Severe Liver Damage Caused by Therapeutic Doses of Acetaminophen

Florén, Claes‐Henrik; Thesleff, Peter; Nilsson, Anders

doi:10.1111/j.0954-6820.1987.tb10672.x

Cited by 31 publications

(6 citation statements)

References 5 publications

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“…Hepatotoxicity of such a high-dose APAP may not be modified by GJIC. In human cases, APAP-associated hepatotoxicity may occur not only with high doses but also with recommended use (Floren, Thesleff, and Nilsson 1987; Moling et al 2006; Seirafi, Iten, and Hadengue 2007). Whether individual variability reflects any differences in gap junction activity remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

“…However, single or cumulative overdose of APAP can cause severe liver injury with the potential to progress to liver failure (Lee 2004; Prescott 1980). Even at normal therapeutic doses, serious liver damage has been reported (Floren, Thesleff, and Nilsson 1987; Seirafi, Iten, and Hadengue 2007). Actually, APAP is the most frequent cause of drug-induced liver failure in the United States and in Great Britain (Lee 2004).…”

Section: Introductionmentioning

confidence: 99%

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Gap Junction Dysfunction Reduces Acetaminophen Hepatotoxicity with Impact on Apoptotic Signaling and Connexin 43 Protein Induction in Rat

et al. 2010

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Acetaminophen (APAP) is a widely used antipyretic and analgesic agent. However, overdosing and sometimes even a recommended dose can lead to serious and conceivably fatal liver toxicity. Therefore, it is important to clarify understand mechanisms of hepatotoxicity induced by APAP. Gap junctions, formed by connexin, have important roles in maintenance of tissue homeostasis and control of cell growth and differentiation. In the liver, Cx32 is a major gap junction protein whose expression is known to gradually decrease with chronic liver disease progression. In the present study, acute hepatotoxic effects of APAP were found to be reduced in Cx32 dominant negative transgenic rats lacking normal gap junctional intercellular communication in the liver. In littermate wild-type rats, the injured centrilobular hepatocytes were positive for TUNEL staining and featured elevated expre ssion of cleaved caspase-3 and Cx43, which is not expressed in normal hepatocytes. These results suggest that APAP hepatotoxicity involves apoptosis, and induction of Cx43 expression may play an important role in the apoptotic signaling. Moreover, gap junctional functions of Cx32 can play important roles in removing damaged hepatocytes by apoptosis for liver tissue homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gap Junction Dysfunction Reduces Acetaminophen Hepatotoxicity with Impact on Apoptotic Signaling and Connexin 43 Protein Induction in Rat

et al. 2010

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“…Case reports and retrospective case series have suggested that chronic alcohol consumption increases the risk of toxicity from paracetamol, perhaps even with therapeutic drug doses [ 95 – 108 ]. A number of case reports describe patients developing acute liver injury and hepatotoxicity from a therapeutic dose and conclude that patients with chronic alcohol use are at heightened risk of paracetamol toxicity [ 95 , 96 , 106 , 108 , 109 ]. However, during alcohol consumption, the sensorium may be clouded making the reliability of the dose history uncertain.…”

Section: Results—are Some People At Higher Risk Of Paracetamol Toxicimentioning

confidence: 99%

“…It has been suggested that chronic alcohol abuse increases susceptibility to paracetamol toxicity due to CYP2E1 induction [ 95 , 96 , 98 – 101 ], that hepatic GSH is reduced leading to reduced NAPQI detoxification [ 95 , 96 , 98 – 101 , 103 , 104 , 106 , 109 ] and/or that glucuronidation is reduced leading to increased fractional oxidation [ 95 – 97 ]. Other theories advanced for the observation of increased toxicity in chronic alcohol consumers include disturbances to hepatocyte membranes rendering them more vulnerable to insult, decreased biliary excretion of paracetamol or reduced clearance [ 97 ].…”

Section: Results—are Some People At Higher Risk Of Paracetamol Toxicimentioning

confidence: 99%

Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature

Caparrotta

Antoine

Dear

2017

Eur J Clin Pharmacol

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PurposeParacetamol is one of the world’s most commonly used drugs. In overdose, it is well established to be hepatotoxic. The aim of this review was to identify factors that have been, or actually are, associated with the development of liver injury after paracetamol exposure in humans.MethodGoogle Scholar and PubMed were searched on various dates between December 2016 and March 2017. Papers identified had their references analysed for further studies that might be relevant.ResultsAt the time of writing, there was little good quality clinical evidence—from studies of paracetamol overdose or therapeutic use—to suggest that any groups of people are relatively protected from, or are at greater risk of, liver injury. The factors that were historically used to indicate higher risk in the UK have no good quality clinical evidence to support their re-introduction into clinical practice. The safe (and still effective) oral dose of paracetamol in patients weighing less than 50 kg has not been established.ConclusionThere is no patient group that is unequivocally at elevated risk of paracetamol-induced liver toxicity. We propose two clinical scenarios that warrant further research. Firstly, there is a need to establish whether the dose of paracetamol should be reduced in patients with low body weight. Secondly, if or when genomic information regarding individual patients becomes readily available to inform prescribing, we propose the contribution of the genome to paracetamol toxicity should be re-investigated with robustly designed studies. Such studies could enhance the safe use of one of the most frequently taken drugs.Electronic supplementary materialThe online version of this article (10.1007/s00228-017-2356-6) contains supplementary material, which is available to authorized users.

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“…Upon overdosing, paracetamol can cause hepatic necrosis in man and experimental animals [1][2][3]. Furthermore, it is known that alcohol may predispose to liver damage caused by therapeutic doses of paracetamol [4]. Because of these toxic side effects paracetamol has been subject to many toxicological studies [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

The Paracetamol Adsorption Behaviour Monitored by Raman and Surface-Enhanced Raman Spectroscopy

Andronie¹,

Canta²,

Cozar³

et al. 2009

AIP Conference Proceedings

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Severe Liver Damage Caused by Therapeutic Doses of Acetaminophen

Abstract: Two patients who ingested therapeutic doses of acetaminophen and who developed a severe hepatotoxicity are reported. Both patients had a rather high alcohol consumption, which probably made them susceptible to the toxic effects of acetaminophen.

Cited by 31 publications

References 5 publications

Gap Junction Dysfunction Reduces Acetaminophen Hepatotoxicity with Impact on Apoptotic Signaling and Connexin 43 Protein Induction in Rat

Gap Junction Dysfunction Reduces Acetaminophen Hepatotoxicity with Impact on Apoptotic Signaling and Connexin 43 Protein Induction in Rat

Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature

The Paracetamol Adsorption Behaviour Monitored by Raman and Surface-Enhanced Raman Spectroscopy

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