Increased Matrix Proteins, Collagen and Transforming Growth Factor are Early Markers of Hepatotoxicity in Patients on Long-Term Methotrexate Therapy
Background: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. Design: This is a retrospective study of immunohistochemical markers of...
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Veröffentlicht in: | Clinical toxicology (Philadelphia, Pa.) Pa.), 1996, Vol.34 (3), p.301-305 |
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description | Background: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. Design: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 ± 0.25 g (n = 20) and 3 ± 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. Conclusions: Immunohistochemical quantification of matrix proteins and collagens type 111 and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate. |
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Standard light microscopy lacks sensitivity for early fibrosis. Design: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 ± 0.25 g (n = 20) and 3 ± 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. Conclusions: Immunohistochemical quantification of matrix proteins and collagens type 111 and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate.</description><identifier>ISSN: 1556-3650</identifier><identifier>ISSN: 0731-3810</identifier><identifier>EISSN: 1556-9519</identifier><identifier>EISSN: 1097-9875</identifier><identifier>DOI: 10.3109/15563659609013794</identifier><identifier>PMID: 8667468</identifier><language>eng</language><publisher>Monticello, NY: Informa UK Ltd</publisher><subject>Adult ; Biological and medical sciences ; Biomarkers - analysis ; Biopsy ; Collagen - analysis ; Drug toxicity and drugs side effects treatment ; Extracellular Matrix Proteins - analysis ; Female ; Humans ; Immunohistochemistry ; Immunosuppressive Agents - adverse effects ; Liver - chemistry ; Liver - drug effects ; Liver - pathology ; Liver Cirrhosis - chemically induced ; Liver Cirrhosis - diagnosis ; Male ; Medical sciences ; Methotrexate - adverse effects ; Middle Aged ; Pharmacology. Drug treatments ; Retrospective Studies ; Toxicity: digestive system ; Transforming Growth Factors - analysis</subject><ispartof>Clinical toxicology (Philadelphia, Pa.), 1996, Vol.34 (3), p.301-305</ispartof><rights>1996 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted 1996</rights><rights>1996 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-850ba00da11bcac1c5d32733e1cb3e633aff333f4f3599e4c9d1092d88ec415d3</citedby><cites>FETCH-LOGICAL-c461t-850ba00da11bcac1c5d32733e1cb3e633aff333f4f3599e4c9d1092d88ec415d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.3109/15563659609013794$$EPDF$$P50$$Ginformahealthcare$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.3109/15563659609013794$$EHTML$$P50$$Ginformahealthcare$$H</linktohtml><link.rule.ids>314,780,784,4024,27923,27924,27925,59647,59753,60436,60542,61221,61256,61402,61437</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3103972$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8667468$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jaskiewicz, K.</creatorcontrib><creatorcontrib>Voigt, H.</creatorcontrib><creatorcontrib>Blakolmer, K.</creatorcontrib><title>Increased Matrix Proteins, Collagen and Transforming Growth Factor are Early Markers of Hepatotoxicity in Patients on Long-Term Methotrexate Therapy</title><title>Clinical toxicology (Philadelphia, Pa.)</title><addtitle>J Toxicol Clin Toxicol</addtitle><description>Background: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. Design: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 ± 0.25 g (n = 20) and 3 ± 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. Conclusions: Immunohistochemical quantification of matrix proteins and collagens type 111 and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate.</description><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Biomarkers - analysis</subject><subject>Biopsy</subject><subject>Collagen - analysis</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Extracellular Matrix Proteins - analysis</subject><subject>Female</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Immunosuppressive Agents - adverse effects</subject><subject>Liver - chemistry</subject><subject>Liver - drug effects</subject><subject>Liver - pathology</subject><subject>Liver Cirrhosis - chemically induced</subject><subject>Liver Cirrhosis - diagnosis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Methotrexate - adverse effects</subject><subject>Middle Aged</subject><subject>Pharmacology. Drug treatments</subject><subject>Retrospective Studies</subject><subject>Toxicity: digestive system</subject><subject>Transforming Growth Factors - analysis</subject><issn>1556-3650</issn><issn>0731-3810</issn><issn>1556-9519</issn><issn>1097-9875</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhSMEKqXwACyQvECsCNjjxBMLNmjUP2kquhjW0R3nZuKS2MO1R528Bw9cjyathJC6suXznSPfc7PsveBfpOD6qyhLJVWpFddcyLkuXmSnh7dcl0K_nO4J4K-zNyHccS6rQouT7KRSal6o6jT7e-0MIQRs2A1Esnt2Sz6ideEzW_i-hw06Bq5hKwIXWk-DdRt2Sf4-duwCTPTEgJCdA_VjiqDfSIH5ll3hFqKPfm-NjSOzjt1CtOhiUh1berfJV0gDu8HY-Ui4h4hs1SHBdnybvWqhD_huOs-yXxfnq8VVvvx5eb34scxNoUTMq5KvgfMGhFgbMMKUjZzNpURh1hKVlNC2Usq2aGWpNRZGN6m0WVNVaAqR4LPs0zF3S_7PDkOsBxsMpqkd-l2oRam04EonUBxBQz4Ewrbekh2Axlrw-rCJ-r9NJM-HKXy3HrB5ckzVJ_3jpEMw0LepX2PDE5ZSpZ7PEvb9iFl3aB_uPfVNHWHsPT165HO_-PaPvUPoY2fSyuo7vyOX6n1mhgfZJ7hd</recordid><startdate>1996</startdate><enddate>1996</enddate><creator>Jaskiewicz, K.</creator><creator>Voigt, H.</creator><creator>Blakolmer, K.</creator><general>Informa UK Ltd</general><general>Taylor & Francis</general><general>Dekker</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>1996</creationdate><title>Increased Matrix Proteins, Collagen and Transforming Growth Factor are Early Markers of Hepatotoxicity in Patients on Long-Term Methotrexate Therapy</title><author>Jaskiewicz, K. ; Voigt, H. ; Blakolmer, K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-850ba00da11bcac1c5d32733e1cb3e633aff333f4f3599e4c9d1092d88ec415d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Biomarkers - analysis</topic><topic>Biopsy</topic><topic>Collagen - analysis</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Extracellular Matrix Proteins - analysis</topic><topic>Female</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Immunosuppressive Agents - adverse effects</topic><topic>Liver - chemistry</topic><topic>Liver - drug effects</topic><topic>Liver - pathology</topic><topic>Liver Cirrhosis - chemically induced</topic><topic>Liver Cirrhosis - diagnosis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Methotrexate - adverse effects</topic><topic>Middle Aged</topic><topic>Pharmacology. Drug treatments</topic><topic>Retrospective Studies</topic><topic>Toxicity: digestive system</topic><topic>Transforming Growth Factors - analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jaskiewicz, K.</creatorcontrib><creatorcontrib>Voigt, H.</creatorcontrib><creatorcontrib>Blakolmer, K.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Clinical toxicology (Philadelphia, Pa.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jaskiewicz, K.</au><au>Voigt, H.</au><au>Blakolmer, K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased Matrix Proteins, Collagen and Transforming Growth Factor are Early Markers of Hepatotoxicity in Patients on Long-Term Methotrexate Therapy</atitle><jtitle>Clinical toxicology (Philadelphia, Pa.)</jtitle><addtitle>J Toxicol Clin Toxicol</addtitle><date>1996</date><risdate>1996</risdate><volume>34</volume><issue>3</issue><spage>301</spage><epage>305</epage><pages>301-305</pages><issn>1556-3650</issn><issn>0731-3810</issn><eissn>1556-9519</eissn><eissn>1097-9875</eissn><abstract>Background: Hepatotoxicity, which may lead to fibrosis and cirrhosis, often limits the use of long-term low dose methotrexate for psoriasis and autoimmune diseases. Standard light microscopy lacks sensitivity for early fibrosis. Design: This is a retrospective study of immunohistochemical markers of early fibrosis including laminin and fibronectin, collagen deposition and lipocyte activation in hepatic biopsies of 36 psoriatic patients treated with methotrexate for one to five years, at an average dose of 20 mg/week. Biopsies before initiation of methotrexate (n = 36) showed minimal immunohistochemical expression of desmin, transforming growth factor alpha, matrix proteins, and collagen. Expression of laminin, fibronectin, collagens III and IV increased significantly and progressively over baseline values after cumulative doses of 1.5 ± 0.25 g (n = 20) and 3 ± 0.5 g methotrexate, respectively. Increases in desmin, smooth muscle actin and collagen type I also occurred but the changes were less consistent. Light microscopic abnormalities of hepatotoxicity were not detectable in any of these biopsies. Conclusions: Immunohistochemical quantification of matrix proteins and collagens type 111 and IV may be early, sensitive and dose responsive markers of methotrexate hepatotoxicity which progress with increasing cumulative doses of methotrexate.</abstract><cop>Monticello, NY</cop><pub>Informa UK Ltd</pub><pmid>8667468</pmid><doi>10.3109/15563659609013794</doi><tpages>5</tpages></addata></record> |
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subjects | Adult Biological and medical sciences Biomarkers - analysis Biopsy Collagen - analysis Drug toxicity and drugs side effects treatment Extracellular Matrix Proteins - analysis Female Humans Immunohistochemistry Immunosuppressive Agents - adverse effects Liver - chemistry Liver - drug effects Liver - pathology Liver Cirrhosis - chemically induced Liver Cirrhosis - diagnosis Male Medical sciences Methotrexate - adverse effects Middle Aged Pharmacology. Drug treatments Retrospective Studies Toxicity: digestive system Transforming Growth Factors - analysis |
title | Increased Matrix Proteins, Collagen and Transforming Growth Factor are Early Markers of Hepatotoxicity in Patients on Long-Term Methotrexate Therapy |
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