Dose-dependent Acute Hepatitis Associated with Administration of High Dose Methotrexate

Banerjee, Anirban; Lakhani, SR; Vincent, Mark; Selby, P.

doi:10.1177/096032718800700608

Cited by 15 publications

(3 citation statements)

References 2 publications

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“…Notably, MTX-induced liver toxicity is mostly associated with its long-term use for the treatment of inflammatory diseases [77,78]. Although some cases of acute hepatitis with marked increase in plasma transaminases and hepatocellular necrosis have been reported in a few patients treated with high doses of intravenous MTX [79,80], this drug mostly induces chronic forms of liver lesion such as steatosis, steatohepatitis, fibrosis and even cirrhosis [31,78,80,81-83]. Psoriatic patients appear to have a higher risk for MTX-induced liver fibrosis.…”

Section: Nafld and Drug-induced Hepatotoxicitymentioning

confidence: 99%

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

et al. 2017

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Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening.

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Section: Nafld and Drug-induced Hepatotoxicitymentioning

confidence: 99%

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

et al. 2017

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“…MTX administration is associated with both acute and chronic hepatotoxicity. Acute MTX-associated hepatotoxicity has been reported after HD-MTX infusions (Jaffe & Traggis 1975;Perez et al 1979;Breithaupt & Kuenzlen 1983;Banerjee et al 1988), whereas chronic hepatotoxicity may occur during long-term lowdose MTX treatment for acute leukaemia and autoimmune diseases (McIntosh e f al. 1977;Ashton et al 1982;Shergy et al 1988).…”

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confidence: 99%

Acute Hepatotoxicity after High‐Dose Methotrexate Administration to Rats

Bremnes

Smeland

Huseby³

et al. 1991

Pharmacology & Toxicology

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Acute hepatotoxicity after administration of 10-1000 mg/kg methotrexate (MTX) to rats was studied by monitoring serum transaminases, liver morphology, and disposition kinetics of MTX and 7-hydroxy-methotrexate (7-OH-MTX). Half the control rats and rats administered 1000 mg/kg MTX, had their bile duct cannulated. One to 2 hr after administration of 1000 mg/kg MTX, 50% of MTX treated bile-drained rats (Ebc) developed cholestasis despite similar or larger initial bile flow rates than those which did not develop cholestasis (Ebn, controls). In Ebc animals, peak serum ASAT and ALAT levels were 6- and 4-fold higher than that of the control rats, and morphologically, prominent hepatocytic changes and grossly dilated bile canaliculi were found. Immediately prior to cholestasis, the Ebc animals reached biliary 7-OH-MTX levels (8.3 +/- 1.3 mM, mean +/- S.E.M.) which were equivalent to the threshold level for precipitation of 7-OH-MTX in rat bile in vitro, and 3-fold higher than the corresponding levels of 7-OH-MTX in the bile of Ebn rats. Ninety-five % of the drug in the precipitated material was 7-OH-MTX. Hence, 7-OH-MTX may play a role in acute MTX hepatotoxicity, a dose-limiting toxicity that may not be counteracted by leukovorin rescue.

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“…Acute halothane hepatotoxicity appears to be due to metabolism to reactive acyl chlorides that bind to proteins and cause mitochondrial damage and oxidative stress [52]. Rare cases of severe acute hepatotoxicity have been reported for numerous other drugs, including cocaine [53], methotrexate [54], amiodarone [55,56], and others.…”

Section: Intrinsic Dilimentioning

confidence: 99%

Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation

McGill

Jaeschke

2018

Expert Review of Molecular Diagnostics

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The difficulty of understanding and diagnosing drug-induced liver injury (DILI) has led to proliferation of serum and genetic biomarkers. Many applications of these biomarkers have been proposed, including investigation of mechanisms, prediction of DILI during early trials or before initiation of therapy in patients, and diagnosis of DILI during therapy. Areas covered: We review the definition and categories of DILI, describe recent developments in DILI biomarker development, and provide guidance for future directions in DILI biomarker research. Expert commentary: There are major obstacles to DILI biomarker development and implementation, including the low prevalence of idiosyncratic DILI (IDILI), weak associations of IDILI with genetic variants, and lack of specificity of many biomarkers for the liver. Certain serum biomarkers, like miR-122, may have clinical utility in early-presenting patients with either intrinsic or idiosyncratic DILI in the future, while others likely will not find use. Future research should focus on implementation of biomarkers to predict later injury and outcome in early presenters with intrinsic DILI, and on development of biomarkers of adaptation and repair in the liver that can be used to determine if a liver test abnormality is likely to be clinically significant in IDILI.

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Dose-dependent Acute Hepatitis Associated with Administration of High Dose Methotrexate

Cited by 15 publications

References 2 publications

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

Acute Hepatotoxicity after High‐Dose Methotrexate Administration to Rats

Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation

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