UNCORRECTED PROOF Estimated risk of hepatotoxicity after an acute acetaminophen overdose in alcoholics Fahad M. Ali * , Edward W. Boyer, Steven B. Bird Division of Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA Received 16 October 2006; received in revised form 1 November 2007; accepted 5 November 2007 Abstract A published logistic regression model based on the Canadian Acetaminophen Overdose Study registry was used to calculate the risk of hepatotoxicity after an acute acetaminophen overdose and to estimate a treatment threshold line for alcoholic patients who did not co-ingest alcohol (i.e., abstinent alcoholics) on the RumackeMatthew nomogram. The risk of hepatotoxicity in nonalcoholic and abstinent alcoholic patients was calculated at the acetaminophen concentration of 150 mg/ml at 4 h (37.5 mg/ml at 12 h) treatment threshold line. This corre- sponds to the ‘‘possible risk’’ line on the RumackeMatthew nomogram and represents a 1.6% risk of hepatotoxicity for nonalcoholic pa- tients at or below this line. At or below this same 150 mg/ml at 4-h line, abstinent alcoholic patients have a hepatotoxicity risk of 10.7%. The risk of hepatotoxicity in abstinent alcoholics’ equivalent to that of nonalcoholics (i.e., 1.6%) occurs at a lower acetaminophen concentra- tions treatment threshold line, that is, 104 mg/ml at 4 h (26 mg/ml at 12 h). Because of difficulties plotting this new line on the familiar RumackeMatthew semilogarithmic scale, a line connecting 100 mg/ml at 4 h (25 mg/ml at 12 h) is proposed. This line equates to a 1.1% risk of hepatotoxicity in abstinent alcoholic patients. The analysis supports the observation that based on the published model; ab- stinent alcoholics might have a greater risk of hepatotoxicity after an acute acetaminophen overdose. This proposed new risk line can be used in hypothesis generation for future clinical studies in this alcohol related problem. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Acetaminophen; Alcoholism; Hepatotoxicity; Overdose; Poisoning; Theoretical models Introduction The RumackeMatthew nomogram is an important clin- ical decision-making tool used by physicians and poison control centers when managing patients presenting with an acute acetaminophen overdose. The nomogram is used to discern which acetaminophen-poisoned patients are at sufficient risk to require treatment with N-acetylcysteine (NAC), but does not incorporate patient-specific risk factors such as history of alcoholism (Rumack, 2002). A lower threshold for treatment of acetaminophen poisoning has been advocated in chronic alcoholics based originally on animal studies, but no human studies have addressed the is- sue of the treatment threshold after an acute acetaminophen overdose in alcoholic patients (Buckley & Srinivasan, 2002). The practice of using a lower plasma acetaminophen concentration threshold for the treatment of acetaminophen poisoning, after an acute overdose in ‘‘high-risk groups’’ such as chronic alcoholism patients, is based on anecdotal case reports and small case series (Dargan & Jones, 2002; Reid & Hazell, 2003). There is no consensus on the use of these lower threshold treatment ‘‘safety lines’’ when making treatment decisions in patients with potentially in- creased risk of hepatotoxicity after an acetaminophen over- dose (Reid & Hazell, 2003). Arguments about the possibility of increased hepatotox- icity risk after an acetaminophen overdose in chronic alco- holics should be differentiated from acute acetaminophen overdose with alcohol coingestion. There is evidence from both animal and human studies that acute alcohol coinges- tion inhibits the toxic metabolic activation of acetamino- phen in the liver. This protective effect can decreases the risk of development of hepatotoxicity after an acetamino- phen overdose, even in cases with preexisting chronic alco- holism (Dargan & Jones, 2002; Prescott, 2000; Tredger, 1985). Furthermore, the possibility of increased hepatotox- icity after an acetaminophen overdose in chronic alcoholics should not be confused with the possibility of increased risk of liver injury in long-term alcoholics at repeated maximum ALC5918_proof  13-2-2008 11-43-8 * Corresponding author. Tel.: þ1-508-421-1401; fax: þ1-508-421- 1490. E-mail address: fahadalimd@hotmail.com (F.M. Ali). 0741-8329/08/$ e see front matter Ó 2008 Elsevier Inc. All rights reserved. doi: 10.1016/j.alcohol.2007.11.005 ARTICLE IN PRESS Alcohol - (2008) 1e6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71