced liver injury with sufficient accuracy what is the positive predictive value? 1. Does a normal ALT exclude paracetamol-induced liver injury with sufficient accuracy what is the negative predictive value?
Method Prospective study of 500 consecutive patients Entry criteria patients admitted to the Royal Infirmary of Edinburgh for acetylcysteine therapy after paracetamol overdose. Need for therapy assessed by treating clinician using standard UK nomogram. Includes single and staggered ingestions Start date March 2011 Primary outcome - paracetamol-induced hepatotoxicity 2 definitions - > double admission > 1000U/L classified as normal (<50U/L) or abnormal (>50U/L)
Method Emergency Department IV acetylcysteine treatment ALT ALT x2 > 1000
Results Summary of study demographics Number of patients entered 500 Number excluded 90 73 NAC stopped early 8 bloods haemolysed 9 no coagulation Age (median, IQR) 36, 22-41 M:F 46:54 % Abnormal admission ALT, > 50U/L (number, %) 68, 17% Time of first ALT 0-8 hrs post ingestion (number, %) 264, 64% Time of first ALT 8-24 hrs post ingestion (number, %) 54, 13% Time of first ALT >24 hrs post ingestion (number, %) 53, 13% Staggered OD (number, %) 39, 10% Hepatotoxicity (number, %) x2 admission ALT 20, 5% Hepatotoxicity (number, %) peak ALT >1000U/L 16, 4%
Results - whole population < 50U/L >50U/L < x2 admission 335 True negative 55 >x2 admission 7 13 True positive PPV = 19% NPV= 98%
Results whole population < 50U/L >50U/L <1000U/L 339 True negative 55 >1000U/L 0 16 True positive PPV = 23% NPV= 100%
Results 0-8 hrs post-ingestion < 50U/L >50U/L < x2 admission 222 True negative 35 > x2 admission 4 3 True positive PPV = 7% NPV= 98%
Results 8-24 hrs post-ingestion < 50U/L >50U/L < x2 admission 46 True negative 5 > x2 admission 2 1 True positive PPV = 17% NPV= 96%
Results >24 hrs post-ingestion < 50U/L >50U/L < x2 admission 36 True negative 8 > x2 admission 1 8 True positive PPV = 50% NPV= 97%
Results Staggered ingestion < 50U/L >50U/L < x2 admission 31 True negative 7 > x2 admission 0 1 True positive PPV = 13% NPV= 100%
Conclusion In the current UK guidelines decisions are based on a timed blood paracetamol concentration - ALT is not included However, a normal ALT has a high negative predictive value in patients fully treated with acetylcysteine Possible advantages: 1. Patients can be advised that they are unlikely to come to harm if normal presentation ALT and treated correctly with NAC 1. For a clinical trial of a new therapeutic/management strategy admission ALT informs inclusion criteria Under development in combination with the paracetamol concentration as the APAP x AT multiplication product. Sivilotti ML, Green TJ, Langmann C, Yarema M, Juurlink D, Johnson D. Multiplying the serum aminotransferase by the acetaminophen concentration to predict toxicity following overdose. Clin Toxicol (Phila);48(8):793-9.