When do the aminotransferases rise after acute acetaminophen overdose?

Green, Thomas J.; Sivilotti, Marco L.A.; Langmann, Caillin; Yarema, Mark; Juurlink, David N.; Burns, Michael J.; Johnson, David W.

doi:10.3109/15563650.2010.523828

Cited by 64 publications

(45 citation statements)

References 30 publications

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“…APAP overdose results in destruction of liver cells in turn resulting in the elevation in serum level of enzymes aminotransferases [28–30]. The measuring serum levels of specific liver enzymes such as ALT, AST, ALP, and γ GT are most commonly used markers in hepatotoxic studies.…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective Effect of Citral on Acetaminophen‐Induced Liver Toxicity in Mice

Uchida

Silva-Filho

Cardia

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

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Section: Discussionmentioning

confidence: 99%

Hepatoprotective Effect of Citral on Acetaminophen‐Induced Liver Toxicity in Mice

Uchida

Silva-Filho

Cardia

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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“…To compare our population sample response with the treatment nomograms, we ran simulations on each simulated patient at four different APAP doses (7.5, 10, 15, and 20 g) with no NAC treatment (Rumack et al, 1981;Sivilotti et al, 2005;Green et al, 2010). In our model after a single overdose of APAP a peak ALT value of 1000 U/liter corresponds to a loss of 18% of hepatocytes, so we defined as hepatotoxic any individual with less than 82% of hepatocytes viable.…”

Section: Methodsmentioning

confidence: 99%

An Analysis ofN-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

Woodhead

Howell²,

Yang³

et al. 2012

J Pharmacol Exp Ther

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N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n ϭ 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V max for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.

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“…There are limits to the utility of the current biomarker, ALT, in assessing the status of potentially APAP-poisoned patients. For example, ALT may take greater than 72 h to reach peak activity in blood (6), and elevated ALT activity is not specific for APAP hepatotoxicity. New biomarkers could serve as more sensitive and specific signatures to predict hepatotoxicity following APAP overdose and to distinguish APAP hepatotoxicity from other causes of liver disease.…”

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confidence: 99%

Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis

Ward

Kanchagar

Veksler-Lublinsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

167

166

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We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.hsa-miR-122-5p | hsa-miR-3646-3p | hsa-miR-412 A cetaminophen (APAP) overdose (OD) is the major cause of acute liver failure and death due to analgesics in the developed world (1-3), with over 500 deaths per year in the United States (3, 4). APAP misuse results in over 78,000 emergency department (ED) visits annually, at a cost of more than $86 million/ year (5).Patients who present with a report of APAP ingestion are assessed for treatment with N-acetyl cysteine (NAC) by measuring serum APAP concentrations and liver function tests, including alanine aminotransferase (ALT) activity (4). There are limits to the utility of the current biomarker, ALT, in assessing the status of potentially APAP-poisoned patients. For example, ALT may take greater than 72 h to reach peak activity in blood (6), and elevated ALT activity is not specific for APAP hepatotoxicity. New biomarkers could serve as more sensitive and specific signatures to predict hepatotoxicity following APAP overdose and to distinguish APAP hepatotoxicity from other causes of liver disease. Ideal biomarkers should identify liver damage at an early stage, accelerating appropriate treatment.MicroRNAs (miRNAs) are short (∼22 nt in length) regulatory RNAs that control gene expression posttranscriptionally (7,8). The human genome contains more than 1,000 genes encoding distinct miRNAs whose levels in a biological sample can be quantified with great sensitivity and precision using quantitative real-time PCR (qRT-PCR) (9). Many miRNAs are expressed tissue-specifically or enriched in certain cell types, with the expression pattern providing signatures for the physiological or pathological status of specific cells and tissues (10, 11). Importantly, miRNAs can be exported from cells and are detectable in stable complexes extracellularly, in blood, serum, or plasma (12).There is ample evidence that circulating extracellular miRNAs in blood can serve as biomarkers for internal organ physiology and pathology (11,13,14). Increased levels of miR-122 and miR-192 were found in the plasma of APAP-overdosed (300 mg/kg) mice (15). A number of additional miRNAs (miR-135a, miR-466g, miR-574-5p, and miR-1196) were elevated in the plasma of mice with hi...

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When do the aminotransferases rise after acute acetaminophen overdose?

Cited by 64 publications

References 30 publications

Hepatoprotective Effect of Citral on Acetaminophen‐Induced Liver Toxicity in Mice

Hepatoprotective Effect of Citral on Acetaminophen‐Induced Liver Toxicity in Mice

An Analysis ofN-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis

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