Obesity and OSA: More Than BMI

Various factors play a role in obesity and obstructive sleep apnea such as excessive daytime sleepiness, fatigue, and endocrine dysfunction.

Obesity is a growing problem in the United States. As defined by the National Institutes of Health (NIH), a person with a body mass index (BMI) between Ž25 and 29.9 is considered to be overweight and a person with a BMI of Ž30 is considered obese. Approximately two thirds of the US population is at least overweight and half are obese.¹ Obesity is also the greatest risk factor for obstructive sleep apnea (OSA). While approximately 2% to 4% of the population is estimated to have OSA, the prevalence increases to 20% to 40% in the obese population.² Current issues involving obesity and OSA include clinical predictors of OSA, physiological contributors to OSA, and other factors that may be confounded by OSA that contribute to obesity. Excessive daytime sleepiness (EDS) and fatigue, which are the main symptoms of OSA, are known to contribute to overeating and being sedentary. Habitually, people eat as a pick-me-up. These habits over time result in obesity, which worsens sleep apnea, leading to a progression of severity for both conditions. Also related to OSA and obesity is the occurrence of endocrine dysfunction, which in turn exacerbates and/or causes hypertension, cardiac problems, and possibly insulin resistance.

Predictors of OSA
Despite the strong association between obesity and OSA, BMI does not consistently correlate with the severity of OSA as measured by the number of apneas and hypopneas per hour of sleep (apnea-hypopnea index—AHI).³ One explanation may be that BMI measures only weight and height and does not include any measure of body composition (muscle versus adipose tissue). Also, BMI consists only of the height and weight ratio and is not a measure of distribution of weight on the patient’s body. Common indicators of OSA in the general population, such as snoring and EDS, do not predict OSA in the obese population. As polysomnography (PSG) is expensive, inconvenient, and often a limited resource, several factors have been investigated to predict OSA. Dixon and colleagues⁴ studied patients with a BMI of Ž35 (n=99). They measured reported symptoms through sleep history (habitual snoring, observed sleep apnea, nocturnal choking, waking unrefreshed, morning headaches, EDS, and poor sleep quality). Biochemical markers of metabolic syndrome that were measured included fasting lipid profile, plasma glucose, glycosylated hemoglobin, plasma, insulin, and liver function panel. Anthropomorphic measurements of weight, height, and neck, waist, and hip circumference were also taken. Lung volume tests included lung volume, single breath carbon monoxide diffusion, maximal inspiratory and expiratory pressures, and flow-loop spirometry. The study found that the single best predictor of an AHI of Ž15 was a neck circumference of Ž43 cm. Other studies have also shown that neck circumference and waist/hip ratio are also predictors of OSA.² Other significant predictors were a BMI of Ž45, age, male gender, observed sleep apnea, HbA1C levels of Ž6% (glycosylated hemoglobin), and a fasting plasma insulin concentration of Ž28 mmol/L. The authors proposed a six point scale assigning a value of 1 to each of these variables. Significant sleep apnea was defined as an AHI of Ž15. In the study, all patients with significant sleep apnea had a score of at least 2. This study provides useful predictive information for physicians in assessing patients for polysomnography and further follow-up treatment. The relationship between apnea severity and metabolic parameters also indicates the widespread impact of OSA and resulting sleep disruption.

Obesity factors that exacerbate OSA
Among the risk factors for OSA, obesity is probably the most important. Seve-ral studies have consistently found an association between increased body weight and risk of OSA. Tomographic scanned images have shown that obesity causes increased fatty deposits in the pharyngeal area.⁴ The deposits encroach on the airway and contribute to airway narrowing. Also, in obese patients as compared to normal controls, fat deposits appear to alter the shape of the upper airway without necessarily reducing the cross-sectional area. Rodenstein et al⁵ used magnetic resonance imaging to investigate differences between obese and normal controls. Coronal sections of awake OSA patients showed elliptical-shaped airways with long axes that were oriented anteroposteriorly; normal controls had airways that were oriented transversely. Studies using computed tomography have produced similar results^4,6; however, another study by Schafer et al,⁷ consisting of 85 males at risk for OSA, did not find a significant correlation between parapharyngeal fat deposits and AHI. Clinically significant OSA was indicated by AHI Ž10 for this study. The authors cite that differences between their conclusions and others may be due to the large sample size of their study, and/or differences in the techniques performed to measure pharyngeal fat deposits. Different cutoff points for clinically significant AHI may also contribute to the different conclusions (AHI Ž15 versus AHI Ž10). Also, the study by Schafer et al consisted of only males; therefore, gender differences may also account for contradictory results.

During sleep, especially rapid eye movement (REM) sleep, support for the airway is compromised due to muscle atonia. A narrowing in the upper airway due to fat deposits and/or decreased rigidity of the tissue due to the presence of adipose tissue may predispose patients to sleep apnea. Second, centrally distributed fat deposition is also proposed as a cause of increased pressure on the thorax and lungs. This leads to decreased lung volume and expenditure of greater effort for respiration. Therefore, distribution of fat in obese patients may be a better predictor than BMI. Other consequences of obesity that are related to OSA include increased respiratory resistance, increased CO2 production, increased O2 consumption, reduced lung volumes, consequent hypoxia, and overall decreased respiratory system compliance.^8,9

OSA Factors that may exacerbate obesity
Leptin Resistance
Evidence also suggests that OSA may contribute to obesity. Patients recently diagnosed with OSA often report recent weight gain. Weight gain in patients with OSA may be related to diet and lifestyle. In addition, weight gain may also be related to endocrine dysfunction. Specifically, leptin is a protein produced by adipose tissue that circulates through the blood and acts on the hypothalamus to inhibit eating.¹⁰ It is associated with suppressed appetite and increased energy expenditure; hence, a propensity for weight loss. In addition, leptin directly affects respiratory control. Sleep-related breathing depression was seen in leptin-deficient mice; specifically, they lacked respiratory response to hypercapnia.¹¹ This was particularly evident in REM sleep. Obese individuals have high leptin levels, and it is presumed that their obesity may persist because of a resistance to the appetite suppressant and the metabolism-increasing effects of leptin (“leptin resistance”). Male patients with OSA have approximately 50% higher leptin levels than similarly obese males without OSA.¹² Therefore, it is likely that sleep apnea is accompanied by leptin resistance or a propensity for leptin resistance. This factor also exists with the obesity condition alone and may be compounded in patients with obesity and OSA. Increased levels may also directly increase the occurrence of apneic events. Therefore, this describes the likelihood of a feed-forward mechanism whereby OSA and obesity contribute to each other leading to a progression in severity for both. Leptin is also proposed as an important link between OSA and cardiovascular implications.

Insulin Resistance
OSA may also impair endocrine functions such as glucose tolerance. Patients with OSA tend to have higher fasting blood glucose levels, insulin, and glycosylated hemoglobin, independent of body weight; however, the data are inconsistent. In some studies, the severity of OSA has correlated with the degree of insulin resistance. This may be due to a hypoxia-induced hormonal stress reaction, which decreases tissue insulin sensitivity. However, upper body obesity is associated with both insulin resistance and sleep apnea; the distribution of fat that contributes to the severity of both conditions is a confounding factor. Impaired glucose tolerance in patients with OSA may be linked to sleep deprivation, sympathetic nervous system activation, and leptin resistance.^13,14 Also, consistent improvement of glucose tolerance with continuous positive airway pressure (CPAP) therapy has not been shown.¹⁵ The lack of consistency in results may be due to variations in the measurements of glucose tolerance, food intake, exercise habits, and other factors that may affect glucose metabolism between different studies and within trials.

Metabolic Syndrome
Key factors of metabolic syndrome are also impacted by OSA. While obesity appears to be the main risk factor for metabolic syndrome, OSA has been shown to independently exacerbate markers of metabolic syndrome (obesity, triglyceride levels, high-density lipoprotein cholesterol [HDL], blood pressure, and fasting glucose levels). Independent of the effects of obesity, OSA has been shown to exacerbate these conditions and thereby may influence obesity and metabolic syndrome.

Weight loss and OSA
The relationship between obesity and OSA also is reinforced by studies of the effects of weight on OSA. In a population-based prospective study of randomly selected Wisconsin residents (n=690), a 10% increase weight gain was associated with a sixfold increase in the odds of developing sleep apnea. The same study also showed that a 10% weight loss predicted a 26% decrease in AHI.¹⁶ Although large-scale studies have not been performed in the obese population, several other small studies and reports have illustrated a similar relationship between weight loss and OSA.¹⁷ In studies investigating the effects of weight loss on sleep-disordered breathing, consistent improvements in parameters have been shown. Reduction in AHIs and normalization of sleep architecture occurred in association with varying amounts of weight loss. Second, weight loss and decrease in visceral body fat have resulted from CPAP therapy.¹⁸ The factors underlying this relationship are probably multifaceted. They may be related to changes in lifestyle and energy levels in addition to improvement in sleep disordered breathing and sleep architecture.

Conclusion
Obesity is a serious national health issue affecting approximately one third of the population. The pathological changes that occur as a result of obesity are significant and affect multiple functions including but not exclusive to the respiratory, endocrine, and cardiovascular systems. Excess adipose tissue characteristic of obesity may contribute to OSA by encroaching on organs (airway narrowing and decrease in lung volume). Endocrine systems are impacted by changes in leptin levels that result from excess adipose tissue. This may further impact breathing centers and cardiovascular wellness. Other problems associated with obesity include glucose metabolism. All of these issues have been shown to be exacerbated by OSA and the resulting disruption of sleep architecture. Fortunately, normalization of these parameters has been demonstrated by studies involving weight loss. Also, weight loss has been demonstrated through treatment of OSA. Just as obesity and OSA are interrelated by several factors, correcting one or the other appears to be beneficial to both.

Mary L. Marzec, RPSGT, is an associate in sleep research at the University of Michigan, General Clinical Research Center, Ann Arbor.

References
1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-1727.
2. Kyzer S, Charuzi I. Obstructive sleep apnea in the obese. World J Surg. 1998;22:998-1001.
3. Fogel RB, Malhotra A, Dalagiorgou G, et al. Anatomic and physiologic predictors of apnea severity in morbidly obese subjects. Sleep. 2003;26:150-155.
4. Dixon JB, Schachter LM, O’Brien PE. Predicting sleep apnea and excessive day sleepiness in the severely obese: indicators for polysomnography. Chest. 2003;123;4:1134-1141.
5. Rodenstein D, Dooms G, Thomas Y, et al. Pharyngeal shape and dimensions in healthy subjects, snorers, and patients with obstructive sleep apnea. Thorax. 1990;45;722-727.
6. Schwab R, Gefter W, Hoffman E, Guptta K, Pack A. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis. 1993;148:1385-1400.
7. Schafer H, Pauleit D, Sudhop T, et al. Body fat distribution, serum leptin, and cardiovascular risk factors in men with obstructive sleep apnea. Chest. 2002;122;3:829-839.
8. Kessler R, Chauouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited. Chest. 2001;120:369-376.
9. Berger K, Ayappa I, Chatr-amontri B, et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest. 2001;120:1231-1238.
10. O’Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith PL. Leptin, obesity and respiratory function. Respir Physiol. 2000;119:173-170.
11. Considine RV, Sinha MK, Heiman ML, et al. Immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292-295.
12. Philips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive and weight gain in obstructive sleep apnea. Am J Physiol. 2000;279:H234-H237.
13. Nagai Y, Nakatsumi Y, Abe T, Nomura G. Is the severity of obstructive sleep apnoea associated with the degree of insulin resistance? Diabet Med. 2003;20:80-82.
14. Tiihonen M, Partinen M, Narvanen S. The severity of obstructive sleep apnoea is associated with insulin resistance. J Sleep Res. 1993;2:56-61.
15. Smurra M, Philip P, Taillard J, et al. CPAP treatment does not affect glucose-insulin metabolism in sleep apneic patients. Sleep Medicine. 2001;2:207-213.
16. Peepard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA. 2000;284:3015-3021.
17. Strobel J, Rosen RC. Obesity and weight loss in obstructive sleep apnea: a critical review. Sleep. 1996;19:104-115.
18. Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation. 1999;100:706-712.