ORIGINAL ARTICLE
METABOLIC SYNDROME AND RELATED DISORDERS Volume X, Number X, 2015 Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/met.2014.0161
Impact of Continuous Positive Airway Pressure Treatment on Leptin Levels in Patients with Obstructive Sleep Apnea Syndrome ¨ mmu¨gu¨lsu¨m Can, MD,3 Sxebnem Yosunkaya, MD,1 Hacer Kuzu Okur, MD,2 U 4 Adil Zamani, MD, and Ruhusxen Kutlu, MD 5
Abstract
Background: There is growing evidence that leptin regulation is altered in obstructive sleep apnea syndrome (OSAS). Several potential mechanisms have been purported to explain how sleep apnea may alter leptin levels. We investigated whether repeated apneas, hypoxia, or excessive daytime sleepiness influenced the levels of leptin in OSAS patients. We also evaluated whether a 3-month continuous positive airway pressure (CPAP) treatment affected leptin levels in patients. Methods: Randomly selected 31 untreated, otherwise healthy male, overweight [body mass index (BMI) > 25 kg/m2] obstructive sleep apnea syndrome (OSAS) patients [apnea–hypopnea index (AHI) ‡ 15] and 25 control (AHI < 5) were included in this study. To confirm the diagnosis, all subjects underwent standard polysomnography. Serum samples were taken at 07:00–08:00 a.m. after overnight fasting. The OSAS patients that had regular CPAP treatment (n = 26) were re-evaulated 3 months later. Results: Leptin levels (50.5 – 17.5 grams/L in OSAS and 56.3 – 25.5 grams/L in controls) and lipid profiles (TC, TGs, HDL-C, and LDL-C) between patient and control groups did not differ (P > 0.05). Leptin levels were not correlated with the AHI, oxygen saturation, or excessive daytime sleepiness. CPAP treatment did not significantly change the (BMI), waist and neck circumference, or leptin levels in OSAS patients. Furthermore, we found no correlation between the decrease in serum leptin levels and parameters that were improved by CPAP treatment. Conclusion: Leptin levels and lipid profile of overweight subjects with and without OSAS were not different, and our results suggest that OSAS-related parameters and CPAP treatment do not play a significant role in the serum leptin levels. for metabolic abnormalities independent of obesity, but pathogenesis of this metabolic consequence has not yet been clearly defined.2 Leptin, an adipocyte-derived hormone, regulates body weight and energy expenditure and acts via the leptin receptor (LEPR).6 Several systemic effects are attributed to leptin. Increased plasma leptin levels and leptin resistance have been related to obesity, arterial hypertension, and glucose and lipid metabolism pathogenesis.7 Serum leptin physiological concentrations in obese people compared to normal weight people are 20–30 times higher. A study, conducted in the United States, that examined the relationship between body mass index (BMI) and leptin found that
Introduction
O
bstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxemia, sleep fragmentation, and increased sympathetic activity that occur due to repetitive collapse of the upper airway during sleep.1 Obesity and particularly visceral obesity are major risk factors for OSAS, and obesity-related metabolic disorders are also highly associated with OSAS.2 OSAS itself is a situation that creates predisposition for progressive obesity,2–4 which is thought to result from changes in serum leptin levels or leptin receptor insensitivity.5 Recent studies have reported that OSAS is associated with risk factors 1
Necmettin Erbakan University, Meram Medical Faculty, Department of Chest Disease, Konya, Turkey. Fatih Sultan Mehmet Education and Research Hospital, Department of Chest Diseases and Thoracic Surgery, Istanbul, Turkey. 3 Konya Education and Research Hospital, Department of Biochemistry, Konya, Turkey. 4 Necmettin Erbakan University, Meram Medical Faculty, Department of Chest Disease, Konya, Turkey. 5 Necmettin Erbakan University, Meram Medical Faculty, Department of Family Physician, Konya, Turkey. 2
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leptin levels in healthy lean individuals were 10 ng/mL or lower; their leptin levels were lower than those of healthy overweight subjects (10–30 ng/mL), whereas leptin levels of obese individuals were 30 ng/mL or higher.8 The association between obesity and leptin is well documented, but the role of OSAS in leptin level remains controversial. There is growing evidence that leptin regulation is altered in OSAS.9–12 Several potential mechanisms have been purported to explain how sleep apnea may alter leptin levels. Recent evidence suggests that leptin levels can be increased in response to hypoxia.11 Obstructive apnea or hypopnea is often terminated by an arousal, which is accompanied with an increase in the sympathetic activity.2 Sympathetic nervous system activation may be associated with abnormal leptin levels that are related to OSAS.2 Additionally, several studies have documented a decrease in fasting leptin levels in OSAS patients that have been placed on continuous positive airway pressure (CPAP) treatment.13–15 On the contrary, some studies have shown that neither high levels of leptin in OSAS patients nor a correlation between any OSAS-related parameters and leptin levels16–18 remained steady despite the treatment of OSAS with CPAP therapy.17–19 These apparently contradictory results may stem from the fact that leptin levels are influenced by a multitude of factors, such as sex, body weight, hypertension, and some medications.20,21 Most previous case–control studies did not adequately control for these confounding characteristics. We developed the current study to investigate the effects of CPAP treatment on leptin levels in OSAS patients while carefully controlling for age, sex, and BMI, and also while excluding individuals with clinically demonstrable comorbid diseases (e.g., diabetes and hypertension). We hypothesized that sleep apnea and hypopnea, intermittent hypoxemia, or sleep fragmentation—the primary concomitants of sleep apnea—play an etiologic role of increase in leptin. Specifically, we investigated whether repeated apneas, hypoxia, or excessive daytime sleepiness (EDS) influenced the levels of leptin in OSAS patients. We also evaluated whether a 3-month CPAP treatment reduced leptin levels in patients.
Material and Methods Subjects The following study protocols were approved by our faculty research ethics committee. Participation in the study was voluntary, and all subjects provided informed written consent. Patients were recruited prospectively from a group of individuals who attended our sleep unit for the investigation of possible OSAS. Male subjects recruited for the study were either overweight or obese [body mass index (BMI > 25 kg/m2]22 and had not previously been diagnosed with or treated for OSAS; none of them were included in a slimming program for weight control. Patients were excluded from the study if they met any of the following criteria: History of cerebrovascular or cardiovascular disease, diabetes (previous physician diagnosis and fasting blood glucose > 126 mg/dL), moderate-to-severe hypertension (previous physician diagnosis and measured blood pressure > 140/90 mmHg), chronic inflammatory diseases, current use of diabetic, antihypertensive, or lipidlowering medications; age < 18 or > 70 years; diagnosis
YOSUNKAYA ET AL.
with central sleep apnea or Cheyne–Stokes respiration; clinical manifestation of severe chronic obstructive pulmonary disease (COPD) or asthma [forced expiratory volume in 1 sec (FEV1) < 70% predicted]. The people who were referred from other clinics with suspected sleep apnea but their apnea–hypoxia index (AHI) value was < 5 were defined as controls (n = 25). Those with AHI ‡ 15 were diagnosed as having moderate-to-severe OSAS (n = 31) and were eligible for CPAP treatment.1 The Epworth sleepiness scale (ESS) was used to assess subjective sleepiness. This test is scored as the possibility of falling asleep in eight different situations, ultimately 0 (not sleepy) to 24 (very sleepy). Values greater than 10 in this test of excessive daytime sleepiness (EDS) is indicative.23 Each subject was examined by a lung specialist. The following parameters were measured: Body weight, measured on subjects wearing only underwear and without shoes, by means of a steel yard scale (precision – 100 grams); body height, measured on subjects without shoes by means of a stadiometer (precision – 1 mm). BMI was calculated as the ratio between weight (in kilograms) and the square of height (in meters); waist circumference (WC) was measured by placing a flexible tape midway between the lowest rib and the iliac crest. Neck circumference (NC) was measured at the level of the superior border of the cricothyroid membrane using a flexible tape measure. Systolic (SBP) and diastolic (DBP) blood pressure was measured according to standard conditions using a sphyngomanometer; three measurements were performed at intervals of 2–5 min and then mean of the three values was calculated. Co-morbid disorders were identified with lung function tests, chest X-rays, and electrocardiography.
Biochemical measurements In the morning between 07:00 and 08:00 a.m. after an allnight polysomnography, we collected fasting blood samples from all study subjects to analyze the following biochemical parameters—total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and lowdensity lipoprotein cholesterol (LDL-C). The measurements were carried out by spectophotometric method using commercial kits with a Beckman Synchron Dx800 (Beckman Coulter, USA) through standard laboratory methods. For serum leptin analysis, blood samples were collected and centrifuged immediately at 1800 · g for 20 min. Serum specimens were stored at - 80C until analysis. Leptin levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (BioVendor-Laboratorni-medicina a.s., Modrice, Czech Republic). To assay for the presence of co-morbid disorders, we also performed a complete blood count and ran tests examining liver, renal, and thyroid functions.
Sleep study Overnight polysomnography (PSG) monitoring was performed on all participants using the VIASYS SleepScreen System (VIASYS Healthcare, Inc., Hoechberg, Germany) and included the following variables: Electroencephalogram (four channels: C3/A2-, C4/A1-, O1/A2, and O2/A1); electro-oculogram (two channels: right, left); electromyogram of submental muscles (three channels); electromyogram of the anterior tibialis muscle of both legs (two channels);
LEPTIN LEVELS IN OSAS PATIENTS
electrocardiogram; and airflow (assessed with an oronasal cannula and a thermistor). Chest and abdominal efforts (two channels) were measured using thoracic and abdominal strain gauges, and arterial oxyhemoglobin saturation (SaO2: one channel) was measured with a finger probe by pulse oximetry. Sleep staging and respiratory event scoring were performed manually by a single doctor according to the guidelines of the American Academy of Sleep Medicine.24 Apneas were defined as the complete cessation of airflow ‡ 10 sec; hypopneas were defined as a > 30% reduction in nasal–oral airflow with an associated ‡ 3% decrease in oxygen saturation or arousal.24 During PSG, the following variables were recorded: Sleep efficiency (SE), calculated as the total sleep time multiplied by time spent in bed; minimum oxygen saturation, the lowest oxygen saturation recorded during sleep; mean oxygen saturation (mean SaO2); the average oxygen saturation recorded during sleep; and time SaO2 ‡ 90% (SaO2 ‡ 90), defined as the total sleep time multipled by time spent of sleep time at ‡ 90% of the saturation level.
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tionship between change of circulating leptin levels and change of physiological/sleep parameters during 3 months. Significance was defined as P < 0.05.
Results General findings Characteristics and clinical findings from all study subjects are shown in Table 1. NC, BMI, blood pressure, sleep efficiency, and ESS scores were similar in both the control and treatment groups. OSAS patients had significantly larger WC values than control individuals (110.8 – 8.5 vs. 105.1 – 5.7 cm; P < 0.001); however, the average WC in both groups was over the accepted abdominal obesity limit of 102 cm.26 OSAS patients had lower minimum SaO2 and mean SaO2 rates and higher AHI rankings than individuals in the control group (all P < 0.001). Among OSAS patients, AHI was positively correlated with BMI and both WC and NC (r = 0.385, r = 0.136, and r = 0.345, respectively; P < 0.05), but negatively correlated with mean SaO2 (r = - 0.412, P = 0.017) (Table 2).
CPAP treatment Automatic titration of the CPAP pressure (AutoSet Spirit, ResMed Corp., San Diego, CA) was performed in the sleep laboratory under polysomnographic control while patients were being monitored by a trained sleep laboratory technician. The optimum pressure required to prevent the majority of apneas, hypopneas (AHI < 10 events/hr), and snoring was confirmed for each patient; this was usually the 95th percentile of pressure.25 After titration, each subject received a CPAP machine and related accessories and received instructions to use the machine for 3 months. Hour meter readings were used to assess patient compliance with the CPAP treatment regime. Daily duration of CPAP use was 5.5 – 0.7 hr [mean – standard deviation (SD). The majority of our patients met the criteria required to consider them ‘‘regular’’ CPAP users. Our final patient sample size was n = 26; five individuals were excluded because of poor CPAP compliance (n = 2), refusal to undergo re-PSG at the end of the study (n = 1), and failure to follow up (n = 2). At the end of the 3-month treatment period, overnight PSG monitoring was performed on patients who use regular CPAP (n = 26) using the VIASYS SleepScreen System, and blood samples were collected again at the end of the PSG recording between 07:00 and 08:00 a.m.
Statistical analysis Data were analyzed using SPSS version 17.0 software (SPSS Inc, Chicago, IL). The results are expressed as mean – SD. The Kolmogorov–Smirnov test was used to assess whether the data were normally distributed. For normally distributed data, we used independent t-tests to investigate differences between OSAS (n = 31) and control (n = 25) groups. AHI parameters were compared between OSAS and control groups using the Mann–Whitney U-test because of these data were not normally disturbed. BMI, WC, NC, leptin levels, and polysomnographic parameters were compared between conditions before and after CPAP using paired t-tests. Comparisons before and after CPAP included the data of 26 participants. Pearson correlations and regression analyses were used to investigate the rela-
Serum leptin and lipid levels Subjects in the control (n = 25) and patient (n = 31) groups had similar levels of TC, TGs, HDL-C, and LDL-C (all P > 0.649) (Table 3). In this study, we demonstrated that the mean value of serum leptin was 50.5 – 17.5 (ng/mL) in OSAS patients and 56.3 – 25.5 (ng/mL) in the nonapneic controls, respectively. This difference was not significant (P = 0.783). Leptin levels were not correlated with AHI, BMI, WC, ESS, minimum SaO2, mean SaO2, or SaO2 ‡ 90 (all P > 0.153; Table 2). Among OSAS patients only, serum leptin levels were positively correlated with NC (r = 0.336, P = 0.048) (Table 2).
Table 1. Characteristics and Clinical Findings of OSAS Patients and Control Individuals OSAS patients n = 31
Controls n = 25
Mean – SD
Mean – SD
Age (year) 43.3 – 8.5 NC (cm) 44.5 – 2.9 WC (cm) 110.8 – 8.5 BMI (kg/m2) 32.9 – 3.6 AHI (event/hr) 44.10 (17.5–99)a Minimum 72.8 – 10.3 SaO2 (%) Mean SaO2 (%) 88.4 – 2.9 SaO2 ‡ 90 (TST%) 47.6 – 29.2 SE 81.0 – 9.4 ESS 10.3 – 5.6 SBP (mmHg) 124.0 – 17.0 DBP (mmHg) 75.0 – 13.0 a
P
41.5 – 9.5 0.100 43.3 – 3.0 0.090 105.1 – 5.7 < 0.001 31.9 – 2.5 0.280 3.75 (0–5)a < 0.001 85.5 – 4.5 < 0.001 92.9 – 2.2 < 0.001 91.9 – 12.2 < 0.001 83.8 – 8.3 0.240 7.6 – 5.6 0.070 119.0 – 13.0 0.150 72.0 – 10.0 0.220
Median (min-max). OSAS, obstructive sleep apnea syndrome; WC, waist circumference; NC, neck circumference; BMI, body mass index; AHI, apnea– hypopnea index; mean SaO2, the average oxygen saturation recorded during sleep; TST, total sleep time; SE, sleep efficiency; SaO2 ‡ 90, amount of total sleep time spent at ‡ 90% saturation; ESS, Epworth sleepiness scale; SBP, systolic blood pressure; DBP, diastolic blood pressure.
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YOSUNKAYA ET AL.
Table 2. Results from Correlations Between Physiological/Sleep Parameters and Both AHI and Leptin Levels in OSAS Patients (n = 31) Leptin
WC (cm) NC (cm) BMI (kg/m2) AHI (event/h) Minimum SaO2% Mean SaO2% SaO2 ‡ 90 (TST%) ESS Leptin
Table 4. OSAS Patient Characteristics Before and After 3 Months of CPAP Treatment Pretreatment n = 26
AHI
r
p
r
p
0.254 0.336 0.271 - 0.231 - 0.224 - 0.005 - 0.049 0.091 —
0.153 0.048 0.128 0.195 0.210 0.978 0.787 0.616 —
0.136 0.345 0.385 — - 0.096 - 0.412 - 0.333 0.640 - 0.231
0.041 0.043 0.040 — 0.587 0.017 0.680 0.725 0.195
AHI, apnea–hypopnea index; OSAS, obstructive sleep apnea syndrome; WC, waist circumference; NC, neck circumference; BMI, body mass index; mean SaO2, average oxygen saturation recorded during sleep, SaO2 ‡ 90, amount of total sleep spent at ‡ 90% of saturation level; TST, total sleep time; ESS, Epworth sleepiness scale.
Results of CPAP treatment Patients who underwent 3 months of CPAP therapy (n = 26) did not experience any changes in BMI or WC and NC (P = 0.137, P = 0.182, and P = 0.201, respectively) (Table 4). On the other hand, ESS was significantly lower after CPAP therapy (P < 0.001); patients also displayed significant improvements in AHI rank, mean SaO2, minimum SaO2, and SaO2 ‡ 90 (P < 0.001, P = 0.042, P < 0.001, and P < 0.001, respectively) (Table 4). A 10% decrease in leptin levels observed in patients who received regular OSAS treatment was nonsignificant (P = 0.279) (Table 4). Reductions in leptin levels were not associated with variations in AHI, ESS, minimum SaO2, mean SaO2, or SaO2 ‡ 90 among OSAS patients who underwent 3 months of CPAP therapy (all P > 0.207) (Table 5).
Discussion This study examined the question of whether leptin levels differ between people with and without OSAS who are matched for age, sex, and BMI. We showed that OSAS patients and nonapneic controls have similar serum leptin levels (50.5 – 17.5 and 56.3 – 25.5). In addition, we found
– SD
Mean Leptin (ng/mL) Minimum SaO2 (%) Mean SaO2 (%) SaO2 ‡ 90 (TST%) ESS AHI (event/hr) WC (cm) NC (cm) BMI (kg/m2)
45.7 97.7
7.3 5.7
0.279 < 0.001
88.2 47.7
3.13 29.9
94.1 96.0
1.7 6.6
< 0.001 < 0.001
10.9 5.8 5.9 1.7 < 0.001 37.7 (17.5–85.3)a 2.0 (0–10)a < 0.001 114.8 5.3 112.9 6.1 0.182 44.6 2.9 44.3 3.0 0.201 33.0 4.0 32.0 3.5 0.137
a
Median (min-max). OSAS, obstructive sleep apnea syndrome; CPAP, continuous positive airway pressure; SD, standard deviation; mean SaO2, average oxygen saturation recorded during sleep; SaO2 ‡ 90, amount of total sleep time spent at ‡ 90% saturation level; TST, total sleep time; ESS, Epworth sleepiness scale; AHI, apnea–hypopnea index; WC, waist circumference; NC, neck circumference; BMI, body mass index.
that 3 months of active CPAP treatment had no significant effect on the levels of leptin, although it did lead to improvements in PSG parameters and subjective sleepiness. Previously, studies stated that leptin levels for healthy normal-weight individuals were 3–5 ng/mL7 or lower than those of obese individuals, which were 30 ng/mL and higher.8 In this study, neither the OSAS group (before and after CPAP treatment) nor the control group (nonapneic) subjects had leptin levels below 30 ng/mL. Furthermore, we found that leptin levels were independent of both AHI and oxygen saturation levels in OSAS patients. Although a statistically significant association between BMI and leptin levels was not found in this study, this situation is probably due to the fact that the range of BMI values was not wide and was more or less similar between the two groups. Thus, we thought that the increase in leptin levels in patients with OSAS was not connected to OSAS-dependent
Table 5. Relationships Between Serum Leptin Levels and Physiological Parameters Impacted by CPAP Treatment Correlation with DLeptin r
Mean
– SD
P
TC (mg/dL) 201.8 TGs (mg/dL) 175.4 LDL-C (mg/dL) 130.2 HDL-C (mg/dL) 38.5 Leptin (ng/mL) 50.5
42.5 83.3 31.5 8.1 17.5
199.4 168.1 127.3 38.9 56.3
30.9 89.5 27.1 6.0 25.5
0.672 0.958 0.649 0.817 0.783
OSAS, obstructive sleep apnea syndrome; TC, total cholesterol; TGs, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
P
16.4 10.3
OSAS patients Control individuals n = 31 n = 25 – SD
Mean – SD
49.7 71.9
Table 3. Results from the Biochemical Analyses of OSAS Patients and Control Individuals
Mean
Posttreatment n = 26
D Minimum SaO2 D Mean SaO2 D SaO2 ‡ 90 (TST%) D ESS D AHI
p
Regression with DLeptin t
p
b
- 0.210 0.313 - 0.845 0.410 - 0.301 - 0.138 0.512 - 0.310 0.760 - 0.605 - 0.171 0.413 - 0.472 0.643 - 0.115 0.261 0.207 1.073 0.298 1.068 - 0.182 0.384 - 1.428 0.172 - 0.338
CPAP, continuous positive airway pressure; D, variation observed as a result of the CPAP treatment; mean SaO2, the average oxygen saturation recorded during sleep; SaO2 ‡ 90, the amount of total sleep time spent at ‡ 90% of saturation level; TST, total sleep time; ESS, Epworth sleepiness scale; AHI, apnea–hypopnea index.
LEPTIN LEVELS IN OSAS PATIENTS
factors. Obesity is the key determinant of the leptin levels in OSAS. A number of studies agree on this point.16–18,27 Ursavas et al.17 used a similar study design to ours and found no differences in leptin levels between OSAS patients and controls, as well as no correlations between serum leptin levels and AHI or other OSAS-related parameters. Both Sharma et al.16 and Barceleo et al.18 reported similar leptin levels in obese patients with and without apnea; however, they also found lower leptin levels among nonapneic patients with normal BMIs. Serum leptin levels were found to be significantly correlated with the AHI, but failed to reach significance after correction with BMI.27. A multiple regression analysis of data from 60 study subjects found no independent indicator for leptin levels, although there was a correlation between AHI and leptin levels.13 Some studies have shown that the use of CPAP therapy decreased leptin levels, which were associated with a decrease in fat accumulation.13,16 We observed decreases in AHI and ESS and increases in mean oxygen saturation in patients who underwent 3 months of CPAP treatment; however, BMI and WC and NC remained consistent across all study subjects. Leptin levels did not show a significant decrease after CPAP therapy. In agreement with the latter, studies have reported that leptin levels are similar in obese OSAS patients when compared to non-OSAS controls and that these levels do not change significantly after 1 month or 1 year of CPAP.18,19 Recently, a meta-analysis was conducted to evaluate the effects of CPAP therapy on serum leptin levels in OSAS; 15 studies involving 427 patients were included in the metaanalysis. The results indicate that the overall standardized mean difference of the leptin levels before and after CPAP therapy was 0.137 (95% confidence interval) (P = 0.046). Subgroup analyses showed that differences in OSAS severity, baseline BMI, compliance, CPAP duration, and leptin assay did not affect the effectiveness of CPAP therapy.28 The evidence for the use of CPAP therapy on decrease of leptin levels in OSAS patients is low.29 In this study, we detected a statistically nonsignificant decrease (10%) in leptin levels of the OSAS patients after CPAP therapy; AHI, oxygen saturation, and ESS variations were not related to leptin variations. Unfortunately, because of the technical difficulties associated with subjecting patients to a placebo version of CPAP, we were not able to use a randomized, placebo-controlled study design to investigate the impacts of CPAP on serum leptin levels. Instead, all patients received CPAP as recommended for the treatment of moderate-to-severe OSAS, according to the guidelines of the American Academy of Sleep Medicine. Although this prevented us from optimizing our study design, we felt that it would be unethical to withhold ventilation from patients in need of this treatment. In conclusion, we have demonstrated that plasma leptin levels and lipid profiles are similar in both otherwise healthy overweight or obese subjects with OSAS and nonapneic controls. This suggests that obesity mediates the association between OSAS and leptin. Furthermore, we found a significant correlation between OSAS severity and WC and NC, supporting previous claims that central obesity with high WC and NC values is associated with diabetes, hypertension, and cardiovascular disease. These results may be independent of OSAS, because dyslipidemia and hyperleptinemia are common among overweight and obese
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people with large WC and NC values. Three months of CPAP therapy failed to produce significant reductions in leptin; however, we cannot exclude the possibility that CPAP treatment in a greater number of OSAS patients might gradually reduce leptin levels.
Author Disclosure Statement No conflicting financial interests exist.
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Address correspondence to: Sxebnem Yosunkaya, PhD Department of Chest Diseases Meram Medical Faculty Necmettin Erbakan University Akyokusx, Meram-Konya 42090 Turkey E-mail: [email protected]
METABOLIC SYNDROME AND RELATED DISORDERS Volume X, Number X, 2015 Mary Ann Liebert, Inc. Pp. 1–6 DOI: 10.1089/met.2014.0161
Impact of Continuous Positive Airway Pressure Treatment on Leptin Levels in Patients with Obstructive Sleep Apnea Syndrome ¨ mmu¨gu¨lsu¨m Can, MD,3 Sxebnem Yosunkaya, MD,1 Hacer Kuzu Okur, MD,2 U 4 Adil Zamani, MD, and Ruhusxen Kutlu, MD 5
Abstract
Background: There is growing evidence that leptin regulation is altered in obstructive sleep apnea syndrome (OSAS). Several potential mechanisms have been purported to explain how sleep apnea may alter leptin levels. We investigated whether repeated apneas, hypoxia, or excessive daytime sleepiness influenced the levels of leptin in OSAS patients. We also evaluated whether a 3-month continuous positive airway pressure (CPAP) treatment affected leptin levels in patients. Methods: Randomly selected 31 untreated, otherwise healthy male, overweight [body mass index (BMI) > 25 kg/m2] obstructive sleep apnea syndrome (OSAS) patients [apnea–hypopnea index (AHI) ‡ 15] and 25 control (AHI < 5) were included in this study. To confirm the diagnosis, all subjects underwent standard polysomnography. Serum samples were taken at 07:00–08:00 a.m. after overnight fasting. The OSAS patients that had regular CPAP treatment (n = 26) were re-evaulated 3 months later. Results: Leptin levels (50.5 – 17.5 grams/L in OSAS and 56.3 – 25.5 grams/L in controls) and lipid profiles (TC, TGs, HDL-C, and LDL-C) between patient and control groups did not differ (P > 0.05). Leptin levels were not correlated with the AHI, oxygen saturation, or excessive daytime sleepiness. CPAP treatment did not significantly change the (BMI), waist and neck circumference, or leptin levels in OSAS patients. Furthermore, we found no correlation between the decrease in serum leptin levels and parameters that were improved by CPAP treatment. Conclusion: Leptin levels and lipid profile of overweight subjects with and without OSAS were not different, and our results suggest that OSAS-related parameters and CPAP treatment do not play a significant role in the serum leptin levels. for metabolic abnormalities independent of obesity, but pathogenesis of this metabolic consequence has not yet been clearly defined.2 Leptin, an adipocyte-derived hormone, regulates body weight and energy expenditure and acts via the leptin receptor (LEPR).6 Several systemic effects are attributed to leptin. Increased plasma leptin levels and leptin resistance have been related to obesity, arterial hypertension, and glucose and lipid metabolism pathogenesis.7 Serum leptin physiological concentrations in obese people compared to normal weight people are 20–30 times higher. A study, conducted in the United States, that examined the relationship between body mass index (BMI) and leptin found that
Introduction
O
bstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxemia, sleep fragmentation, and increased sympathetic activity that occur due to repetitive collapse of the upper airway during sleep.1 Obesity and particularly visceral obesity are major risk factors for OSAS, and obesity-related metabolic disorders are also highly associated with OSAS.2 OSAS itself is a situation that creates predisposition for progressive obesity,2–4 which is thought to result from changes in serum leptin levels or leptin receptor insensitivity.5 Recent studies have reported that OSAS is associated with risk factors 1
Necmettin Erbakan University, Meram Medical Faculty, Department of Chest Disease, Konya, Turkey. Fatih Sultan Mehmet Education and Research Hospital, Department of Chest Diseases and Thoracic Surgery, Istanbul, Turkey. 3 Konya Education and Research Hospital, Department of Biochemistry, Konya, Turkey. 4 Necmettin Erbakan University, Meram Medical Faculty, Department of Chest Disease, Konya, Turkey. 5 Necmettin Erbakan University, Meram Medical Faculty, Department of Family Physician, Konya, Turkey. 2
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leptin levels in healthy lean individuals were 10 ng/mL or lower; their leptin levels were lower than those of healthy overweight subjects (10–30 ng/mL), whereas leptin levels of obese individuals were 30 ng/mL or higher.8 The association between obesity and leptin is well documented, but the role of OSAS in leptin level remains controversial. There is growing evidence that leptin regulation is altered in OSAS.9–12 Several potential mechanisms have been purported to explain how sleep apnea may alter leptin levels. Recent evidence suggests that leptin levels can be increased in response to hypoxia.11 Obstructive apnea or hypopnea is often terminated by an arousal, which is accompanied with an increase in the sympathetic activity.2 Sympathetic nervous system activation may be associated with abnormal leptin levels that are related to OSAS.2 Additionally, several studies have documented a decrease in fasting leptin levels in OSAS patients that have been placed on continuous positive airway pressure (CPAP) treatment.13–15 On the contrary, some studies have shown that neither high levels of leptin in OSAS patients nor a correlation between any OSAS-related parameters and leptin levels16–18 remained steady despite the treatment of OSAS with CPAP therapy.17–19 These apparently contradictory results may stem from the fact that leptin levels are influenced by a multitude of factors, such as sex, body weight, hypertension, and some medications.20,21 Most previous case–control studies did not adequately control for these confounding characteristics. We developed the current study to investigate the effects of CPAP treatment on leptin levels in OSAS patients while carefully controlling for age, sex, and BMI, and also while excluding individuals with clinically demonstrable comorbid diseases (e.g., diabetes and hypertension). We hypothesized that sleep apnea and hypopnea, intermittent hypoxemia, or sleep fragmentation—the primary concomitants of sleep apnea—play an etiologic role of increase in leptin. Specifically, we investigated whether repeated apneas, hypoxia, or excessive daytime sleepiness (EDS) influenced the levels of leptin in OSAS patients. We also evaluated whether a 3-month CPAP treatment reduced leptin levels in patients.
Material and Methods Subjects The following study protocols were approved by our faculty research ethics committee. Participation in the study was voluntary, and all subjects provided informed written consent. Patients were recruited prospectively from a group of individuals who attended our sleep unit for the investigation of possible OSAS. Male subjects recruited for the study were either overweight or obese [body mass index (BMI > 25 kg/m2]22 and had not previously been diagnosed with or treated for OSAS; none of them were included in a slimming program for weight control. Patients were excluded from the study if they met any of the following criteria: History of cerebrovascular or cardiovascular disease, diabetes (previous physician diagnosis and fasting blood glucose > 126 mg/dL), moderate-to-severe hypertension (previous physician diagnosis and measured blood pressure > 140/90 mmHg), chronic inflammatory diseases, current use of diabetic, antihypertensive, or lipidlowering medications; age < 18 or > 70 years; diagnosis
YOSUNKAYA ET AL.
with central sleep apnea or Cheyne–Stokes respiration; clinical manifestation of severe chronic obstructive pulmonary disease (COPD) or asthma [forced expiratory volume in 1 sec (FEV1) < 70% predicted]. The people who were referred from other clinics with suspected sleep apnea but their apnea–hypoxia index (AHI) value was < 5 were defined as controls (n = 25). Those with AHI ‡ 15 were diagnosed as having moderate-to-severe OSAS (n = 31) and were eligible for CPAP treatment.1 The Epworth sleepiness scale (ESS) was used to assess subjective sleepiness. This test is scored as the possibility of falling asleep in eight different situations, ultimately 0 (not sleepy) to 24 (very sleepy). Values greater than 10 in this test of excessive daytime sleepiness (EDS) is indicative.23 Each subject was examined by a lung specialist. The following parameters were measured: Body weight, measured on subjects wearing only underwear and without shoes, by means of a steel yard scale (precision – 100 grams); body height, measured on subjects without shoes by means of a stadiometer (precision – 1 mm). BMI was calculated as the ratio between weight (in kilograms) and the square of height (in meters); waist circumference (WC) was measured by placing a flexible tape midway between the lowest rib and the iliac crest. Neck circumference (NC) was measured at the level of the superior border of the cricothyroid membrane using a flexible tape measure. Systolic (SBP) and diastolic (DBP) blood pressure was measured according to standard conditions using a sphyngomanometer; three measurements were performed at intervals of 2–5 min and then mean of the three values was calculated. Co-morbid disorders were identified with lung function tests, chest X-rays, and electrocardiography.
Biochemical measurements In the morning between 07:00 and 08:00 a.m. after an allnight polysomnography, we collected fasting blood samples from all study subjects to analyze the following biochemical parameters—total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and lowdensity lipoprotein cholesterol (LDL-C). The measurements were carried out by spectophotometric method using commercial kits with a Beckman Synchron Dx800 (Beckman Coulter, USA) through standard laboratory methods. For serum leptin analysis, blood samples were collected and centrifuged immediately at 1800 · g for 20 min. Serum specimens were stored at - 80C until analysis. Leptin levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit (BioVendor-Laboratorni-medicina a.s., Modrice, Czech Republic). To assay for the presence of co-morbid disorders, we also performed a complete blood count and ran tests examining liver, renal, and thyroid functions.
Sleep study Overnight polysomnography (PSG) monitoring was performed on all participants using the VIASYS SleepScreen System (VIASYS Healthcare, Inc., Hoechberg, Germany) and included the following variables: Electroencephalogram (four channels: C3/A2-, C4/A1-, O1/A2, and O2/A1); electro-oculogram (two channels: right, left); electromyogram of submental muscles (three channels); electromyogram of the anterior tibialis muscle of both legs (two channels);
LEPTIN LEVELS IN OSAS PATIENTS
electrocardiogram; and airflow (assessed with an oronasal cannula and a thermistor). Chest and abdominal efforts (two channels) were measured using thoracic and abdominal strain gauges, and arterial oxyhemoglobin saturation (SaO2: one channel) was measured with a finger probe by pulse oximetry. Sleep staging and respiratory event scoring were performed manually by a single doctor according to the guidelines of the American Academy of Sleep Medicine.24 Apneas were defined as the complete cessation of airflow ‡ 10 sec; hypopneas were defined as a > 30% reduction in nasal–oral airflow with an associated ‡ 3% decrease in oxygen saturation or arousal.24 During PSG, the following variables were recorded: Sleep efficiency (SE), calculated as the total sleep time multiplied by time spent in bed; minimum oxygen saturation, the lowest oxygen saturation recorded during sleep; mean oxygen saturation (mean SaO2); the average oxygen saturation recorded during sleep; and time SaO2 ‡ 90% (SaO2 ‡ 90), defined as the total sleep time multipled by time spent of sleep time at ‡ 90% of the saturation level.
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tionship between change of circulating leptin levels and change of physiological/sleep parameters during 3 months. Significance was defined as P < 0.05.
Results General findings Characteristics and clinical findings from all study subjects are shown in Table 1. NC, BMI, blood pressure, sleep efficiency, and ESS scores were similar in both the control and treatment groups. OSAS patients had significantly larger WC values than control individuals (110.8 – 8.5 vs. 105.1 – 5.7 cm; P < 0.001); however, the average WC in both groups was over the accepted abdominal obesity limit of 102 cm.26 OSAS patients had lower minimum SaO2 and mean SaO2 rates and higher AHI rankings than individuals in the control group (all P < 0.001). Among OSAS patients, AHI was positively correlated with BMI and both WC and NC (r = 0.385, r = 0.136, and r = 0.345, respectively; P < 0.05), but negatively correlated with mean SaO2 (r = - 0.412, P = 0.017) (Table 2).
CPAP treatment Automatic titration of the CPAP pressure (AutoSet Spirit, ResMed Corp., San Diego, CA) was performed in the sleep laboratory under polysomnographic control while patients were being monitored by a trained sleep laboratory technician. The optimum pressure required to prevent the majority of apneas, hypopneas (AHI < 10 events/hr), and snoring was confirmed for each patient; this was usually the 95th percentile of pressure.25 After titration, each subject received a CPAP machine and related accessories and received instructions to use the machine for 3 months. Hour meter readings were used to assess patient compliance with the CPAP treatment regime. Daily duration of CPAP use was 5.5 – 0.7 hr [mean – standard deviation (SD). The majority of our patients met the criteria required to consider them ‘‘regular’’ CPAP users. Our final patient sample size was n = 26; five individuals were excluded because of poor CPAP compliance (n = 2), refusal to undergo re-PSG at the end of the study (n = 1), and failure to follow up (n = 2). At the end of the 3-month treatment period, overnight PSG monitoring was performed on patients who use regular CPAP (n = 26) using the VIASYS SleepScreen System, and blood samples were collected again at the end of the PSG recording between 07:00 and 08:00 a.m.
Statistical analysis Data were analyzed using SPSS version 17.0 software (SPSS Inc, Chicago, IL). The results are expressed as mean – SD. The Kolmogorov–Smirnov test was used to assess whether the data were normally distributed. For normally distributed data, we used independent t-tests to investigate differences between OSAS (n = 31) and control (n = 25) groups. AHI parameters were compared between OSAS and control groups using the Mann–Whitney U-test because of these data were not normally disturbed. BMI, WC, NC, leptin levels, and polysomnographic parameters were compared between conditions before and after CPAP using paired t-tests. Comparisons before and after CPAP included the data of 26 participants. Pearson correlations and regression analyses were used to investigate the rela-
Serum leptin and lipid levels Subjects in the control (n = 25) and patient (n = 31) groups had similar levels of TC, TGs, HDL-C, and LDL-C (all P > 0.649) (Table 3). In this study, we demonstrated that the mean value of serum leptin was 50.5 – 17.5 (ng/mL) in OSAS patients and 56.3 – 25.5 (ng/mL) in the nonapneic controls, respectively. This difference was not significant (P = 0.783). Leptin levels were not correlated with AHI, BMI, WC, ESS, minimum SaO2, mean SaO2, or SaO2 ‡ 90 (all P > 0.153; Table 2). Among OSAS patients only, serum leptin levels were positively correlated with NC (r = 0.336, P = 0.048) (Table 2).
Table 1. Characteristics and Clinical Findings of OSAS Patients and Control Individuals OSAS patients n = 31
Controls n = 25
Mean – SD
Mean – SD
Age (year) 43.3 – 8.5 NC (cm) 44.5 – 2.9 WC (cm) 110.8 – 8.5 BMI (kg/m2) 32.9 – 3.6 AHI (event/hr) 44.10 (17.5–99)a Minimum 72.8 – 10.3 SaO2 (%) Mean SaO2 (%) 88.4 – 2.9 SaO2 ‡ 90 (TST%) 47.6 – 29.2 SE 81.0 – 9.4 ESS 10.3 – 5.6 SBP (mmHg) 124.0 – 17.0 DBP (mmHg) 75.0 – 13.0 a
P
41.5 – 9.5 0.100 43.3 – 3.0 0.090 105.1 – 5.7 < 0.001 31.9 – 2.5 0.280 3.75 (0–5)a < 0.001 85.5 – 4.5 < 0.001 92.9 – 2.2 < 0.001 91.9 – 12.2 < 0.001 83.8 – 8.3 0.240 7.6 – 5.6 0.070 119.0 – 13.0 0.150 72.0 – 10.0 0.220
Median (min-max). OSAS, obstructive sleep apnea syndrome; WC, waist circumference; NC, neck circumference; BMI, body mass index; AHI, apnea– hypopnea index; mean SaO2, the average oxygen saturation recorded during sleep; TST, total sleep time; SE, sleep efficiency; SaO2 ‡ 90, amount of total sleep time spent at ‡ 90% saturation; ESS, Epworth sleepiness scale; SBP, systolic blood pressure; DBP, diastolic blood pressure.
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YOSUNKAYA ET AL.
Table 2. Results from Correlations Between Physiological/Sleep Parameters and Both AHI and Leptin Levels in OSAS Patients (n = 31) Leptin
WC (cm) NC (cm) BMI (kg/m2) AHI (event/h) Minimum SaO2% Mean SaO2% SaO2 ‡ 90 (TST%) ESS Leptin
Table 4. OSAS Patient Characteristics Before and After 3 Months of CPAP Treatment Pretreatment n = 26
AHI
r
p
r
p
0.254 0.336 0.271 - 0.231 - 0.224 - 0.005 - 0.049 0.091 —
0.153 0.048 0.128 0.195 0.210 0.978 0.787 0.616 —
0.136 0.345 0.385 — - 0.096 - 0.412 - 0.333 0.640 - 0.231
0.041 0.043 0.040 — 0.587 0.017 0.680 0.725 0.195
AHI, apnea–hypopnea index; OSAS, obstructive sleep apnea syndrome; WC, waist circumference; NC, neck circumference; BMI, body mass index; mean SaO2, average oxygen saturation recorded during sleep, SaO2 ‡ 90, amount of total sleep spent at ‡ 90% of saturation level; TST, total sleep time; ESS, Epworth sleepiness scale.
Results of CPAP treatment Patients who underwent 3 months of CPAP therapy (n = 26) did not experience any changes in BMI or WC and NC (P = 0.137, P = 0.182, and P = 0.201, respectively) (Table 4). On the other hand, ESS was significantly lower after CPAP therapy (P < 0.001); patients also displayed significant improvements in AHI rank, mean SaO2, minimum SaO2, and SaO2 ‡ 90 (P < 0.001, P = 0.042, P < 0.001, and P < 0.001, respectively) (Table 4). A 10% decrease in leptin levels observed in patients who received regular OSAS treatment was nonsignificant (P = 0.279) (Table 4). Reductions in leptin levels were not associated with variations in AHI, ESS, minimum SaO2, mean SaO2, or SaO2 ‡ 90 among OSAS patients who underwent 3 months of CPAP therapy (all P > 0.207) (Table 5).
Discussion This study examined the question of whether leptin levels differ between people with and without OSAS who are matched for age, sex, and BMI. We showed that OSAS patients and nonapneic controls have similar serum leptin levels (50.5 – 17.5 and 56.3 – 25.5). In addition, we found
– SD
Mean Leptin (ng/mL) Minimum SaO2 (%) Mean SaO2 (%) SaO2 ‡ 90 (TST%) ESS AHI (event/hr) WC (cm) NC (cm) BMI (kg/m2)
45.7 97.7
7.3 5.7
0.279 < 0.001
88.2 47.7
3.13 29.9
94.1 96.0
1.7 6.6
< 0.001 < 0.001
10.9 5.8 5.9 1.7 < 0.001 37.7 (17.5–85.3)a 2.0 (0–10)a < 0.001 114.8 5.3 112.9 6.1 0.182 44.6 2.9 44.3 3.0 0.201 33.0 4.0 32.0 3.5 0.137
a
Median (min-max). OSAS, obstructive sleep apnea syndrome; CPAP, continuous positive airway pressure; SD, standard deviation; mean SaO2, average oxygen saturation recorded during sleep; SaO2 ‡ 90, amount of total sleep time spent at ‡ 90% saturation level; TST, total sleep time; ESS, Epworth sleepiness scale; AHI, apnea–hypopnea index; WC, waist circumference; NC, neck circumference; BMI, body mass index.
that 3 months of active CPAP treatment had no significant effect on the levels of leptin, although it did lead to improvements in PSG parameters and subjective sleepiness. Previously, studies stated that leptin levels for healthy normal-weight individuals were 3–5 ng/mL7 or lower than those of obese individuals, which were 30 ng/mL and higher.8 In this study, neither the OSAS group (before and after CPAP treatment) nor the control group (nonapneic) subjects had leptin levels below 30 ng/mL. Furthermore, we found that leptin levels were independent of both AHI and oxygen saturation levels in OSAS patients. Although a statistically significant association between BMI and leptin levels was not found in this study, this situation is probably due to the fact that the range of BMI values was not wide and was more or less similar between the two groups. Thus, we thought that the increase in leptin levels in patients with OSAS was not connected to OSAS-dependent
Table 5. Relationships Between Serum Leptin Levels and Physiological Parameters Impacted by CPAP Treatment Correlation with DLeptin r
Mean
– SD
P
TC (mg/dL) 201.8 TGs (mg/dL) 175.4 LDL-C (mg/dL) 130.2 HDL-C (mg/dL) 38.5 Leptin (ng/mL) 50.5
42.5 83.3 31.5 8.1 17.5
199.4 168.1 127.3 38.9 56.3
30.9 89.5 27.1 6.0 25.5
0.672 0.958 0.649 0.817 0.783
OSAS, obstructive sleep apnea syndrome; TC, total cholesterol; TGs, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.
P
16.4 10.3
OSAS patients Control individuals n = 31 n = 25 – SD
Mean – SD
49.7 71.9
Table 3. Results from the Biochemical Analyses of OSAS Patients and Control Individuals
Mean
Posttreatment n = 26
D Minimum SaO2 D Mean SaO2 D SaO2 ‡ 90 (TST%) D ESS D AHI
p
Regression with DLeptin t
p
b
- 0.210 0.313 - 0.845 0.410 - 0.301 - 0.138 0.512 - 0.310 0.760 - 0.605 - 0.171 0.413 - 0.472 0.643 - 0.115 0.261 0.207 1.073 0.298 1.068 - 0.182 0.384 - 1.428 0.172 - 0.338
CPAP, continuous positive airway pressure; D, variation observed as a result of the CPAP treatment; mean SaO2, the average oxygen saturation recorded during sleep; SaO2 ‡ 90, the amount of total sleep time spent at ‡ 90% of saturation level; TST, total sleep time; ESS, Epworth sleepiness scale; AHI, apnea–hypopnea index.
LEPTIN LEVELS IN OSAS PATIENTS
factors. Obesity is the key determinant of the leptin levels in OSAS. A number of studies agree on this point.16–18,27 Ursavas et al.17 used a similar study design to ours and found no differences in leptin levels between OSAS patients and controls, as well as no correlations between serum leptin levels and AHI or other OSAS-related parameters. Both Sharma et al.16 and Barceleo et al.18 reported similar leptin levels in obese patients with and without apnea; however, they also found lower leptin levels among nonapneic patients with normal BMIs. Serum leptin levels were found to be significantly correlated with the AHI, but failed to reach significance after correction with BMI.27. A multiple regression analysis of data from 60 study subjects found no independent indicator for leptin levels, although there was a correlation between AHI and leptin levels.13 Some studies have shown that the use of CPAP therapy decreased leptin levels, which were associated with a decrease in fat accumulation.13,16 We observed decreases in AHI and ESS and increases in mean oxygen saturation in patients who underwent 3 months of CPAP treatment; however, BMI and WC and NC remained consistent across all study subjects. Leptin levels did not show a significant decrease after CPAP therapy. In agreement with the latter, studies have reported that leptin levels are similar in obese OSAS patients when compared to non-OSAS controls and that these levels do not change significantly after 1 month or 1 year of CPAP.18,19 Recently, a meta-analysis was conducted to evaluate the effects of CPAP therapy on serum leptin levels in OSAS; 15 studies involving 427 patients were included in the metaanalysis. The results indicate that the overall standardized mean difference of the leptin levels before and after CPAP therapy was 0.137 (95% confidence interval) (P = 0.046). Subgroup analyses showed that differences in OSAS severity, baseline BMI, compliance, CPAP duration, and leptin assay did not affect the effectiveness of CPAP therapy.28 The evidence for the use of CPAP therapy on decrease of leptin levels in OSAS patients is low.29 In this study, we detected a statistically nonsignificant decrease (10%) in leptin levels of the OSAS patients after CPAP therapy; AHI, oxygen saturation, and ESS variations were not related to leptin variations. Unfortunately, because of the technical difficulties associated with subjecting patients to a placebo version of CPAP, we were not able to use a randomized, placebo-controlled study design to investigate the impacts of CPAP on serum leptin levels. Instead, all patients received CPAP as recommended for the treatment of moderate-to-severe OSAS, according to the guidelines of the American Academy of Sleep Medicine. Although this prevented us from optimizing our study design, we felt that it would be unethical to withhold ventilation from patients in need of this treatment. In conclusion, we have demonstrated that plasma leptin levels and lipid profiles are similar in both otherwise healthy overweight or obese subjects with OSAS and nonapneic controls. This suggests that obesity mediates the association between OSAS and leptin. Furthermore, we found a significant correlation between OSAS severity and WC and NC, supporting previous claims that central obesity with high WC and NC values is associated with diabetes, hypertension, and cardiovascular disease. These results may be independent of OSAS, because dyslipidemia and hyperleptinemia are common among overweight and obese
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people with large WC and NC values. Three months of CPAP therapy failed to produce significant reductions in leptin; however, we cannot exclude the possibility that CPAP treatment in a greater number of OSAS patients might gradually reduce leptin levels.
Author Disclosure Statement No conflicting financial interests exist.
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Address correspondence to: Sxebnem Yosunkaya, PhD Department of Chest Diseases Meram Medical Faculty Necmettin Erbakan University Akyokusx, Meram-Konya 42090 Turkey E-mail: [email protected]
