Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.

<h4>Background</h4>Pathological mutations in Alpha-1 Antitrypsin (AAT) protein cause retention of toxic polymers in the hepatocyte endoplasmic reticulum. The risk for cirrhosis in AAT deficiency is likely directly related to retention of these polymers within the liver. Polymers are clas...

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Autores principales:	George Marek, Amy Collinsworth, Chen Liu, Mark Brantly, Virginia Clark
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/12ff8aa72c8747d68b904154ccd60fbf
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spelling	oai:doaj.org-article:12ff8aa72c8747d68b904154ccd60fbf2021-12-02T20:18:03ZQuantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.1932-620310.1371/journal.pone.0256117https://doaj.org/article/12ff8aa72c8747d68b904154ccd60fbf2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0256117https://doaj.org/toc/1932-6203<h4>Background</h4>Pathological mutations in Alpha-1 Antitrypsin (AAT) protein cause retention of toxic polymers in the hepatocyte endoplasmic reticulum. The risk for cirrhosis in AAT deficiency is likely directly related to retention of these polymers within the liver. Polymers are classically identified on liver biopsy as inclusion bodies by periodic acid schiff staining after diastase treatment and immunohistochemistry. However, characterization of the polymer burden within a biopsy sample is limited to a semi-quantitative scale as described by a pathologist. Better methods to quantify polymer are needed to advance our understanding of pathogenesis of disease. Therefore, we developed a method to quantify polymer aggregation from standard histologic specimens. In addition, we sought to understand the relationship of polymer burden and other histologic findings to the presence of liver fibrosis.<h4>Methods</h4>Liver samples from a well-categorized AATD cohort were used to develop histo-morphometric tools to measure protein aggregation.<h4>Results</h4>Whole-slide morphometry reliably quantifies aggregates in AATD individuals. Despite very low levels of inclusions present (0-0.41%), accumulation of globules is not linear and is associated with higher fibrosis stages. Immunohistochemistry demonstrates that fibrosis is associated with polymer accumulation and not total AAT. A proportion of patients were found to be "heavy accumulators" with a polymer burden above the upper 25% of normal distribution. Males had significantly more liver inclusions and polymer than females. These measurements also highlight interrelated phenotypes of hepatocellular degeneration and autophagy in AATD liver disease.<h4>Conclusion</h4>Quantitative inclusion analysis measures AAT accumulation in liver biopsy specimens. Quantification of polymer may identify individuals at risk for progressive disease and candidates for therapeutic interventions. Furthermore, these methods may be useful for evaluating efficacy of drugs targeting accumulation of AAT.George MarekAmy CollinsworthChen LiuMark BrantlyVirginia ClarkPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 8, p e0256117 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q George Marek Amy Collinsworth Chen Liu Mark Brantly Virginia Clark Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
description	<h4>Background</h4>Pathological mutations in Alpha-1 Antitrypsin (AAT) protein cause retention of toxic polymers in the hepatocyte endoplasmic reticulum. The risk for cirrhosis in AAT deficiency is likely directly related to retention of these polymers within the liver. Polymers are classically identified on liver biopsy as inclusion bodies by periodic acid schiff staining after diastase treatment and immunohistochemistry. However, characterization of the polymer burden within a biopsy sample is limited to a semi-quantitative scale as described by a pathologist. Better methods to quantify polymer are needed to advance our understanding of pathogenesis of disease. Therefore, we developed a method to quantify polymer aggregation from standard histologic specimens. In addition, we sought to understand the relationship of polymer burden and other histologic findings to the presence of liver fibrosis.<h4>Methods</h4>Liver samples from a well-categorized AATD cohort were used to develop histo-morphometric tools to measure protein aggregation.<h4>Results</h4>Whole-slide morphometry reliably quantifies aggregates in AATD individuals. Despite very low levels of inclusions present (0-0.41%), accumulation of globules is not linear and is associated with higher fibrosis stages. Immunohistochemistry demonstrates that fibrosis is associated with polymer accumulation and not total AAT. A proportion of patients were found to be "heavy accumulators" with a polymer burden above the upper 25% of normal distribution. Males had significantly more liver inclusions and polymer than females. These measurements also highlight interrelated phenotypes of hepatocellular degeneration and autophagy in AATD liver disease.<h4>Conclusion</h4>Quantitative inclusion analysis measures AAT accumulation in liver biopsy specimens. Quantification of polymer may identify individuals at risk for progressive disease and candidates for therapeutic interventions. Furthermore, these methods may be useful for evaluating efficacy of drugs targeting accumulation of AAT.
format	article
author	George Marek Amy Collinsworth Chen Liu Mark Brantly Virginia Clark
author_facet	George Marek Amy Collinsworth Chen Liu Mark Brantly Virginia Clark
author_sort	George Marek
title	Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
title_short	Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
title_full	Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
title_fullStr	Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
title_full_unstemmed	Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
title_sort	quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/12ff8aa72c8747d68b904154ccd60fbf
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Quantitative measurement of the histological features of alpha-1 antitrypsin deficiency-associated liver disease in biopsy specimens.

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