Reply

Abstract

We appreciate Drs Holubek and Nelson’s interest in our paper recently published in Gastroenterology and agree that measurement of acetaminophen-protein adducts represents a new and very promising part of the diagnostic evaluation of patients with acute liver failure (ALF).1Davern 2nd, T.J. James L.P. Hinson J.A. Polson J. Larson A.M. Fontana R.J. Lalani E. Munoz S. Shakil A.O. Lee W.M. Acute Liver Failure Study GroupMeasurement of serum acetaminophen-protein adducts in patients with acute liver failure.Gastroenterology. 2006; 130: 687-694Abstract Full Text Full Text PDF Scopus (238) Google Scholar However, the authors appear to have misinterpreted the diagnostic criteria for acetaminophen-related ALF used in our multicenter study. These criteria included rapid onset ALF in patients with a history of recent, excessive (> 4 g over 24 hours and typically much more) consumption of acetaminophen, detection of acetaminophen in blood, and serum alanine aminotransferase > 3500 IU/L, which is common in acetaminophen-related cases, but relatively rare in other forms of ALF.1Davern 2nd, T.J. James L.P. Hinson J.A. Polson J. Larson A.M. Fontana R.J. Lalani E. Munoz S. Shakil A.O. Lee W.M. Acute Liver Failure Study GroupMeasurement of serum acetaminophen-protein adducts in patients with acute liver failure.Gastroenterology. 2006; 130: 687-694Abstract Full Text Full Text PDF Scopus (238) Google Scholar To develop the patient group that were certain acetaminophen cases, we required not just an acetaminophen level but the other criteria as well in virtually every case. In our study, acetaminophen adducts were detected in sera from all the patients tested who had ALF attributed to acetaminophen hepatotoxicity using these criteria, whereas no patient who had ALF attributed to other well-defined causes (eg, viral hepatitis) had adducts in their sera.2Larson A.M. Polson J. Fontana R.J. Davern T.J. Lalani E. Hynan L.S. Reisch J.S. Schiodt F.V. Ostapowicz G. Shakil A.O. Lee W.M. Acute Liver Failure Study GroupAcetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.Hepatology. 2005; 42: 1364-1372Google Scholar Most important, almost 20% of patients with ALF of indeterminate cause had high levels of acetaminophen adducts, strongly suggesting that occult acetaminophen hepatotoxicity was present in these patients. We agree that further validation of the assay is needed, particularly in patients taking therapeutic doses of acetaminophen, some of whom may develop significant serum aminotransferase elevations.3Watkins P.B. Kaplowitz N. Slattery J.T. Colonese C.R. Colucci S.V. Stewart P.W. Harris S.C. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.JAMA. 2006; 296: 87-93Google Scholar These studies are underway. We also agree that it is difficult to prove that acetaminophen played a primary rather than a secondary role in the development of liver injury in the 20% of patients with indeterminate ALF with high adduct levels. However, these patients had an extensive and ultimately unrevealing evaluation for other causes of ALF, including viral hepatitis, and their adduct levels were at least equal in all cases to those observed in the known acetaminophen cases. In addition, their clinical courses and other laboratory values were very similar to the known acetaminophen group, strongly supporting the notion that ALF was caused by otherwise occult acetaminophen toxicity in these cases.1Davern 2nd, T.J. James L.P. Hinson J.A. Polson J. Larson A.M. Fontana R.J. Lalani E. Munoz S. Shakil A.O. Lee W.M. Acute Liver Failure Study GroupMeasurement of serum acetaminophen-protein adducts in patients with acute liver failure.Gastroenterology. 2006; 130: 687-694Abstract Full Text Full Text PDF Scopus (238) Google Scholar There are many reasons why patients may not admit to taking acetaminophen, the most prominent being subsequent denial of a suicide attempt, but others include embarrassment at the problem they have caused, or that they are already comatose on admission to the referral center and thus cannot answer questions. Although we agree that N-acetylcysteine (NAC), a highly effective antidote for acetaminophen poisoning, should be promptly administered to all patients in whom acetaminophen overdose is suspected, we strongly disagree with the authors that published studies support the use of NAC for “all patients with ALF regardless of cause.” There are no such studies. Indeed, because the role of NAC in this setting is undefined, the National Institutes of Health are currently sponsoring a multicenter, double-blind, placebo-controlled study that is being conducted by our group to better define the role of NAC in nonacetaminophen ALF (www.acuteliverfailure.org). We anticipate the results of this important study will help to guide the rational management of patients with ALF. Acetaminophen Protein Adducts: Is Acetaminophen to Blame?GastroenterologyVol. 131Issue 4PreviewWe read with great interest the article1 reporting serum acetaminophen–protein adducts in patients with acute liver failure (ALF). We believe that testing for these adducts holds great potential for the determination of the etiology of ALF. Full-Text PDF