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Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

ABSTRACT: AIMS:To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI). METHODS:Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage. RESULTS:In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ?1000 IU l(-1) , liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ?6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US-Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration < 20 mg l(-1) and a normal ALT/AST on initial presentation or when RSPI was first suspected, but both of these values were only available for 79 (40%) cases. CONCLUSIONS:Severe liver damage is reported after RSPI in adults and children, sometimes involving reported doses below current thresholds for intervention. Paracetamol concentrations <20 mg l(-1) with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases.

SUBMITTER: Acheampong P

PROVIDER: S-EPMC5137817 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

Acheampong Paul P Thomas Simon H L SH

British journal of clinical pharmacology 20160803 4

<h4>Aims</h4>To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI).<h4>Methods</h4>Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage.<h4>Resu ...[more]

PMID: 27261770

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Project description:Background: Malignant odontogenic tumours (MOTs) arise either de novo from the tooth forming tissues, their developmental residues or from existing odontogenic epithelial or mesenchymal neoplasms in the jaws. Their management requires extensive surgery due to their infiltrative nature and risk of metastasis. There is a need to understand the clinical and pathological features of MOTs to inform both treatment algorithms and prognostication. This is an area of diagnostic pathology which presents substantial difficulties in diagnosis, compounded by inconsistent use of terminology. Thus, this systematic review aimed to describe the clinical and pathological features of MOTs with a view to consolidating the literature and defining problematic areas in diagnosis and classification. Methods: An electronic database search was conducted in Web of Science, PubMed/Medline, and Embase. Additionally, the grey literature and reference lists of selected papers searched for completeness. Nine hundred and sixty articles were initially identified. Following removal of duplicates and application of inclusion/exclusion criteria, 312 articles were included for qualitative analysis. Results: The 312 articles encompassed a total of 507 patients with most lesions located within the mandible (74.3%). The most common first histological diagnosis was ameloblastic carcinoma (25.7% of all diagnoses), but there is considerable variation in how and when various diagnostic terms are used, and several misdiagnoses were reported. An initial benign diagnosis was made in 24.7% of patients, followed by a later malignant diagnosis and in this sub-group, the most common benign first diagnosis was ameloblastoma (42.4%). Cervical lymph nodes were the most common site of metastasis (9.3% of patients). With respect to distant metastasis (DM), the lungs were the most common organ affected (11.2% of DM patients) with metastasising ameloblastoma the most commonly reported tumour which metastasised to the lungs. Overall, 26.8% of patients developed recurrence. Conclusion: Overall, the quality of the literature on MOTs is poor. This review of the literature has highlighted variations in diagnostic terms and criteria which has resulted in areas of confusion with potential for misdiagnosis. This consolidation of primary data has identified key areas for targeted research including further discussion on the malignant potential of ameloblastoma.

Project description:Background: Fetal exposure to paracetamol (acetaminophen) has been shown to be associated with asthma and other atopic disorders, as well as behavioural problems including hyperactivity, in childhood. However, there is little information on scholastic abilities among children exposed to paracetamol in pregnancy. Objectives: To determine whether there are any differences in scholastic abilities among the offspring of women who ingested paracetamol during pregnancy compared with non-exposed children. Methods: Mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) had recorded the frequency with which they had taken the medication over two time periods during pregnancy: i) the first 18 weeks and ii) 18-32 weeks. The offspring have been followed up ever since. For this study we use as outcomes: a) 14 tests of ability at reading and 2 of spelling using the study's tests and the national education system test results; b) 6 of mathematical abilities including tests of arithmetic and mathematical reasoning, and c) 1 of scientific understanding. Multiple regression was used, adjusting for 15 different exposures including reasons for taking the medication as well as demographic features. Results: Almost all unadjusted and adjusted mean differences were negative (i.e., those exposed to maternal intake of paracetamol did less well), but negative associations for exposures between 18 and 32 weeks of gestation were much more evident than for exposures earlier in pregnancy. Of the later exposures, after adjustment, 12 of the 23 scholastic tests were associated with prenatal exposure to paracetamol at p < 0.05. These negative effects were found in the girls (12 tests at p < 0.05) but not boys (0 tests at p < 0.05). Conclusion: Evidence from this longitudinal study suggests that maternal exposure to paracetamol is associated with disadvantages to the offspring in scholastic abilities such as mathematics and reading at secondary school ages. This raises the question as to whether there are longer-lasting effects on educational attainment from age 15 years onwards, including at university level. Clearly these results should be tested in other settings, but meanwhile they add to a growing accumulation of known adverse effects of exposure to paracetamol in pregnancy.

Project description:Background and purposeParacetamol, a major cause of acute liver failure (ALF) represents a significant clinical problem. Adrenoceptor stimulation or antagonism can modulate chemical-induced hepatotoxicity. We investigated the role of endogenous catecholamines and alpha(1)-adrenoceptors in the development of paracetamol- induced hepatotoxicity.Experimental approachParacetamol (3.5 mmol kg(-1)) was administered to male CD-1 mice, with and without alpha(1)-adrenoceptor antagonists (prazosin, doxazosin, terazosin and tamsulosin; 35.7 micromol kg(-1)). Serum transaminases and hepatic glutathione (GSH) levels were assessed as markers of hepatic damage. Paracetamol bioactivation was assessed by covalent binding, hepatic and urinary conjugate formation and uridine glucuronosyltransferase activity. Plasma catecholamines levels and hepatic congestion were also analysed.Key resultsPlasma catecholamine levels were significantly elevated 5 h post paracetamol administration. Prazosin prevented hepatotoxicity when administered 1 h before a toxic paracetamol insult and importantly, when administered up to 1 h post paracetamol injection. Prazosin had no effect on paracetamol-induced depletion of hepatic GSH, paracetamol bioactivation or paracetamol-induced transcription of defence genes. Paracetamol toxicity is associated with marked accumulation of erythrocytes within hepatic sinusoids and prazosin completely prevented this accumulation.Conclusion and implicationsParacetamol-induced hepatocellular damage is associated with increased circulating catecholamines. alpha(1)-Adrenoceptor antagonists conferred complete protection from paracetamol -induced hepatotoxicity. Protection was associated with absence of hepatic erythrocyte accumulation. Increased catecholamine levels may contribute to the pathophysiology of paracetamol-induced hepatotoxicity by compromising hepatic perfusion. Protection against paracetamol toxicity by alpha(1) antagonists in mice has implications for therapeutic management of patients presenting with paracetamol overdose and ALF.

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Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

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Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

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