Gene Expression Analysis Offers Unique Advantages to Histopathology in Liver Biopsy Evaluations

National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2007; 35(2):276-83. DOI: 10.1080/01926230601178207
Source: PubMed


Liver diseases that induce nonuniform lesions often give rise to greatly varying histopathology results in needle biopsy samples from the same patient. This study examines whether gene expression analysis of such biopsies could provide a more representative picture of the overall condition of the liver. We utilized acetaminophen (APAP) as a model hepatotoxicant that gives a multifocal pattern of necrosis following toxic doses. Rats were treated with a single toxic or subtoxic dose of APAP and sacrificed 6, 24, or 48 hours after exposure. Left liver lobes were harvested, and both gene expression and histopathological analysis were performed on biopsy-sized samples. While histopathological evaluation of such small samples revealed significant sample to sample differences after toxic doses of APAP, gene expression analysis provided a very homogeneous picture and allowed clear distinction between subtoxic and toxic doses. The main biological function differentiating animals that received sub-toxic from those that had received toxic doses was an acute stress response at 6 hours and signs of energy depletion at later time points. Our results suggest that the use of genomic analysis of biopsy samples together with histopathological analysis could provide a more precise representation of the overall condition of a patient's liver than histopathological evaluation alone.

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    • "Heinloth et al. (2007). "
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    ABSTRACT: The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo.
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    • "One potential reason for this could be that the microarray samples are from the whole liver whereas the histopathology samples used for scoring the extent of necrosis are only from two independent slices of the liver specimen. In a limited study, Heinloth et al. [13] also showed that gene expression analysis is more informative than histopathologic evaluations and offers unique advantages to liver biopsy evaluations. Another explanation could be that certain animals may develop the phenotype at a later time point after treatment than the time point when the samples were taken for analysis. "
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