Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance
Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown. To assess the relationship of OSAS with liver injury in pediatric N...
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| Veröffentlicht in: | American journal of respiratory and critical care medicine 2014-01, Vol.189 (1), p.66-76 |
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| creator | Nobili, Valerio Cutrera, Renato Liccardo, Daniela Pavone, Martino Devito, Rita Giorgio, Valentina Verrillo, Elisabetta Baviera, Giuseppe Musso, Giovanni |
| description | Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown.
To assess the relationship of OSAS with liver injury in pediatric NAFLD.
Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h.
Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis.
In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials. |
| doi_str_mv | 10.1164/rccm.201307-1339oc |
| format | Article |
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To assess the relationship of OSAS with liver injury in pediatric NAFLD.
Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h.
Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis.
In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.</description><identifier>ISSN: 1073-449X</identifier><identifier>EISSN: 1535-4970</identifier><identifier>DOI: 10.1164/rccm.201307-1339oc</identifier><identifier>PMID: 24256086</identifier><language>eng</language><publisher>United States: American Thoracic Society</publisher><subject>Age ; Apoptosis ; Biopsy ; Blood pressure ; Body mass index ; C-Reactive Protein - analysis ; Child ; Children & youth ; Confidence intervals ; Cytokines ; Diabetes ; Enzymes ; Fatty Liver - etiology ; Fatty Liver - pathology ; Female ; Glucose ; Histology ; Humans ; Hyaluronic Acid - blood ; Hypoxia ; Insulin Resistance ; Interleukin-6 - blood ; Keratin-18 - blood ; Leukocytes ; Liver - pathology ; Liver cirrhosis ; Liver diseases ; Male ; Metabolic syndrome ; Non-alcoholic Fatty Liver Disease ; Obesity ; Obesity - complications ; Pediatrics ; Polysomnography ; Sleep apnea ; Sleep Apnea, Obstructive - complications ; Sleep Apnea, Obstructive - pathology ; Sleep Apnea, Obstructive - physiopathology ; Triglycerides ; Tumor Necrosis Factor-alpha - blood</subject><ispartof>American journal of respiratory and critical care medicine, 2014-01, Vol.189 (1), p.66-76</ispartof><rights>Copyright American Thoracic Society Jan 1, 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c397t-188e9716a7d782e957d89758cd2f3b265e613c828553ce509c1c38a1e0a3a04f3</citedby><cites>FETCH-LOGICAL-c397t-188e9716a7d782e957d89758cd2f3b265e613c828553ce509c1c38a1e0a3a04f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4025,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24256086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nobili, Valerio</creatorcontrib><creatorcontrib>Cutrera, Renato</creatorcontrib><creatorcontrib>Liccardo, Daniela</creatorcontrib><creatorcontrib>Pavone, Martino</creatorcontrib><creatorcontrib>Devito, Rita</creatorcontrib><creatorcontrib>Giorgio, Valentina</creatorcontrib><creatorcontrib>Verrillo, Elisabetta</creatorcontrib><creatorcontrib>Baviera, Giuseppe</creatorcontrib><creatorcontrib>Musso, Giovanni</creatorcontrib><title>Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance</title><title>American journal of respiratory and critical care medicine</title><addtitle>Am J Respir Crit Care Med</addtitle><description>Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown.
To assess the relationship of OSAS with liver injury in pediatric NAFLD.
Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h.
Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis.
In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.</description><subject>Age</subject><subject>Apoptosis</subject><subject>Biopsy</subject><subject>Blood pressure</subject><subject>Body mass index</subject><subject>C-Reactive Protein - analysis</subject><subject>Child</subject><subject>Children & youth</subject><subject>Confidence intervals</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Enzymes</subject><subject>Fatty Liver - etiology</subject><subject>Fatty Liver - pathology</subject><subject>Female</subject><subject>Glucose</subject><subject>Histology</subject><subject>Humans</subject><subject>Hyaluronic Acid - blood</subject><subject>Hypoxia</subject><subject>Insulin Resistance</subject><subject>Interleukin-6 - blood</subject><subject>Keratin-18 - blood</subject><subject>Leukocytes</subject><subject>Liver - pathology</subject><subject>Liver cirrhosis</subject><subject>Liver diseases</subject><subject>Male</subject><subject>Metabolic syndrome</subject><subject>Non-alcoholic Fatty Liver Disease</subject><subject>Obesity</subject><subject>Obesity - complications</subject><subject>Pediatrics</subject><subject>Polysomnography</subject><subject>Sleep apnea</subject><subject>Sleep Apnea, Obstructive - complications</subject><subject>Sleep Apnea, Obstructive - pathology</subject><subject>Sleep Apnea, Obstructive - physiopathology</subject><subject>Triglycerides</subject><subject>Tumor Necrosis Factor-alpha - blood</subject><issn>1073-449X</issn><issn>1535-4970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkU2LFDEQhhtR3A_9Ax4k4MWDvZuPTnf6KIO6wsJcFLw1Nenq3SzpZEylhf5Z_kPTzOjBU1LUUw9UvVX1RvAbIdrmNlk730guFO9qoVQf7bPqUmil66bv-PPy552qm6b_cVFdET1xLqQR_GV1IRupW27ay-r3_kA5LTa7X8jIIx4ZHAMCozWMKc7IYJrQZmK-EIk9OsrRx4eVQRiZC5OHeYYc08oses9gM0F2MZQmO-LoICdnWYgBvI2P0ZdigpzXs3B0hED4gSV8gDR6JGJxYvGA5PJ66wItvphSKSlDsPiqejGBJ3x9fq-r758_fdvd1ff7L193H-9rq_ou18IY7DvRQjd2RmKvu9H0nTZ2lJM6yFZjK5Q10mitLGreW2GVAYEcFPBmUtfV-5P3mOLPBSkPs6NtRwgYFxpE05fzmnLugr77D32KSyoLb1SnedO0ShZKniibIlHCaTgmN0NaB8GHLdBhC3Q4BTpsge53ZejtWb0cZhz_jfxNUP0BMeShqQ</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Nobili, Valerio</creator><creator>Cutrera, Renato</creator><creator>Liccardo, Daniela</creator><creator>Pavone, Martino</creator><creator>Devito, Rita</creator><creator>Giorgio, Valentina</creator><creator>Verrillo, Elisabetta</creator><creator>Baviera, Giuseppe</creator><creator>Musso, Giovanni</creator><general>American Thoracic Society</general><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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20140101</creationdate><title>Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance</title><author>Nobili, Valerio ; Cutrera, Renato ; Liccardo, Daniela ; Pavone, Martino ; Devito, Rita ; Giorgio, Valentina ; Verrillo, Elisabetta ; Baviera, Giuseppe ; Musso, Giovanni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c397t-188e9716a7d782e957d89758cd2f3b265e613c828553ce509c1c38a1e0a3a04f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Age</topic><topic>Apoptosis</topic><topic>Biopsy</topic><topic>Blood pressure</topic><topic>Body mass index</topic><topic>C-Reactive Protein - analysis</topic><topic>Child</topic><topic>Children & youth</topic><topic>Confidence intervals</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Enzymes</topic><topic>Fatty Liver - etiology</topic><topic>Fatty Liver - pathology</topic><topic>Female</topic><topic>Glucose</topic><topic>Histology</topic><topic>Humans</topic><topic>Hyaluronic Acid - blood</topic><topic>Hypoxia</topic><topic>Insulin Resistance</topic><topic>Interleukin-6 - blood</topic><topic>Keratin-18 - blood</topic><topic>Leukocytes</topic><topic>Liver - pathology</topic><topic>Liver cirrhosis</topic><topic>Liver diseases</topic><topic>Male</topic><topic>Metabolic syndrome</topic><topic>Non-alcoholic Fatty Liver Disease</topic><topic>Obesity</topic><topic>Obesity - complications</topic><topic>Pediatrics</topic><topic>Polysomnography</topic><topic>Sleep apnea</topic><topic>Sleep Apnea, Obstructive - complications</topic><topic>Sleep Apnea, Obstructive - pathology</topic><topic>Sleep Apnea, Obstructive - physiopathology</topic><topic>Triglycerides</topic><topic>Tumor Necrosis Factor-alpha - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nobili, Valerio</creatorcontrib><creatorcontrib>Cutrera, Renato</creatorcontrib><creatorcontrib>Liccardo, Daniela</creatorcontrib><creatorcontrib>Pavone, Martino</creatorcontrib><creatorcontrib>Devito, Rita</creatorcontrib><creatorcontrib>Giorgio, Valentina</creatorcontrib><creatorcontrib>Verrillo, Elisabetta</creatorcontrib><creatorcontrib>Baviera, Giuseppe</creatorcontrib><creatorcontrib>Musso, Giovanni</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of respiratory and critical care medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nobili, Valerio</au><au>Cutrera, Renato</au><au>Liccardo, Daniela</au><au>Pavone, Martino</au><au>Devito, Rita</au><au>Giorgio, Valentina</au><au>Verrillo, Elisabetta</au><au>Baviera, Giuseppe</au><au>Musso, Giovanni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance</atitle><jtitle>American journal of respiratory and critical care medicine</jtitle><addtitle>Am J Respir Crit Care Med</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>189</volume><issue>1</issue><spage>66</spage><epage>76</epage><pages>66-76</pages><issn>1073-449X</issn><eissn>1535-4970</eissn><abstract>Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown.
To assess the relationship of OSAS with liver injury in pediatric NAFLD.
Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h.
Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis.
In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.</abstract><cop>United States</cop><pub>American Thoracic Society</pub><pmid>24256086</pmid><doi>10.1164/rccm.201307-1339oc</doi><tpages>11</tpages></addata></record> |
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| ispartof | American journal of respiratory and critical care medicine, 2014-01, Vol.189 (1), p.66-76 |
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| source | MEDLINE; Journals@Ovid Complete; American Thoracic Society (ATS) Journals Online; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Age Apoptosis Biopsy Blood pressure Body mass index C-Reactive Protein - analysis Child Children & youth Confidence intervals Cytokines Diabetes Enzymes Fatty Liver - etiology Fatty Liver - pathology Female Glucose Histology Humans Hyaluronic Acid - blood Hypoxia Insulin Resistance Interleukin-6 - blood Keratin-18 - blood Leukocytes Liver - pathology Liver cirrhosis Liver diseases Male Metabolic syndrome Non-alcoholic Fatty Liver Disease Obesity Obesity - complications Pediatrics Polysomnography Sleep apnea Sleep Apnea, Obstructive - complications Sleep Apnea, Obstructive - pathology Sleep Apnea, Obstructive - physiopathology Triglycerides Tumor Necrosis Factor-alpha - blood |
| title | Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance |
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