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Cause And Effect Essay Example Obesity Hypoventilation

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27. Akashiba T, Akahoshi T, Kawahara S, Uematsu A, Katsura K, Sakurai S, et al. Clinical characteristics of obesity-hypoventilation syndrome in Japan: A multicenter study. Intern Med. 2006;45:1121–5.[PubMed]

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29. Laaban JP, Chailleux E. Daytime hypercapnia in adult patients with obstructive sleep apnea syndrome in France, before initiating nocturnal nasal continuous positive airway pressure therapy. Chest. 2005;127:710–5.[PubMed]

30. Resta O, Bonfitto P, Sabato R, De Pergola G, Barbaro MP. Prevalence of obstructive sleep apnoea in a sample of obese women: Effect of menopause. Diabetes Nutr Metab. 2004;17:296–303.[PubMed]

31. Verin E, Tardif C, Pasquis P. Prevalence of daytime hypercapnia or hypoxia in patients with OSAS and normal lung function. Respir Med. 2001;95:693–6.[PubMed]

32. Nowbar S, Burkart KM, Gonzales R, Fedorowicz A, Gozansky WS, Gaudio JC, et al. Obesity-associated hypoventilation in hospitalized patients: Prevalence, effects, and outcome. Am J Med. 2004;116:1–7.[PubMed]

33. Berg G, Delaive K, Manfreda J, Walld R, Kryger MH. The use of health-care resources in obesity-hypoventilation syndrome. Chest. 2001;120:377–83.[PubMed]

34. Mokhlesi B, Kryger MH, Grunstein RR. Assessment and management of patients with obesity hypoventilation syndrome. Proc Am Thorac Soc. 2008;5:218–25.[PMC free article][PubMed]

35. Imagawa S, Yamaguchi Y, Ogawa K, Obara N, Suzuki N, Yamamoto M, et al. Interleukin-6 and tumor necrosis factor-alpha in patients with obstructive sleep apnea-hypopnea syndrome. Respiration. 2004;71:24–9.[PubMed]

36. Osborn O, Gram H, Zorrilla E, Conti B, Bartfai T. Insights into the roles of the inflammatory mediators IL-1, IL-18 and PGE2 in obesity and insulin resistance. Swiss Med Wkly. 2008;138:665–73.[PubMed]

37. Punjabi NM, Beamer BA. C-reactive protein is associated with sleep disordered breathing independent of adiposity. Sleep. 2007;30:29–34.[PMC free article][PubMed]

38. Vgontzas AN. Does obesity play a major role in the pathogenesis of sleep apnoea and its associated manifestations via inflammation, visceral adiposity, and insulin resistance? Arch Physiol Biochem. 2008;114:211–23.[PubMed]

39. Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: Role of sleep disturbance and obesity. J Clin Endocrinol Metab. 1997;82:1313–6.[PubMed]

40. Zamarron C, Garcia Paz V, Riveiro A. Obstructive sleep apnea syndrome is a systemic disease: Current evidence. Eur J Intern Med. 2008;19:390–8.[PubMed]

41. Hatipoglu U, Rubinstein I. Inflammation and obstructive sleep apnea syndrome pathogenesis: A working hypothesis. Respiration. 2003;70:665–71.[PubMed]

42. Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci. 1998;18:559–72.[PubMed]

43. Shimura R, Tatsumi K, Nakamura A, Kasahara Y, Tanabe N, Takiguchi Y, et al. Fat accumulation, leptin, and hypercapnia in obstructive sleep apneahypopnea syndrome. Chest. 2005;127:543–9.[PubMed]

44. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–5.[PubMed]

45. Phipps PR, Starritt E, Caterson I, Grunstein RR. Association of serum leptin with hypoventilation in human obesity. Thorax. 2002;57:75–6.[PMC free article][PubMed]

46. Atwood CW. Sleep-related hypoventilation: t0 he evolving role of leptin. Chest. 2005;128:1079–81.[PubMed]

47. Campo A, Fruhbeck G, Zulueta JJ, Iriarte J, Seijo LM, Alcaide AB, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J. 2007;30:223–31.[PubMed]

48. Perez de Llano LA, Golpe R, Ortiz Piquer M, Veres Racamonde A, Vazquez Caruncho M, Caballero Muinelos O, et al. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesityhypoventilation syndrome. Chest. 2005;128:587–94.[PubMed]

49. Rapoport DM, Garay SM, Epstein H, Goldring RM. Hypercapnia in the obstructive sleep apnea syndrome: A reevaluation of the “Pickwickian syndrome” Chest. 1986;89:627–35.[PubMed]

50. Mokhlesi B, Tulaimat A, Evans AT, Wang Y, Itani AA, Hassaballa HA, et al. Impact of adherence with positive airway pressure therapy on hypercapnia in obstructive sleep apnea. J Clin Sleep Med. 2006;2:57–62.[PMC free article][PubMed]

51. Han F, Chen E, Wei H, He Q, Ding D, Strohl KP. Treatment effects on carbon dioxide retention in patients with obstructive sleep apnea-hypopnea syndrome. Chest. 2001;119:1814–9.[PubMed]

52. Kawata N, Tatsumi K, Terada J, Tada Y, Tanabe N, Takiguchi Y, et al. Daytime hypercapnia in obstructive sleep apnea syndrome. Chest. 2007;132:1832–8.[PubMed]

53. Garay SM, Rapoport D, Sorkin B, Epstein H, Feinberg I, Goldring RM. Regulation of ventilation in the obstructive sleep apnea syndrome. Am Rev Respir Dis. 1981;124:451–7.[PubMed]

54. Javaheri S, Colangelo G, Lacey W, Gartside PS. Chronic hypercapnia in obstructive sleep apnea-hypopnea syndrome. Sleep. 1994;17:416–23.[PubMed]

55. Zwillich CW, Sutton FD, Pierson DJ, Greagh EM, Weil JV. Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med. 1975;59:343–8.[PubMed]

56. Gold AR, Schwartz AR, Wise RA, Smith PL. Pulmonary function and respiratory chemosensitivity in moderately obese patients with sleep apnea. Chest. 1993;103:1325–9.[PubMed]

57. Ahmed Q, Chung-Park M, Tomashefski JF., Jr Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome. Hum Pathol. 1997;28:264–9.[PubMed]

58. Scheuller M, Weider D. Bariatric surgery for treatment of sleep apnea syndrome in 15 morbidly obese patients: Long-term results. Otolaryngol Head Neck Surg. 2001;125:299–302.[PubMed]

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A possible role for leptin or its analogues in the treatment of the obesity hypoventilation syndrome

The discovery of the anti-obesity hormone leptin (the name is derived from the Greek “leptos” meaning “thin”), the product of the ob gene,1 has fuelled a recent surge of interest in the mechanisms regulating mammalian fat stores. Leptin, a 16 kD protein of 167 amino acids with a similar crystal structure to cytokines,2 is produced primarily by white adipose tissue.3 The hormone elicits appetite suppression and weight loss.4,5 Leptin circulates in the plasma in the free and protein bound forms. Circulating plasma leptin levels reflect the amount of energy storage in adipose tissue and increase exponentially with increasing fat mass.6 Plasma leptin levels also respond to short term energy imbalance, increasing during periods of overfeeding and decreasing with fasting.7,8 The hormone activates specific receptors9 located at several sites throughout the brain, but plays a key role at the hypothalamus, in particular, where it alters the expression of several hypothalamic neuropeptides.10,11 One of these, neuropeptide Y (NPY), is a potent stimulator of food intake and activator of the hypothalamic-pituitary-gonadal axis. Leptin inhibits synthesis of hypothalamic NPY and downregulation of NPY is associated with appetite suppression, increased sympathetic nervous system outflow, and increased energy expenditure.12 Increasing leptin levels activate the thyroid hormone, gonadal, and growth hormone axes and suppress the pituitary-adrenal axis.13 It must be emphasised that human obesity is a complex disorder, probably resulting from both multigenetic and environmental predispositions, and that leptin deficiency is a very rare cause of human obesity.14 Indeed, circulating leptin levels are typically higher than normal in human obesity, indicating that it is a leptin resistant state.15 Even within the hypothalamus the NPY axis is clearly not a final common pathway for appetite control as the appetite stimulating orexins can induce feeding despite blockade of the NPY axis.16


Leptin production is regulated by several factors.17,18 Insulin and glucocorticoids act directly on adipocytes to increase leptin production, and chronic hyperinsulinaemia and increased cortisol turnover may underlie the increase in leptin expression observed in obesity. Similarly, the observed increase in serum leptin levels 4–7 hours after meals is probably related to increased circulating insulin in concert with the permissive effects of cortisol. Fasting results in decreased serum leptin levels—probably through falling insulin levels and the ability of catecholamines to decrease leptin expression (isoproterenol and β3 adrenergic receptor agonists reduce leptin production by adipocytes). Women have been noted to have higher serum leptin levels than men, and this could relate to a difference in body fat composition between the sexes or the permissive effects of oestrogen and progesterone on leptin production. Under conditions of constant enteral feeding, circulating leptin levels are higher at night than during the day; in addition to a small circadian influence, sleep is associated with an increase in plasma leptin levels in normal subjects.19


Apart from its anti-obesity effects, leptin exerts important physiological effects on the control of respiration.20 Ob/ob mice, which lack the gene responsible for production of leptin, demonstrate hypoventilation in addition to marked obesity (Paco2 on average 1.5 kPa higher than wild type mice during wakefulness).21 Furthermore, these animals have an impaired hypercapnic ventilatory response (HCVR) during both wakefulness and sleep. During REM sleep the HCVR is absent in ob/ob mice. This impairment of the HCVR in ob/ob mice relative to wild type mice cannot be attributed to the mechanical effects of obesity as it precedes the development of the latter.20 Furthermore, leptin replacement studies in ob/ob mice have shown improvements in baseline minute ventilation and HCVR during wakefulness and sleep under experimental conditions which prevented a concomitant weight change in the animal.21,22


The high prevalence of obstructive sleep apnoea (OSA) in obese humans23 and the established role of leptin as a respiratory stimulant and appetite suppressant in the mouse raised the possibility that sleep apnoea could be a leptin deficient state. Several groups have shown, however, that patients with OSA have even higher circulating leptin levels (approximately 50%) than subjects without OSA matched for age and body mass index.24–26 This finding suggests that, independent of the known relationship between obesity and increased circulating leptin levels, OSA could represent a leptin resistant state. Two groups have shown that treatment of OSA with nasal continuous positive airway pressure (NCPAP) for 6 months is associated with a reduction in circulating leptin to a level similar to individuals without OSA.24,26 The physiological explanation for the fall in circulating leptin levels in patients with OSA treated with NCPAP has not been fully elucidated, but some plausible explanations include a reduction in visceral fat accumulation,27 reduction in muscle sympathetic nerve activity,28 reduced level of stress,29 and a change in insulin responsiveness30 with NCPAP treatment. The fact that circulating leptin levels fall with NCPAP treatment of OSA, however, suggests that OSA may be a stimulant of leptin production rather than a consequence of the action of leptin.

The obesity hypoventilation syndrome (OHS) is characterised by obesity and hypercapnia while awake in the absence of an alternative neuromuscular, mechanical, or metabolic explanation for hypoventilation. Most patients with OHS suffer from OSA and in many (but not all) cases treatment of OSA with NCPAP restores daytime eucapnia.31,32 In some patients OHS cannot be explained on the basis of OSA,33 and daytime hypercapnia appears to result from inadequate physiological compensation for the development of obesity alone. This condition remains an enigma. Why do certain obese individuals hypoventilate during wakefulness while others with similar or greater levels of obesity do not? Could leptin be the key to understanding this conundrum?

The paper by Phipps and colleagues34 in this issue of Thorax contributes an interesting additional piece of information. The authors discovered that the mean serum leptin level was twice as high in a group of 12 hypercapnic obese humans as in a group of 44 eucapnic individuals with a similar percentage of body fat. Both groups had a mean apnoea-hypopnoea index in the severe OSA range but were not significantly different from each other. This finding raises the intriguing possibility that a profound degree of leptin resistance (more than that observed with eucapnic obesity or OSA alone) underpins the development of OHS. If this is the case, then leptin or analogues of leptin could have a role in the treatment of OHS. However, this preliminary finding by Phipps and colleagues will require further exploration to determine whether the marked increase in serum leptin levels found in patients with OHS truly signals a causative mechanism or whether it is simply an epiphenomenon of the condition. In particular, it would be interesting to know whether serum leptin levels are raised in patients with OHS but without significant OSA compared with patients with a similar level of simple obesity, whether leptin levels are increased in non-obese patients with hypoventilation, and whether the serum leptin level in patients with OHS reverts with treatment to the level observed in simple obesity, as might be expected if the increased serum leptin levels are a consequence rather than a causative factor in OHS. These questions and others with regard to the potential respiratory modulating role of leptin in humans, an exciting new research area, will probably find an answer within the next few years.

A possible role for leptin or its analogues in the treatment of the obesity hypoventilation syndrome


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