Detection of Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause

James, Laura P.; Alonso, Estella M.; Hynan, Linda S.; Hinson, Jack; Davern, Timothy J.; Lee, William M.; Squires, Robert H.; Rodriguez‐Baez, Norberto; Murray, Karen F.; Shepherd, Ross W.; Rosenthal, Phillip; Schneider, Benjamin; Emre, Sükrü; Horslen, Simon; Martı́n, Martı́n G.; López, Mariana; McGuire, Brendan M.; Narkewicz, Michael R.; Jonas, Maureen M.; Schwarz, Kathleen B.; Lobritto, Steven; Thomas, D. Winton; Rand, Liz; Dhawan, Anil; Ng, Vicky L.; Kelly, Déirdre; Quiros, Ruben; Lavine, Joel E.; Soriano, Humberto E.

doi:10.1542/peds.2006-0069

Cited by 91 publications

(81 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3-para-cysteinyl APAP has been demonstrated in human patients with fulminant hepatic failure thought to be related to APAP, as well as following acute overdose of APAP [2] and after ingestion of therapeutic doses of APAP in 4 g/day doses [4,6,7,8].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

et al. 2015

View full text Add to dashboard Cite

Generation of protein-derived acetaminophencysteine (APAP-CYS) is reported after ingestion of large and therapeutic dosages of acetaminophen in healthy and in liver-damaged patients. The incidence of proteinderived APAP-CYS adducts in repeated supratherapeutic dosages of APAP is not known. Methods: for 12 months, a standardized and comprehensive questionnaire was used to interview every consecutive patient at a pain management clinic. Patients found to ingest more than 4 g of APAP per day for a minimum of 14 consecutive days at the time of the encounter were invited to have blood drawn for hepatic transaminases and APAP-CYS adduct levels. Twelve subjects out of 990 interviewees met inclusion criteria. Ten of the 12 had measurable protein-derived APAP-CYS, none had evidence of liver injury. Patients that ingest repeated supratherapeutic amounts of APAP over several weeks may generate APAP-CYS protein adducts in the absence of hepatic injury.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Several early studies explored the possibility of using APAP-CYS protein adducts to identify and confirm APAP as the etiology behind unexplained hepatic failure [7,8], but specificity and accuracy for this purpose are unproven.…”

Section: Discussionmentioning

confidence: 99%

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It is possible that some of the patients diagnosed as non-APAP-induced ALF may in fact have been APAP-adduct positive, suggesting "subtoxic" exposure to APAP, which would significantly impact disease progression. 11 Although the presence of APAP-adducts in a subset of patients may confound the effects of NAC and the results of this study, one could argue that patients accrued in all eras should be equally misdiagnosed. Alternatively, the improved clinical outcomes observed in the patient groups receiving NAC could be accounted for by other factors related to improved clinical management over time or dissimilar patient populations.…”

mentioning

confidence: 86%

Is there a “NAC” to treating acute liver failure in children?

Leonis

Balistreri

2007

Liver Transpl

View full text Add to dashboard Cite

“…Antoine et al, 2013 (35) found 3 possible biomarkers: elevation of microRNA-122, a marker of necrosis (HMGB-1) and markers of necrosis and apoptosis (K18). On the other hand, studies performed by the covalent junctions that form between NAPQI and cellular proteins can be used to identify patients with occult toxicity by paracetamol (26,36) . The metabolic technology (with mass spectrometry and nuclear magnetic resonance) may have the ability to identify specifi c biomarkers of adverse events and toxicity in the early stages (24) .…”

Section: Ethical Aspectsmentioning

confidence: 99%

“…In a situation where paracetamol overdose, or in circumstances where there is a reduction of glutathione, the metabolite NAPQI is covalently bound to the cellular proteins forming adducts (25) . James LP et al recognized that there was a correlation between adducts and clinical markers of hepatotoxicity commonly used in children and adolescents with paracetamol overdose (26) . In addition, the adducts were not found in patients with other known causes of acute hepatic failure and in those patients receiving N-acetyl cysteine treatment were able to detect low levels of adducts.…”

Section: Introductionmentioning

confidence: 99%

Acute and chronic paracetamol overdose in paediatric population: Protocol of a prospective study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity

Tong

Garcia²,

Garcia³

et al. 2017

IBJ Clin Pharmacol

View full text Add to dashboard Cite

I., Borobia Pérez AM., Carcas Sansuán AJ., Martí nez Ávila JC., Ramírez García E. Acute and chronic paracetamol overdose in paediatric populati on: Protocol of a prospecti ve study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity. IBJ Clin Pharmacol 2017 1(1):e0007. Funding: The authors have no fi nancial relati onships relevant to this arti cle to disclose. Competi ng Interests:The authors declare no confl icts of interest. Background:In Spain, 30% of cases of acute liver failure remaining undetermined. Paracetamol is the main drug causing acute liver failure in children of some countries like the United States, UK and other European countries. The key factors to assess in paracetamol toxicity, the ingested dose and the ti me from the poisoning, are diffi cult to assess in children where accidental acute poisoning or medicati on errors are not rare. Metabolomics technology may be able to identi fy specifi c biomarkers of toxicity and adverse events in early stages. The identi fi cati on of paracetamol toxicity biomarkers could have important clinical implicati ons for pati ents who can not apply the Rumack-Matt hew nomogram and could be useful in the evaluati on of children with acute liver failure of unknown eti ology, and to predict liver damage before elevati on of transaminases. Methods and design:This is an observati onal prospecti ve study of case control. The protocol was approved by the Clinical Research Ethics Committ ee of the La Paz University Hospital. It will recruit pati ents who will be att ending in the emergency paediatric at La Paz University Hospital, at Niño Jesus University Hospital, and at Gregorio Marañón University hospital with suspected acute or chronic intake of paracetamol. Likewise, two cohorts of control will be recruited. It is expected to recruit at least 36 cases and 144 controls, matched for age and clinical characteristi cs. Peripheral blood, plasma, serum and urine samples will be collected, paracetamol serum concentrati ons, hepati c and renal functi on, coagulati on and metabolomic analysis. Discussion:It is important to determine the clinical factors and biomarkers that predict the development of hepatotoxicity in paediatric populati on following acute and chronic intake of paracetamol and develop a predicti ve model to assess the risk of hepatotoxicity in both type of intoxicati on by paracetamol suited to paediatric pati ents for use in clinical practi ce. Study registrati on: Editor: Jesús Frías IniestaCite as: Tong HY., Díaz García L., García García S., Ruiz Domínguez JA., Martí n Sánchez J., Storch de Gracias P., Rivas A., Muñoz M., Hernández Zabala R., García García I., Borobia Pérez AM., Carcas Sansuán AJ., Martí nez Ávila JC., Ramírez García E. Acute and chronic paracetamol overdose in paediatric populati on: Protocol of a prospecti ve study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity. IBJ Clin Pharmacol 2017 1(1):e0007. Funding: The authors have no fi nancial relati onships...

show abstract

Detection of Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause

Cited by 91 publications

References 18 publications

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

Protein-Derived Acetaminophen-Cysteine Can Be Detected After Repeated Supratherapeutic Ingestion of Acetaminophen in the Absence of Hepatotoxicity

Is there a “NAC” to treating acute liver failure in children?

Acute and chronic paracetamol overdose in paediatric population: Protocol of a prospective study of cohort to evaluate clinic factor and biomarkers to predict development of hepatotoxicity

Contact Info

Product

Resources

About