EDITORIALS because it will also improve cough. Respiratory muscle training alone is simple; it can be done using resistive or threshold devices, or even singing, to load inspiratory, expiratory, or both sets of muscles (6). But whole-body exercise in patients with SCI also improves ventilatory function, the most recent example being the study by Terson de Paleville and colleagues (7; see their article for additional references). In that study, pulmonary function (FVC and FEV1), maximum respiratory pressures, and surface EMG during pressure generation of eight individuals with chronic SCI (C3–T12) all improved after 12 weeks of daily, except weekends, 60-minute assisted treadmill locomotion. Using treadmill exercise to elicit improvements in ventilatory function requires mechanical support for the patient and supervisory personnel; the time and expense are of little consequence if exercise is part of the normal rehabilitation process. The studies of Terson de Paleville and colleagues (7) and of Tester and colleagues (1) have in common only the measurement of FVC and FEV1; the subjects of the latter study had worse pulmonary function (FVC, % predicted, averaged 64 vs. 80 and FEV1, % predicted, averaged 62 vs. 75). Both hypoxia and exercise induced small average increases in FVC and FEV1 (z5 and 3%, respectively, for hypoxia; 10 and 2.7%, respectively, for exercise), with considerable intersubject variation. Thus, regardless of initial pulmonary function status, the improvements were similar. However, we do not know if baseline differences in ventilatory function, perhaps reflecting the extent of SCI, are important in the ventilatory expression of LTF. Because LTF is expressed, at least in animal-based experiments, by modulation of motoneuronal excitability at the spinal level (for review, see Reference 8), it would be surprising if this were not the case. Consideration should also be given to the possibility that some combination of IH and exercise training would provide greater enhancements in ventilatory function than either modality alone. In conclusion, future studies need to use standardized measures to enable comparisons of the effectiveness of the options available to improve ventilatory function. These include ventilation, (forced) VC and FEV1, maximum inspiratory (or sniff) and expiratory pressures, dyspnea (Borg scale), and quality of life. Rehabilitated individuals should also be followed to determine if they have a reduced incidence of respiratory infections and other complications, as suggested by Van Houtte and colleagues (9). If this is verified, the cost of even marginal improvements in ventilatory function is likely to be outweighed by reductions in healthcare expenditures associated with hospitalization for respiratory
problems. And the value of improvements of quality of life is beyond measure. n Author disclosures are available with the text of this article at www. atsjournals.org. Steve Iscoe, Ph.D. Department of Biomedical and Molecular Sciences Queen’s University Kingston, Ontario, Canada and Anthony DiMarco, M.D. Department of Physical Medicine and Rehabilitation Case Western Reserve University and MetroHealth Medical Center Cleveland, Ohio
References 1. Tester NJ, Fuller DD, Fromm JS, Spiess MR, Behrman AL, Mateika JH. Long-term facilitation of ventilation in humans with chronic spinal cord injury. Am J Respir Crit Care Med 2014;189:57–65. 2. Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, Bavis RW, Mack KJ, Olson EBJ Jr. Invited review: intermittent hypoxia and respiratory plasticity. J Appl Physiol (1985) 2001;90:2466–2475. 3. Diep TT, Khan TR, Zhang R, Duffin J. Long-term facilitation of breathing is absent after episodes of hypercapnic hypoxia in awake humans. Respir Physiol Neurobiol 2007;156:132–136. 4. Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair 2012;26:163–172. 5. Hayes HB, Jayaraman A, Herrmann M, Mitchell GS, Rymer WZ, Trumbower RD. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology [online ahead of print] 27 Nov 2013; DOI: 10.1212/01.WNL.0000437416.34298.43. 6. Berlowitz DJ, Tamplin J. Respiratory muscle training for cervical spinal cord injury. Cochrane Database Syst Rev 2013;7: CD008507. 7. Terson de Paleville D, McKay W, Aslan S, Folz R, Sayenko D, Ovechkin A. Locomotor step training with body weight support improves respiratory motor function in individuals with chronic spinal cord injury. Respir Physiol Neurobiol 2013;189: 491–497. 8. Xing T, Fong AY, Bautista TG, Pilowsky PM. Acute intermittent hypoxia induced neural plasticity in respiratory motor control. Clin Exp Pharmacol Physiol 2013;40:602–609. 9. Van Houtte S, Vanlandewijck Y, Kiekens C, Spengler CM, Gosselink R. Patients with acute spinal cord injury benefit from normocapnic hyperpnoea training. J Rehabil Med 2008;40:119–125. Copyright © 2014 by the American Thoracic Society
Metabolic Complications and Obstructive Sleep Apnea in Obese Children: Time to Wake Up! Obstructive sleep apnea (OSA) is highly prevalent in pediatric obesity. It affects 13 to 59% of obese children, depending on the definitions used (1). Repetitive apneas and hypopneas cause intermittent hypoxia and sleep fragmentation, resulting in increased local and systemic inflammation and sympathetic activity. OSA is an independent risk factor for the metabolic
Editorials
syndrome and several of its components, including dyslipidemia, insulin resistance, and cardiovascular comorbidities (2–4). However, the link between OSA and full-blown manifestations of end-organ damage in pediatrics such as diabetes or daytime hypertension has not been established. Although the association between OSA during childhood and premature onset of these
13
EDITORIALS conditions in adulthood is hypothesized, current longitudinal data are lacking. The study in this issue of the Journal by Nobili and colleagues (pp. 66–76) is one of the first studies linking OSA to a serious marker of metabolic end-organ morbidity, namely nonalcoholic fatty liver disease (NAFLD) (5). NAFLD is often diagnosed in pediatric obesity, and it comprises an entire spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) (6). It is clinically assessed by abdominal ultrasound and the serial measurement of serum transaminases with a final diagnosis and staging made by liver biopsy. NAFLD is a serious liver disease and has been reported in very young children with reports of NASH-related cirrhosis in children below 10 years old (7). Furthermore, there is an increased risk for severe liver-related complications in adult life as well. The development of NAFLD requires what has been called a “two-hit” mechanism: first, the development of steatosis resulting from fatty infiltration of the liver due to obesity and insulin resistance, followed by inflammatory bursts, potentially due to oxidative stress (7, 8). OSA could contribute to the pathogenesis of NAFLD via its effects on dyslipidemia, insulin resistance, oxidative stress, and inflammation. Only a few reports have looked at the association between OSA and NAFLD, and these studies only examined the association between OSA and elevated liver enzymes and/or ultrasonographic findings suggesting liver steatosis (9, 10). Liver tissue has never been examined in otherwise healthy children and adolescents to establish an association of NASH with OSA. The study of Nobili and colleagues examined the association between OSA and NASH correcting for confounders such as fat distribution, insulin resistance, and other components of the metabolic syndrome (5). Therefore, 65 obese and nonobese patients were studied with ultrasonographic diagnosis of NAFLD, elevated liver enzymes for over 6 months, and suspected OSA. All patients underwent liver biopsy and full polysomnography. The presence of the metabolic syndrome and some cytokines linked to inflammation, hepatocyte apoptosis, and liver fibrosis were also assessed. Approximately 75% of subjects were obese, and 20% were diagnosed with the metabolic syndrome. All patients had biopsy-proven NAFLD, with 55% having NASH on liver biopsy, and only 17% of all subjects had no signs of fibrosis. OSA was also present in 60% of the study population, and it was more prevalent in subjects with NASH. The severity of OSA was associated with the severity of NAFLD on liver biopsy, independent of the degree of obesity, altered pattern of glucose homeostasis, and the presence of components of the metabolic syndrome. The inflammatory reaction at the level of the liver tissue was mostly mediated by lower nocturnal oxygen saturation. The major strength of this study is the elaborate assessment of liver pathology, although analyzed by a single pathologist, and cytokines involved in the pathogenesis of NASH by mediating hepatocyte apoptosis and liver fibrosis. The authors used the well-known NAFLD activity score to differentiate between NASH and not-NASH and described the different stages of fibrosis. All of the components of the metabolic syndrome and insulin resistance were assessed to control for these possible confounders in the different statistical models. This is of great importance, as it is known from previous data that factors of metabolic dysregulation can also mediate the development of NAFLD and NASH. The major limitation of this report is the cross-sectional nature of the study design. Interesting associations are described and results are controlled for factors 14
such as obesity and metabolic dysregulation, but unfortunately, no conclusions can be drawn regarding underlying pathophysiological mechanisms. The effects of OSA treatment with either upper airway surgery or noninvasive ventilation were not described. No data on the effects of weight loss in the obese subgroup, either on the severity of NAFLD or the degree of OSA, were reported either. A second limitation is the highly selected population of subjects with a suggestive diagnosis of NAFLD rather than looking for NAFLD in a population at risk for OSA, although a large study with liver biopsies in children would be ethically impossible. In this perspective, proposed screening tests for the diagnosis of NAFLD in children should be investigated further (11). In spite of these limitations, the findings of the present study are of great value in the field of pediatric sleep apnea, as they show the feasibility of performing a liver biopsy in a population of children and adolescents with suggested NAFLD and OSA. An important conclusion is the need for actively looking for OSA in children with a diagnosis of NAFLD. Second, future research should focus on the underlying pathophysiological mechanisms linking severe OSA to the development of NASH, preferably by intervention studies in the obese population who are most at risk for both complications. It is well known that the treatment of OSA in the obese population is quite challenging and more studies are urgently needed to study the effects of treatment on both OSAand obesity-related complications. Adenotonsillectomy is frequently performed but associated with a high incidence of residual OSA and a frequent increase in body mass index (12, 13). This could result in a possible worsening of several complications. Noninvasive ventilation is effective, but compliance can be an issue, especially in obese children, who often have mild disease and limited daytime symptoms. Weight loss has positive effects on both OSA and metabolic complications and should therefore be a firstline treatment for OSA in obese children (14, 15). However, significant weight loss can be difficult to achieve, and long-term success is unknown. Other treatment strategies interfering with direct pathophysiological mechanisms are therefore important to study. An interesting finding of the present study is that hypoxia was a strong correlate of liver-related inflammation and fibrogenesis, implicating oxidative stress as one of the main mechanisms to tackle. Possible interventions originating from animal studies or from limited human studies include physical activity, vitamins, and other antioxidant therapies, including allopurinol or N-acetylcysteine. These interventions have not been studied yet in a pediatric population, but studies are urgently needed in view of the disadvantages of our current treatments. Another common link between OSA and NAFLD could be increased inflammation via a negative influence on the gut microbiome (16, 17), which could result in additional noninvasive treatment options as well. Finally, NAFLD is a complex entity resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers (18). Genetic modification of inflammatory pathways has also been described in children with OSA (19). The role of possible modifiers or shared genetic risk factors between OSA and NAFLD in children remains to be elucidated. Both obesity and OSA are associated with increased healthcare use (20, 21). Second, obese children tend to become obese adults with a likely premature onset of metabolic and cardiovascular disease. Our field should therefore maximize the efforts to stimulate further
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 1 | January 2014
EDITORIALS studies looking at various treatment strategies to diminish the influence of OSA on further enhancing these complications. The high prevalence of obesity and OSA in this population makes this a public health priority: it is time to wake up and be active! n Author disclosures are available with the text of this article at www. atsjournals.org. Kim Van Hoorenbeeck, M.D., Ph.D. Stijn L. Verhulst, M.D., Ph.D. Department of Pediatrics Antwerp University Hospital Edegem, Belgium
References 1. Verhulst SL, Van Gaal L, De Backer W, Desager K. The prevalence, anatomical correlates and treatment of sleep-disordered breathing in obese children and adolescents. Sleep Med Rev 2008;12:339–346. 2. Redline S, Storfer-Isser A, Rosen CL, Johnson NL, Kirchner HL, Emancipator J, Kibler AM. Association between metabolic syndrome and sleep-disordered breathing in adolescents. Am J Respir Crit Care Med 2007;176:401–408. 3. Verhulst SL, Schrauwen N, Haentjens D, Rooman RP, Van Gaal L, De Backer WA, Desager KN. Sleep-disordered breathing and the metabolic syndrome in overweight and obese children and adolescents. J Pediatr 2007;150:608–612. 4. Amin R, Somers VK, McConnell K, Willging P, Myer C, Sherman M, McPhail G, Morgenthal A, Fenchel M, Bean J, et al. Activity-adjusted 24-hour ambulatory blood pressure and cardiac remodeling in children with sleep disordered breathing. Hypertension 2008;51:84–91. 5. Nobili V, Cutrera R, Liccardo D, Pavone M, Devito R, Giorgio V, Verrillo E, Baviera G, Musso G. Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance. Am J Respir Crit Care Med 2014;189:66–76. 6. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617–649. 7. Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB, Lavine JE. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr 2006;43:413–427. 8. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998;114:842–845. 9. Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest 2008;133:92–99.
Editorials
10. Verhulst SL, Jacobs S, Aerts L, Schrauwen N, Haentjens D, Rooman RP, Gaal LV, De Backer WA, Desager KN. Sleep-disordered breathing: a new risk factor of suspected fatty liver disease in overweight children and adolescents? Sleep Breath 2009;13: 207–210. 11. Alkhouri N, Cikach F, Eng K, Moses J, Patel N, Yan C, Hanouneh I, Grove D, Lopez R, Dweik R. Analysis of breath volatile organic compounds as a noninvasive tool to diagnose nonalcoholic fatty liver disease in children. Eur J Gastroenterol Hepatol 2014;26: 82–87. 12. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, Mitchell RB, Promchiarak J, Simakajornboon N, Kaditis AG, Splaingard D, Splaingard M, Brooks LJ, et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med 2010;182: 676–683. 13. Amin R, Anthony L, Somers V, Fenchel M, McConnell K, Jefferies J, Willging P, Kalra M, Daniels S. Growth velocity predicts recurrence of sleep-disordered breathing 1 year after adenotonsillectomy. Am J Respir Crit Care Med 2008;177:654–659. 14. Van Hoorenbeeck K, Franckx H, Debode P, Aerts P, Ramet J, Van Gaal LF, Desager KN, De Backer WA, Verhulst SL. Metabolic disregulation in obese adolescents with sleep-disordered breathing before and after weight loss. Obesity (Silver Spring) 2013;21: 1446–1450. 15. Van Hoorenbeeck K, Franckx H, Debode P, Aerts P, Wouters K, Ramet J, Van Gaal LF, Desager KN, De Backer WA, Verhulst SL. Weight loss and sleep-disordered breathing in childhood obesity: effects on inflammation and uric acid. Obesity (Silver Spring) 2012;20:172–177. 16. Kheirandish-Gozal L, Peris E, Wang Y, Tamae Kakazu M, Khalyfa A, Carreras A, Gozal D. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab (In press) 17. Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrateproducing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS ONE 2013;8:e63388. 18. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013;10:645–655. 19. Kim J, Bhattacharjee R, Khalyfa A, Kheirandish-Gozal L, Capdevila OS, Wang Y, Gozal D. DNA methylation in inflammatory genes among children with obstructive sleep apnea. Am J Respir Crit Care Med 2012;185:330–338. 20. Wenig CM, Knopf H, Menn P. Juvenile obesity and its association with utilisation and costs of pharmaceuticals—results from the KiGGS study. BMC Health Serv Res 2011;11:340. 21. Tarasiuk A, Greenberg-Dotan S, Simon-Tuval T, Freidman B, Goldbart AD, Tal A, Reuveni H. Elevated morbidity and health care use in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2007;175:55–61. Copyright © 2014 by the American Thoracic Society
15
problems. And the value of improvements of quality of life is beyond measure. n Author disclosures are available with the text of this article at www. atsjournals.org. Steve Iscoe, Ph.D. Department of Biomedical and Molecular Sciences Queen’s University Kingston, Ontario, Canada and Anthony DiMarco, M.D. Department of Physical Medicine and Rehabilitation Case Western Reserve University and MetroHealth Medical Center Cleveland, Ohio
References 1. Tester NJ, Fuller DD, Fromm JS, Spiess MR, Behrman AL, Mateika JH. Long-term facilitation of ventilation in humans with chronic spinal cord injury. Am J Respir Crit Care Med 2014;189:57–65. 2. Mitchell GS, Baker TL, Nanda SA, Fuller DD, Zabka AG, Hodgeman BA, Bavis RW, Mack KJ, Olson EBJ Jr. Invited review: intermittent hypoxia and respiratory plasticity. J Appl Physiol (1985) 2001;90:2466–2475. 3. Diep TT, Khan TR, Zhang R, Duffin J. Long-term facilitation of breathing is absent after episodes of hypercapnic hypoxia in awake humans. Respir Physiol Neurobiol 2007;156:132–136. 4. Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair 2012;26:163–172. 5. Hayes HB, Jayaraman A, Herrmann M, Mitchell GS, Rymer WZ, Trumbower RD. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology [online ahead of print] 27 Nov 2013; DOI: 10.1212/01.WNL.0000437416.34298.43. 6. Berlowitz DJ, Tamplin J. Respiratory muscle training for cervical spinal cord injury. Cochrane Database Syst Rev 2013;7: CD008507. 7. Terson de Paleville D, McKay W, Aslan S, Folz R, Sayenko D, Ovechkin A. Locomotor step training with body weight support improves respiratory motor function in individuals with chronic spinal cord injury. Respir Physiol Neurobiol 2013;189: 491–497. 8. Xing T, Fong AY, Bautista TG, Pilowsky PM. Acute intermittent hypoxia induced neural plasticity in respiratory motor control. Clin Exp Pharmacol Physiol 2013;40:602–609. 9. Van Houtte S, Vanlandewijck Y, Kiekens C, Spengler CM, Gosselink R. Patients with acute spinal cord injury benefit from normocapnic hyperpnoea training. J Rehabil Med 2008;40:119–125. Copyright © 2014 by the American Thoracic Society
Metabolic Complications and Obstructive Sleep Apnea in Obese Children: Time to Wake Up! Obstructive sleep apnea (OSA) is highly prevalent in pediatric obesity. It affects 13 to 59% of obese children, depending on the definitions used (1). Repetitive apneas and hypopneas cause intermittent hypoxia and sleep fragmentation, resulting in increased local and systemic inflammation and sympathetic activity. OSA is an independent risk factor for the metabolic
Editorials
syndrome and several of its components, including dyslipidemia, insulin resistance, and cardiovascular comorbidities (2–4). However, the link between OSA and full-blown manifestations of end-organ damage in pediatrics such as diabetes or daytime hypertension has not been established. Although the association between OSA during childhood and premature onset of these
13
EDITORIALS conditions in adulthood is hypothesized, current longitudinal data are lacking. The study in this issue of the Journal by Nobili and colleagues (pp. 66–76) is one of the first studies linking OSA to a serious marker of metabolic end-organ morbidity, namely nonalcoholic fatty liver disease (NAFLD) (5). NAFLD is often diagnosed in pediatric obesity, and it comprises an entire spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) (6). It is clinically assessed by abdominal ultrasound and the serial measurement of serum transaminases with a final diagnosis and staging made by liver biopsy. NAFLD is a serious liver disease and has been reported in very young children with reports of NASH-related cirrhosis in children below 10 years old (7). Furthermore, there is an increased risk for severe liver-related complications in adult life as well. The development of NAFLD requires what has been called a “two-hit” mechanism: first, the development of steatosis resulting from fatty infiltration of the liver due to obesity and insulin resistance, followed by inflammatory bursts, potentially due to oxidative stress (7, 8). OSA could contribute to the pathogenesis of NAFLD via its effects on dyslipidemia, insulin resistance, oxidative stress, and inflammation. Only a few reports have looked at the association between OSA and NAFLD, and these studies only examined the association between OSA and elevated liver enzymes and/or ultrasonographic findings suggesting liver steatosis (9, 10). Liver tissue has never been examined in otherwise healthy children and adolescents to establish an association of NASH with OSA. The study of Nobili and colleagues examined the association between OSA and NASH correcting for confounders such as fat distribution, insulin resistance, and other components of the metabolic syndrome (5). Therefore, 65 obese and nonobese patients were studied with ultrasonographic diagnosis of NAFLD, elevated liver enzymes for over 6 months, and suspected OSA. All patients underwent liver biopsy and full polysomnography. The presence of the metabolic syndrome and some cytokines linked to inflammation, hepatocyte apoptosis, and liver fibrosis were also assessed. Approximately 75% of subjects were obese, and 20% were diagnosed with the metabolic syndrome. All patients had biopsy-proven NAFLD, with 55% having NASH on liver biopsy, and only 17% of all subjects had no signs of fibrosis. OSA was also present in 60% of the study population, and it was more prevalent in subjects with NASH. The severity of OSA was associated with the severity of NAFLD on liver biopsy, independent of the degree of obesity, altered pattern of glucose homeostasis, and the presence of components of the metabolic syndrome. The inflammatory reaction at the level of the liver tissue was mostly mediated by lower nocturnal oxygen saturation. The major strength of this study is the elaborate assessment of liver pathology, although analyzed by a single pathologist, and cytokines involved in the pathogenesis of NASH by mediating hepatocyte apoptosis and liver fibrosis. The authors used the well-known NAFLD activity score to differentiate between NASH and not-NASH and described the different stages of fibrosis. All of the components of the metabolic syndrome and insulin resistance were assessed to control for these possible confounders in the different statistical models. This is of great importance, as it is known from previous data that factors of metabolic dysregulation can also mediate the development of NAFLD and NASH. The major limitation of this report is the cross-sectional nature of the study design. Interesting associations are described and results are controlled for factors 14
such as obesity and metabolic dysregulation, but unfortunately, no conclusions can be drawn regarding underlying pathophysiological mechanisms. The effects of OSA treatment with either upper airway surgery or noninvasive ventilation were not described. No data on the effects of weight loss in the obese subgroup, either on the severity of NAFLD or the degree of OSA, were reported either. A second limitation is the highly selected population of subjects with a suggestive diagnosis of NAFLD rather than looking for NAFLD in a population at risk for OSA, although a large study with liver biopsies in children would be ethically impossible. In this perspective, proposed screening tests for the diagnosis of NAFLD in children should be investigated further (11). In spite of these limitations, the findings of the present study are of great value in the field of pediatric sleep apnea, as they show the feasibility of performing a liver biopsy in a population of children and adolescents with suggested NAFLD and OSA. An important conclusion is the need for actively looking for OSA in children with a diagnosis of NAFLD. Second, future research should focus on the underlying pathophysiological mechanisms linking severe OSA to the development of NASH, preferably by intervention studies in the obese population who are most at risk for both complications. It is well known that the treatment of OSA in the obese population is quite challenging and more studies are urgently needed to study the effects of treatment on both OSAand obesity-related complications. Adenotonsillectomy is frequently performed but associated with a high incidence of residual OSA and a frequent increase in body mass index (12, 13). This could result in a possible worsening of several complications. Noninvasive ventilation is effective, but compliance can be an issue, especially in obese children, who often have mild disease and limited daytime symptoms. Weight loss has positive effects on both OSA and metabolic complications and should therefore be a firstline treatment for OSA in obese children (14, 15). However, significant weight loss can be difficult to achieve, and long-term success is unknown. Other treatment strategies interfering with direct pathophysiological mechanisms are therefore important to study. An interesting finding of the present study is that hypoxia was a strong correlate of liver-related inflammation and fibrogenesis, implicating oxidative stress as one of the main mechanisms to tackle. Possible interventions originating from animal studies or from limited human studies include physical activity, vitamins, and other antioxidant therapies, including allopurinol or N-acetylcysteine. These interventions have not been studied yet in a pediatric population, but studies are urgently needed in view of the disadvantages of our current treatments. Another common link between OSA and NAFLD could be increased inflammation via a negative influence on the gut microbiome (16, 17), which could result in additional noninvasive treatment options as well. Finally, NAFLD is a complex entity resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers (18). Genetic modification of inflammatory pathways has also been described in children with OSA (19). The role of possible modifiers or shared genetic risk factors between OSA and NAFLD in children remains to be elucidated. Both obesity and OSA are associated with increased healthcare use (20, 21). Second, obese children tend to become obese adults with a likely premature onset of metabolic and cardiovascular disease. Our field should therefore maximize the efforts to stimulate further
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 1 | January 2014
EDITORIALS studies looking at various treatment strategies to diminish the influence of OSA on further enhancing these complications. The high prevalence of obesity and OSA in this population makes this a public health priority: it is time to wake up and be active! n Author disclosures are available with the text of this article at www. atsjournals.org. Kim Van Hoorenbeeck, M.D., Ph.D. Stijn L. Verhulst, M.D., Ph.D. Department of Pediatrics Antwerp University Hospital Edegem, Belgium
References 1. Verhulst SL, Van Gaal L, De Backer W, Desager K. The prevalence, anatomical correlates and treatment of sleep-disordered breathing in obese children and adolescents. Sleep Med Rev 2008;12:339–346. 2. Redline S, Storfer-Isser A, Rosen CL, Johnson NL, Kirchner HL, Emancipator J, Kibler AM. Association between metabolic syndrome and sleep-disordered breathing in adolescents. Am J Respir Crit Care Med 2007;176:401–408. 3. Verhulst SL, Schrauwen N, Haentjens D, Rooman RP, Van Gaal L, De Backer WA, Desager KN. Sleep-disordered breathing and the metabolic syndrome in overweight and obese children and adolescents. J Pediatr 2007;150:608–612. 4. Amin R, Somers VK, McConnell K, Willging P, Myer C, Sherman M, McPhail G, Morgenthal A, Fenchel M, Bean J, et al. Activity-adjusted 24-hour ambulatory blood pressure and cardiac remodeling in children with sleep disordered breathing. Hypertension 2008;51:84–91. 5. Nobili V, Cutrera R, Liccardo D, Pavone M, Devito R, Giorgio V, Verrillo E, Baviera G, Musso G. Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance. Am J Respir Crit Care Med 2014;189:66–76. 6. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43:617–649. 7. Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB, Lavine JE. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J Pediatr Gastroenterol Nutr 2006;43:413–427. 8. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998;114:842–845. 9. Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest 2008;133:92–99.
Editorials
10. Verhulst SL, Jacobs S, Aerts L, Schrauwen N, Haentjens D, Rooman RP, Gaal LV, De Backer WA, Desager KN. Sleep-disordered breathing: a new risk factor of suspected fatty liver disease in overweight children and adolescents? Sleep Breath 2009;13: 207–210. 11. Alkhouri N, Cikach F, Eng K, Moses J, Patel N, Yan C, Hanouneh I, Grove D, Lopez R, Dweik R. Analysis of breath volatile organic compounds as a noninvasive tool to diagnose nonalcoholic fatty liver disease in children. Eur J Gastroenterol Hepatol 2014;26: 82–87. 12. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, Mitchell RB, Promchiarak J, Simakajornboon N, Kaditis AG, Splaingard D, Splaingard M, Brooks LJ, et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med 2010;182: 676–683. 13. Amin R, Anthony L, Somers V, Fenchel M, McConnell K, Jefferies J, Willging P, Kalra M, Daniels S. Growth velocity predicts recurrence of sleep-disordered breathing 1 year after adenotonsillectomy. Am J Respir Crit Care Med 2008;177:654–659. 14. Van Hoorenbeeck K, Franckx H, Debode P, Aerts P, Ramet J, Van Gaal LF, Desager KN, De Backer WA, Verhulst SL. Metabolic disregulation in obese adolescents with sleep-disordered breathing before and after weight loss. Obesity (Silver Spring) 2013;21: 1446–1450. 15. Van Hoorenbeeck K, Franckx H, Debode P, Aerts P, Wouters K, Ramet J, Van Gaal LF, Desager KN, De Backer WA, Verhulst SL. Weight loss and sleep-disordered breathing in childhood obesity: effects on inflammation and uric acid. Obesity (Silver Spring) 2012;20:172–177. 16. Kheirandish-Gozal L, Peris E, Wang Y, Tamae Kakazu M, Khalyfa A, Carreras A, Gozal D. Lipopolysaccharide-binding protein plasma levels in children: effects of obstructive sleep apnea and obesity. J Clin Endocrinol Metab (In press) 17. Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrateproducing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS ONE 2013;8:e63388. 18. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013;10:645–655. 19. Kim J, Bhattacharjee R, Khalyfa A, Kheirandish-Gozal L, Capdevila OS, Wang Y, Gozal D. DNA methylation in inflammatory genes among children with obstructive sleep apnea. Am J Respir Crit Care Med 2012;185:330–338. 20. Wenig CM, Knopf H, Menn P. Juvenile obesity and its association with utilisation and costs of pharmaceuticals—results from the KiGGS study. BMC Health Serv Res 2011;11:340. 21. Tarasiuk A, Greenberg-Dotan S, Simon-Tuval T, Freidman B, Goldbart AD, Tal A, Reuveni H. Elevated morbidity and health care use in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2007;175:55–61. Copyright © 2014 by the American Thoracic Society
15
