Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease – a physiopathological and clinical integrated view

Bessone, Fernando; Dirchwolf, Melisa; Rodil, María Agustina; Razori, María Valeria; Roma, Marcelo G.

doi:10.1111/apt.14952

Cited by 82 publications

(68 citation statements)

References 300 publications

(596 reference statements)

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“…In conclusion, our data suggest that zileuton-induced hepatotoxicity in genetically sensitive individuals is mediated by nitrosative stress and a subsequent impairment in key functions of mitochondria which then result in fatty changes and cellular necrosis in the liver. The proposed mechanism is illustrated in Figure 6 (Ananthanarayanan et al, 2001;Bessone et al, 2018;Cipriani et al, 2010;Figge et al, 2004;Heni et al, 2013;Iorga et al, 2017;Joshi et al, 2004Joshi et al, , 2009Liu et al, 2018;Makishima et al, 1999;Nassir and Ibdah, 2014;Natarajan et al, 2006;Plass et al, 2002;Preidis et al, 2017;Sinal et al, 2000;Walters, 2000;Watanabe et al, 2004;Zhang et al, 2012). This figure synthesizes the previous findings and new results from our study.…”

Section: Fatty Acid Homeostasissupporting

confidence: 78%

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

You

Lyn‐Cook

Gatti

et al. 2020

Toxicological Sciences

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Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.

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Section: Fatty Acid Homeostasissupporting

confidence: 78%

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

You

Lyn‐Cook

Gatti

et al. 2020

Toxicological Sciences

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“…However, our patients had no such obvious adverse reactions, and the median ALT level was 50 (40.0-70.0) U/L in this cohort. Histologically, although both SARS-CoV-2 infection and drugs might result in liver steatosis, [18][19][20] the pathological features of no obvious eosinophil infiltration, cholestasis, fibrin deposition, granuloma, massive central necrosis, or interface hepatitis in the 2 biopsied cases were not suggestive of DILI. Nevertheless, we could not exclude DILI as a participating cause since only 2 cases were biopsied.…”

Section: Discussionmentioning

confidence: 90%

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19

Wang

Liu

et al. 2020

Journal of Hepatology

555

713

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Liver enzyme abnormalities in patients with COVID-19 are associated with disease severity. Patients with liver enzyme abnormalities have higher A-aDO2 and GGT, lower albumin and decreased circulating CD4+ T cells and B lymphocytes. SARS-CoV-2 is able to infect the liver and cause conspicuous hepatic cytopathy. Massive apoptosis and binuclear hepatocytes were the predominant histological features of SARS-CoV-2-infected liver.

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“…Initially, appropriate history taking should identify other causes of hepatic steatosis, including steatogenic medications ( 31 ), refeeding syndrome, total parenteral nutrition and lipodystrophy ( 32 ). Although excess alcohol intake requires exclusion as a common aetiology for liver steatosis, this is often difficult in clinical reality.…”

Section: Choosing Your Battlesmentioning

confidence: 99%

Fighting liver fat

Koeckerling

Tomlinson

Cobbold

2020

Endocrine Connections

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Non-alcoholic fatty liver disease is a chronic liver disease which is closely associated with components of the metabolic syndrome. Its high clinical burden results from the growing prevalence, inherent cardiometabolic risk and potential of progressing to cirrhosis. Patients with non-alcoholic fatty liver disease show variable rates of disease progression through a histological spectrum ranging from steatosis to steatohepatitis with or without fibrosis. The presence and severity of fibrosis are the most important prognostic factors in non-alcoholic fatty liver disease. This necessitates risk stratification of patients by fibrosis stage using combinations of non-invasive methods such as composite scoring systems and/or transient elastography. A multidisciplinary approach to treatment is advised, centred on amelioration of cardiometabolic risk through lifestyle and pharmacological interventions. Despite the current lack of licensed, liver-targeted pharmacotherapy, several promising agents are undergoing late-phase clinical trials to complement standard management in patients with advanced disease. This review summarises the current concepts in diagnosis and disease progression of non-alcoholic liver disease, focusing on pragmatic approaches to risk assessment and management in both primary and secondary care settings.

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Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease – a physiopathological and clinical integrated view

Cited by 82 publications

References 300 publications

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19

Fighting liver fat

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