Liver and Pancreas

Greaves, Peter

doi:10.1016/b978-044452771-4/50010-9

Cited by 22 publications

(40 citation statements)

References 430 publications

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“…At the ESTP liver hypertrophy expert group, it was generally agreed that an increase in liver weight of at least 20% was required to histologically detect a change in hepatocyte cell size (corresponding with other publications; Ennulat, Walker, et al 2010). However, whereas the assessment of zonal changes in liver cell size is relatively straightforward, diffuse changes are considerably more difficult to detect by examination of standard H&E stained sections without reliance upon morphometry (Greaves 2007).…”

Section: Histological Assessmentmentioning

confidence: 99%

“…PPARa is the major PPAR found in the liver, but is also distributed and highly expressed in the kidney and intestine (Bookout et al 2006) as well as heart and brown adipose tissue (Xu, Li, and Kong 2005). PPARg is expressed predominantly in the adipose tissues but also in pancreatic beta-cells, intestines and spleen whereas PPARb/d is expressed nearly ubiquitously (Bookout et al 2006;Greaves 2007).…”

Section: Peroxisome Proliferator-activated Receptor Alphamentioning

confidence: 99%

“…Natural ligands for PPARa include saturated and unsaturated fatty acids, eicosinoids, and linoleic acid metabolites. However, a diverse range of xenobiotics from many classes and structures are also able to activate PPARa such as the fibrate hypolipidaemic agents (clofibrate, fenofibrate, gemfibrozil amongst others), methaphenilene, thromboxane synthetase inhibitors, dehydroepiandosterone, non-steroidal anti-oestrogens, ibuprofen, Wy-14,643, diphenyl ether herbicides, and phenoxy herbicides (Greaves 2007).…”

Section: Peroxisome Proliferator-activated Receptor Alphamentioning

confidence: 99%

“…Studies using human hepatocytes (Bentley et al 1993;Lake 2009) as well as human biopsy material exposed to gemfibrozil for up to 27 months (Greaves 2007) have generally concluded that humans are insensitive and unresponsive to peroxisomal proliferators at therapeutic dose levels and that humans are not at an increased risk of developing liver tumors (Cattley et al 1998; International Agency for Research on Cancer [IARC] 1995). In one study, humans were given oral fibrate therapy for 8 weeks and no differences in peroxisomal acyl CoA oxidase mRNA transcripts were detected in groups receiving either fenofibrate, bezafibrate, or gemfibrozil compared to placebo controls (Roglans et al 2002).…”

Section: Epidemiology and Risk To Manmentioning

confidence: 99%

“…Treatment-related increases in liver weight may result from a wide variety of causes such as hyperplasia (of any of the resident cell types), hypertrophy, inflammation, fibrosis, abnormal storage of metabolism products, particles, or cleavage products, neoplasia, and congestion (Carthew et al 1996;Greaves 2007). Typically, these changes do not occur in isolation, so in the absence of overt adverse changes such as inflammation, necrosis, or degeneration, it is important to recognize that increases in liver weight may be induced by hypertrophy, hyperplasia, or very frequently a combination of the two (Maronpot et al 2010).…”

Section: Histological Assessmentmentioning

confidence: 99%

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Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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Section: Histological Assessmentmentioning

confidence: 99%