Histological patterns in drug-induced liver disease

Ramachandran, Rageshree; Kakar, Sanjay

doi:10.1136/jcp.2008.058248

Cited by 282 publications

(226 citation statements)

References 132 publications

(97 reference statements)

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“…Importantly, the abnormalities were not localized to a particular liver lobule or zone but instead were evenly distributed throughout the entire liver. The homogenous pattern of expression was distinct from most models of liver injury, which tend to affect either periportal or perivenous zones disproportionately, and suggested that the primary defect was intrinsic to hepatocytes (25).…”

Section: Resultsmentioning

confidence: 97%

Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis

Hudson

Frederick

Drake

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Nucleotide hydrolysis is essential for many aspects of cellular function. In the case of 3′,5′-bisphosphorylated nucleotides, mammals possess two related 3′-nucleotidases, Golgi-resident 3′-phosphoadenosine 5′-phosphate (PAP) phosphatase (gPAPP) and Bisphosphate 3′-nucleotidase 1 (Bpnt1). gPAPP and Bpnt1 localize to distinct subcellular compartments and are members of a conserved family of metal-dependent lithium-sensitive enzymes. Although recent studies have demonstrated the importance of gPAPP for proper skeletal development in mice and humans, the role of Bpnt1 in mammals remains largely unknown. Here we report that mice deficient for Bpnt1 do not exhibit skeletal defects but instead develop severe liver pathologies, including hypoproteinemia, hepatocellular damage, and in severe cases, frank wholebody edema and death. Accompanying these phenotypes, we observed tissue-specific elevations of the substrate PAP, up to 50-fold in liver, repressed translation, and aberrant nucleolar architecture. Remarkably, the phenotypes of the Bpnt1 knockout are rescued by generating a double mutant mouse deficient for both PAP synthesis and hydrolysis, consistent with a mechanism in which PAP accumulation is toxic to tissue function independent of sulfation. Overall, our study defines a role for Bpnt1 in mammalian physiology and provides mechanistic insights into the importance of sulfur assimilation and cytoplasmic PAP hydrolysis to normal liver function.ribosome biogenesis | nucleolus | phosphoadenosine phosphosulfate | exoribonuclease

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Section: Resultsmentioning

confidence: 97%

Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis

Hudson

Frederick

Drake

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The hallmarks of acute hepatocellular injury are inflammation and/or necrosis (34). Both inflammation (green arrows) and necrosis (yellow arrows) were found in liver tissues from the mice treated with T-DM1 at the dose of 30 mg/kg, whereas inflammation and necrosis were not observed in liver tissues from control mice (Table 1; Fig.…”

Section: T-dm1 Treatment Induces Inflammation and Necrosis In Liver Tmentioning

confidence: 99%

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Yan

Endo

Shen

et al. 2016

Molecular Cancer Therapeutics

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Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFa in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFa enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. Mol Cancer Ther; 15(3); 480-90. Ó2015 AACR.

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“…impredecibles, no dosis-dependiente, no reproducibles y afectan una pequeña proporción de pacientes (entre 1/1000 y 1/100 000 pacientes expuestos) (11)(12)(13)(14)(15)(16)(17).…”

Section: Reacciones Idiosincrásicas (Inmunes O Metabólicas)unclassified

“…La hepatotoxicidad intrínseca es menos común, mientras que la idiosincrásica es la más asociada con este evento adverso (12,(18)(19)(20). La histología hepática es la herramienta ideal para definir el patrón de toxicidad hepática; sin embargo, en la práctica clínica, la mayoría de las lesiones hepatotóxicas se clasifica de acuerdo con pruebas bioquí-micas (21).…”

Section: Reacciones Idiosincrásicas (Inmunes O Metabólicas)unclassified

“…La histología hepática es la herramienta ideal para definir el patrón de toxicidad hepática; sin embargo, en la práctica clínica, la mayoría de las lesiones hepatotóxicas se clasifica de acuerdo con pruebas bioquí-micas (21). Según el consenso internacional del Council for Internacional Organizations of Medical Sciences (CIOMS), se considera daño hepático si las enzimas hepá-ticas se aumentan en más de 2 veces el límite superior normal (LSN); por su parte, el tipo de lesión generada se clasifica en (12,22,23):…”

Section: Reacciones Idiosincrásicas (Inmunes O Metabólicas)unclassified

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Toxicidad hepática causada por medicamentos: revisión estucturada

P²,

Amariles

2017

Rev. Colomb. Gastroenterol.

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ResumenObjetivos: elaborar un listado actualizado de medicamentos causantes de hepatotoxicidad e identificar, de acuerdo con la evidencia científica, los medicamentos con mayor probabilidad de causar hepatotoxicidad. Método: se realizó una búsqueda en PubMed/Medline utilizando términos Mesh: "liver disease" y "druginduced liver injury". La búsqueda se filtró por: reportes de casos, revisiones, ensayos clínicos, metaanálisis y cartas, hasta diciembre de 2015, en inglés, español y francés. Se incluyeron artículos con evidencia de hepatotoxicidad causada por medicamentos y referencias relevantes; fueron excluidos artículos sin relación con los objetivos de la búsqueda, relacionados con hepatotoxicidad por agentes diferentes, concernientes a otras causas de enfermedad hepática o relacionados con ensayos predictivos o células madre. Algunos aspectos de los medicamentos hepatotóxicos fueron: aparición de hepatotoxicidad, tipo de lesión, mecanismos de hepatotoxicidad, factores de riesgo y manifestaciones clínicas. Para valorar la probabilidad de aparición de hepatotoxicidad y del tipo de lesión se establecieron 3 categorías: definida, probable y posible. Resultados: se identificaron 610 artículos de los cuales se eligieron 402, se excluyeron 208 artículos. Se elaboró un listado con 181 medicamentos y 17 formas farmacéuticas combinadas o regímenes terapéuticos con probabilidad de causar hepatotoxicidad; de estos, 6 medicamentos tuvieron probabilidad definida (metotrexato, minociclina, vancomicina, everolimus, isoniazida y tamoxifeno). Conclusiones: se identificaron más de 180 medicamentos hepatotóxicos, 6 tienen una probabilidad definida, mientras que para la mayoría es posible. La consolidación de la información demostró que diversas categorías de medicamentos tienen mayor probabilidad de ser causantes de hepatotoxicidad. Palabras claveEnfermedad hepática, daño hepático inducido por medicamentos. Revisión de tema

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Histological patterns in drug-induced liver disease

Abstract: The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins.

Cited by 282 publications

References 132 publications

Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis

Role for cytoplasmic nucleotide hydrolysis in hepatic function and protein synthesis

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Toxicidad hepática causada por medicamentos: revisión estucturada

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