Disturbances in Glucose Metabolism in Patients with Liver Damage Due to Paracetamol Overdose

Record, C. O.; Chase, R. A.; Alberti, K. G. M. M.; Williams, Roger

doi:10.1042/cs0490473

Cited by 15 publications

(7 citation statements)

References 8 publications

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“…Literature has shown metabolic complications of APAP overdose to include hypophosphataemia, (as a result of accompanying phosphaturia), metabolic acidosis, hypoglycaemia, among others (Jones et al, 1989;Makin et al, 1995). APAP-induced hypoglycaemia is proposed to be mediated via several mechanisms which include impaired glycogeneolysis, gluconeogenesis and hyperinsulinaemia (Record et al, 1975). As shown in figure 4, acetaminophen-induced hepatotoxicity was associated with significant (P<0.05) hypoglycaemia.…”

Section: Discussionmentioning

confidence: 82%

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Adeneye¹,

Olagunju²

2010

African Journal of Biomedical Research

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The incidence of acetaminophen-induced hepatotoxicity is reported to be on the increase, with limited therapeutic or chemoprophylactic options. In the present in vivo study, single daily oral doses (100 -500 mg/kg) of ascorbic acid (ASC) were investigated for their protective effects against acetaminophen (APAP)-induced hepatotoxicity in 4 groups of rats made up of 6 rats per group for 14 days. Also, effects of the doses on body weights taken on the 1 st , 7 th and 15 th day of the experiment were also investigated. On the 15 th day, blood samples for serum ALT, AST and FBG assay were collected through cardiac puncture under inhaled diethyl ether anaesthesia. Rat livers were also studied for histopathology. Results showed that treatment with APAP intraperitoneal injection induced significant (P<0.001) elevation in the serum levels of ALT and AST while inducing significant (P<0.05) decrease in the serum FBG. The hepatotoxicity was also corroborated by the histopathological lesion of lipid peroxidation characterized by diffuse ballooning degeneration with lymphocytic infiltration. Significant (P<0.01) weight loss and hypoglycaemia were also associated with APAP-induced hepatotoxicity. However, these alterations were attenuated in ASC pretreated rats dose dependently. Also, APAP-induced hypoglycaemia and weight loss were significantly (P<0.01, P<0.001) enhanced by ASC in dose related pattern. Thus, results of this study showed that 100 -500 mg/kg/day was protective against APAP-induced hepatotoxicity, effect which could have been mediated via its inherent free radical scavenging and/or free radicals generation inhibiting activities.

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Section: Discussionmentioning

confidence: 82%

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Adeneye¹,

Olagunju²

2010

African Journal of Biomedical Research

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“…Concerning the sugar metabolism pathway, carbohydrate homeostasis is essential for normal liver function. It is well known that during APAP-induced liver failure, these processes are severely affected (Record et al 1975 ). Finally, RIG-I-MDA5-mediated induction of IFN-alpha–beta is a process that has been linked to several liver pathologies like hepatitis A/B/C and hepatic steatosis (Kawai et al 2005 ; Toyoda et al 2013 ; Wei et al 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes

Jetten

Ruiz‐Aracama²,

Coonen

et al. 2015

Arch Toxicol

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Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this variability in susceptibility are still largely unknown. The aim of this study was to better understand this variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes (PHH) from several donors (n = 5) exposed in vitro to a non-toxic to toxic APAP dose range. To evaluate interindividual variation, gene expression data/levels of metabolites were plotted against APAP dose/donor. The correlation in APAP dose response between donors was calculated by comparing data points from one donor to the data points of all other donors using a Pearson-based correlation analysis. From that, a correlation score/donor for each gene/metabolite was defined, representing the similarity of the omics response to APAP in PHH of a particular donor to all other donors. The top 1 % highest variable genes were selected for further evaluation using gene set overrepresentation analysis. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Additionally, the interindividual variation in the expression of these genes could be associated with the variability in expression levels of hydroxyl/methoxy-APAP and C8H13O5N-APAP-glucuronide. The before-mentioned metabolites or their derivatives have also been reported in blood of humans exposed to therapeutic APAP doses. Possibly these findings can contribute to elucidating the causative factors of interindividual susceptibility toward APAP. Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1545-2) contains supplementary material, which is available to authorized users.

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“…Paracetamol, a widely used analgesic, is known to cause acute hepatic necrosis (Henry & Volans 1984;Meredith et al 1986), which is sometimes fatal in adults when taken in overdose (Davidson & Eastham 1966;Clark et al 1973;Prescott &Wright 1973;Koch-Weser 1976). The clinical course of patients with liver damage following paracetamol overdose is often complicated by the development of hypoglycaemia 24-72 h after overdose (Record et al 1975). In a study of glucose metabolism in fourteen patients with liver damage due to paracetamal overdose, impaired gluconeogenesis was suggested by mild fasting hypoglycaemia in four patients and raised fasting blood lactate levels (Record et al 1981).…”

Section: Discussionmentioning

confidence: 99%

The effect of therapeutic doses of paracetamol on liver function in the rat perfused liver

Khedun

Maharaj

Leary

et al. 1993

Journal of Pharmacy and Pharmacology

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The isolated liver perfusion technique was used to study the effect of therapeutic doses of paracetamol on hepatic gluconeogenesis and bromosulphthalein clearance from the perfusate and biliary excretion of the dye in the rat. Six groups of rats were studied; those in the three experimental groups were given 0.02 g kg-1 paracetamol daily for ninety days. The livers of animals in the control group and in one of the experimental groups were perfused with a medium containing pyruvate. The animals in the second experimental and control group were perfused with a medium containing bromosulphthalein (10 mg/100 mL). The livers of the third experimental and control group were subjected to histological examination. The rate of glucose formation and glucose concentrations were decreased, while, lactate levels and lactate: pyruvate ratios were increased in paracetamol-treated rats. The mean concentration of bromosulphthalein in the perfusate and biliary excretion of the dye were decreased. Macro and micro vesicular fatty change was present in the livers of paracetamol-treated rats. This study demonstrates that chronic administration of therapeutic doses of paracetamol to rats adversely affects liver function, as evidenced by impaired gluconeogenesis and bromosulphthalein clearance from the perfusate, and excretion of the dye into the bile, and provides histological evidence of hepatic damage in rats.

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Disturbances in Glucose Metabolism in Patients with Liver Damage Due to Paracetamol Overdose

Cited by 15 publications

References 8 publications

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes

The effect of therapeutic doses of paracetamol on liver function in the rat perfused liver

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