Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance

Valerio Nobili, Renato Cutrera, Daniela Liccardo, Martino Pavone, Rita Devito, Valentina Giorgio, Elisabetta Verrillo, Giuseppe Baviera, Giovanni Musso

Research output: Contribution to journalArticle

Abstract

Rationale: 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. Objectives: To assess the relationship of OSAS with liver injury in pediatric NAFLD. Methods: 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. Measurements and Main Results: 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 (b, 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 (SaO2 <90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. Conclusions: 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.

Original languageEnglish
Pages (from-to)66-76
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume189
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

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Obstructive Sleep Apnea
Insulin Resistance
Histology
Obesity
Pediatrics
Liver
Fibrosis
Kupffer Cells
Apnea
Non-alcoholic Fatty Liver Disease
Hepatocytes
Body Mass Index
Leukocytes
Macrophages
Odds Ratio
Confidence Intervals
Apoptosis
Keratin-18
Polysomnography
Adiposity

Keywords

  • Fibrosis
  • Hypoxia
  • Nonalcoholic fatty liver disease
  • Sleep apnea
  • Steatosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

@article{4c12c55388b341b6ae0f9f9f83465835,
title = "Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance",
abstract = "Rationale: 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. Objectives: To assess the relationship of OSAS with liver injury in pediatric NAFLD. Methods: 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. Measurements and Main Results: 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 (b, 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 (SaO2 <90{\%}) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. Conclusions: 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.",
keywords = "Fibrosis, Hypoxia, Nonalcoholic fatty liver disease, Sleep apnea, Steatosis",
author = "Valerio Nobili and Renato Cutrera and Daniela Liccardo and Martino Pavone and Rita Devito and Valentina Giorgio and Elisabetta Verrillo and Giuseppe Baviera and Giovanni Musso",
year = "2014",
month = "1",
day = "1",
doi = "10.1164/rccm.201307-1339OC",
language = "English",
volume = "189",
pages = "66--76",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society - AJRCCM",
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}

TY - JOUR

T1 - Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance

AU - Nobili, Valerio

AU - Cutrera, Renato

AU - Liccardo, Daniela

AU - Pavone, Martino

AU - Devito, Rita

AU - Giorgio, Valentina

AU - Verrillo, Elisabetta

AU - Baviera, Giuseppe

AU - Musso, Giovanni

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Rationale: 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. Objectives: To assess the relationship of OSAS with liver injury in pediatric NAFLD. Methods: 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. Measurements and Main Results: 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 (b, 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 (SaO2 <90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. Conclusions: 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.

AB - Rationale: 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. Objectives: To assess the relationship of OSAS with liver injury in pediatric NAFLD. Methods: 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. Measurements and Main Results: 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 (b, 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 (SaO2 <90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. Conclusions: 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.

KW - Fibrosis

KW - Hypoxia

KW - Nonalcoholic fatty liver disease

KW - Sleep apnea

KW - Steatosis

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U2 - 10.1164/rccm.201307-1339OC

DO - 10.1164/rccm.201307-1339OC

M3 - Article

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EP - 76

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

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