P. coaom|des, P. 8a|a|os, P. kylbreol|s, |. h||o|opou|os, A. 8as|da||s Resp|ralory la||ure Cerler, 8ol|r|a Al|ers 0erera| hosp|la| ol C|esl D|seases key Words: 0bslrucl|ve s|eep apaea syadrome, obese, serum |epl|a Le|ia |ere|s aa4 aa|hroome|ric charac|eris|ics oj a|iea|s i|h obs|rac|ire s|ee aaea s;a4rome SUMMARY. Obstructive sleep apnea syndrome (OSAS) is char- acterized by repeated episodes of upper airway obstruction during sleep. Most subjects with OSAS are obese. Leptin, a hormone pro- duced by adipocytes, plays a regulatory role on body weight. In- creased leptin levels occur in obese patients with OSAS. Our ob- jective was to determine the anthropometric characteristics and examine the relationship between circulating leptin levels and sleep-related breathing disorders in a group of obese patients with OSAS. Twenty-eight patients with confirmed OSAS underwent overnight polysomnography, in addition, anthropometric measure- ments were performed and serum leptin levels were determined. No correlation was detected between AHI and any of the examined anthropometric characteristics. The mean levels of circulating lep- tin (iSD) were 15.5 ng/mL (i11.9). Serum leptin levels did not correlate with AHI, even when adjusted for fat mass. Moreover, no correlations were found between leptin levels and sleep time with oxygen saturation <90%, or lowest level of oxygen saturation during sleep. Serum leptin levels correlated with BMI and abdo- men circumference. Circulating leptin levels and anthropometric measures in subjects with OSAS are not related to the severity of sleep apnea, as assessed by AHI or other sleep-disorder parame- ters, such as sleep time with oxygen desaturation <90% and low- est level of oxygen saturation during sleep. Paeamoa 2006, 19(2)131-136. |NTPODUCT|ON Obstiuctive sleep apnea syndiome (OSAS) is chaiacteiized by iepeat- ed episodes of uppei aiiway obstiuction duiing sleep that iesult in hemo- globulin desatuiation and sleep disoideis 1 . The incidence of the syndiome ianges fiom 2-4% among adults 2 . The syndiome is associated with incieased caidiovasculai moibidity and moitality 3,4 . It has been suggested that OSAS ielated moibidity is also attiibutable to obesity. Obesity is iecognized as a Corresporderce lo. A. Ras|da||s Ass. Prolessor |r Pu|uorary Ned|c|re, D|reclor ol lCu/RlC 122, Nessoeor 8lr., 0R-11527 Al|ers Te|.. 21O-777O21O la/. 21O-777O21O CIinicaI Study 132 /NEMON 7s0o 2o, 7oo 19o, 4np|/|o - /o0t|o 2006 ma|oi iisk factoi foi the occuiience of OSAS: moie than 50% of patients with OSAS aie obese 5 . In addition, the- se patients aie having difficulty losing weight and tend to fuithei gain weight compaied to patients without OSAS 6 . The mechanisms leading to obesity in patients with OSAS aie not fully undeistood. Ieptin, a hoimone pioduced by adipocytes, plays a iegulatoiy iole in body weight by contiolling appetite and eneigy consumption- 7,8 . Fuithei, it affects neuioendociine mechanisms and iegulates the hypothalamus-pituitaiy axis 9 . Most obese people have high ciiculating levels of leptin: leptin leve- ls inciease exponentially with incieased body fat mass. It has been suggested that in these peisons obesity is ass- ociated with a foim of iesistance to the action of leptin 10 . Studies have shown that the high levels of leptin found in obese patients with OSAS deciease with the use of continuous positive aiiway piessuie (CPAP) 11 . The association between OSAS, anthiopometiic chai- acteiistics and seium leptin levels has been an active fie- ld of contempoiaiy ieseaich: howevei, it iemains inade- quately compiehended 11,12 . Some studies have attempt- ed to establish a possible association between leptin lev- els and seveiity of OSAS 12,13 . The ob|ective of the piesent study is to desciibe the anthiopometiic chaiacteiistics and investigate the pos- sible association between leptin levels and the seveiity of OSAS in a gioup of adult obese patients with OSAS. MATEP|AL AND METHODS S/a0j 0es/q0 a00 a//e0/s All patients weie infoimed in wiitten and gave theii consent foi theii inclusion in the study. The study gioup included 28 patients (24 male, 4 female) with confiimed OSAS. Study sub|ects had piesented to oui sleep study clinic foi possible OSAS fiom Febiuaiy to June 2003. They all weie non-smokeis oi foimei smokeis, with no histoiy of thyioid disease, noimal levels of thyioid hoi- mones and noimal lung function paiameteis. The mean (:SD) age of the patients was 55.1 yeais (:12.9: iange: 34-79 yeais). S/a0j me/0o0 All patients undeiwent oveinight polysomnogiaphy in oui sleep study clinic using the polysomnogiaphy sys- tem Alice 4 Heathdyne: Respiionics: Pittsbuigh, PA. Recoidings included two-lead electioencephalogiam (IIC), submental electiomyogiam (IMC), and contin- uous electiocaidiogiam (ICC). The movements of low- ei extiemities weie detected by anteiioi tibial electiomyo- giam: bieathing sounds weie iecoided by a miciophone placed at the height of the |ugulai vein. Aiiflow iecoid- ings weie peifoimed with a combination of oionasal thei- mistois: thoiacic and abdominal wall movements weie evaluated by means of inductive plethysmogiaphy. He- moglobulin oxygen satuiation in aiteiial blood was mea- suied using pulse oximetiy. Sleep stages weie deteimined by two expeiienced physicians accoiding to established ciiteiia 14 . OSAS was defined by the known ciiteiia 12 . Hypopnea was defined as a >50% ieduction in aii flow (compaied to the aii flow in the aleit sub|ect at iest) last- ing foi at least 10 seconds, followed by eithei oxygen de- satuiation by >4% oi awakening. The total numbei of apnea and hypopnea episodes was divided by the total sleep time to obtain the apnea-hypopnea index (AHI). A value of AHI >10/houi classified the sub|ect as hav- ing OSAS. Regaiding seveiity, OSAS was consideied mild if 10<AHI20: modeiate if 20<AHI40: oi seveie if AHI =40. Blood was diawn fiom the patients at 08:00 a.m. af- tei oveinight fasting. Blood samples weie centiifuged: plasma was sepaiated and stoied in the fieezei until the time of measuiements. Ieptin levels weie deteimined using an immunoiad- iometiic assay (Human Ieptin IRMA, Diagnostic Sys- tems Iaboiatoiies Inc, Texas, USA): thyioid hoimones, T3 and T4, weie measuied using a iadioimmunologic as- say (T3 125 I) RIA kit, Institute of Isotopes Co, Itd, Budapest, T4 Totale RIA, Medicoip Inc, Montieal, Can- ada): and TSH levels weie deteimined using an immu- noiadiometiic assay (TSH IRMA, Medicoip Inc, Mont- ieal, Canada). Anthiopometiic chaiacteiistics weie deteimined ac- coiding to the cuiiently applicable pioceduies. Body mass index (BMI) calculations weie based on body weight (BW) and height (H) accoiding to the foimula: BMI = BW (in kg)/[H (in m)j 2 . BMI values weie used to classify study sub|ects in the following five classes: class 0: 20<BMI25, class I: 25<BMI30, class II: 30<BMI35, class III: 35<BMI40, class IV: BMI>40 15 . Fat mass (%) 133 PNEUMON N0moer 2, vo|. 19, 4pr|| - 10ne 2006 was measuied using a special device (Bioelectiic imped- ance analysis BIA - 101S System RJM systems, Mt Cle- mens MI). Height measuiements weie made using a wall-mount height measuiing device with study sub|ects in upiight position, without shoes: a deviation of 0.5 cm was allowed in these measuiements. A measuiing tape was used foi the measuiements of neck and abdomen ciicumfeience. Iung function tests weie peifoimed with the spiiometei Spiio 232 (Moigan Medical Itd, Kent, Ingland). Iung function paiameteis weie expiessed as peicent of the piedicted values (% pied). S/a//s//ca/ a0a/js/s Results weie expiessed as mean : standaid devia- tion (SD). Compaiisons between gioups weie made us- ing the Mann-Whitney U test foi non-paiametiic vaii- ables. The coiielation of leptin levels with othei paiam- eteis was assessed with Speaiman iank coiielation test. Statistical significance was defined as a P value <0.05. The statistical package SPSS (SPSS Inc: Chicago II) was used foi the statistical analysis. PESULTS S/ee s/a0j The iesults of the polysomnogiaphy studies showed that two (7.1%) of the study sub|ects had 10<AHI<20: two (7.1%) had 20<AHI<40: and 24 (85.7%) had AHI>40. Theie was no association between age and HAI. 40/0roome/r/c c0arac/er/s//cs The demogiaphic and anthiopometiic chaiacteiistics of the study sub|ects aie listed in Table 1. The mean (:SD) weight was 111.4 (20) kg: height 171.6 (8.5) cm: and BMI 37.5 (4.8). Consideiing the above-desciibed obesity classification accoiding to BMI, none of the sub- |ects enteied classes 0 oi I: 9 (32%) sub|ects enteied class II: 7 (25%) sub|ects enteied class IV. Theie was no asso- ciation between AHI and any of the examined anthio- pometiic chaiacteiistics. In paiticulai, AHI was not ie- lated to the ciicumfeience of the neck (P=0.382: i=0.172) oi the abdomen (P=0.198: i=0.251). Ta||e 1 C|aa:/e|s/|: Pa/|en/s a|/| OSAS (N=28) Age (yeais) 55.1:12.9 Cendei (M/F) 24/4 Height (m) 171.6:8.5 Weight (kg) 111.4:20 BMI (kg/m 2 ) 37.5:4.8 Neck ciicumfeience (cm) 45.5:4 Abdomen ciicumfeience (cm) 125.5:11.4 Fat mass (%) 35.3:5.9 Ieptin levels (ng/mI) 42.05:28.32 AHI 63.9:21.7 Minimum satuiation (%) 75.4:8.6 Iength of sleep time with oxygen 69.8:68.4 satuiation <90% (min) FIV 1 /FVC 81.6:4 FIV 1 94:12.5 All paiameteis aie expiessed as mean value :SD. Seram /e//0 /ere/s The mean (:SD) value of seium leptin levels was 42.05 (:28.32) ng/mI. Theie was a positive ielationship between seium leptin levels and BMI (P=0.034: i=0.402). Ieptin levels weie not associated with the se- veiity of OSAS as indicated by AHI (P=0.179: i=0.261). Iven aftei ad|usting foi fat mass (by calculating the lep- tin-to-fat mass iatio), leptin levels weie not associated with AHI (P=0.234: i=0.232). A positive ielationship was found between seium leptin levels and AHI (P=0.004: i=0.522). Howevei, leptin levels weie not associated with the length of sleep time with oxygen satuiation <90% (P=0.748: i=0.064) oi the lowest aiteiial satuiation dui- ing sleep (P=0.706: i=-0.074). Iven when the subgioup of patients with seveie OSAS was examined sepaiately, leptin levels weie associated with none of the anthiopometiic chaiacteiistics oi sleep- associated paiameteis. Fat mass ad|usted leptin levels weie consistently associated only with body mass index (P=0.04: i=0.423). D|SCUSS|ON This study desciibed the anthiopometiic chaiactei- 134 /NEMON 7s0o 2o, 7oo 19o, 4np|/|o - /o0t|o 2006 istics, and examined the ielationship between seium lep- tin levels and OSAS seveiity in patients with confiimed OSAS. Theie was no association between the seveiity of OSAS (as indicated by AHI) and anthiopometiic paiam- eteis of obesity in patients with confiimed OSAS. How- evei, a iecent study showed that OSAS ielated to an- thiopometiic paiameteis of obesity in patients with OSAS: in paiticulai, the peicentage of abdominal fat was found to be associated with the occuiience of the syn- diome 12 . Some studies suggest that BMI is an aggiavat- ing factoi foi the occuiience of OSAS: howevei, othei studies have shown that cential obesity, as assessed by waist-to-hip iatio, is a bettei piedictoi foi the occuiience of OSAS than BMI 10,12,16 . Ieptin is a hoimone pioduced by adipocytes that ieg- ulates body weight by contiolling appetite and eneigy consumption. 17 The action of leptin staits with its bind- ing on specific ieceptois in the hypothalamus, which modulates the expiession of neuiopeptides that iegulate neuioendociine functions, as well as the intake and con- sumption of eneigy 10 . Ieptin levels inciease exponentially with the inciease in fat mass: most obese individual have high seium leptin levels 18 . Studies on animals have found that leptin pievents iespiiatoiy aiiest in obesity, and that leptin deficiency in the cential neivous system oi the absence of its action may cause hypoventilation and Pick- wick syndiome in the obese. Oui study showed a significant ielationship between leptin levels and BMI, a finding consistent with those iepoited in othei studies 11,12 . Ieptin levels weie also found to be ielated to the ciicumfeience of the abdo- men. A causative ielationship between leptin levels and OSAS has been suggested 20 . Howevei, leptin levels, even when ad|usted foi fat mass, weie not found to be associ- ated with OSAS, oi othei disoideied sleep-paiameteis, such as the length of sleep time with oxygen satuiation <90% oi the lowest aiteiial satuiation duiing sleep. This is a contioveisial issue, since some investigatois suppoit an association between leptin levels and OSAS, while otheis aigue against such an association. This may be in pait attiibutable to diffeiences in the chaiacteiistics of the patient seiies examined by diffeient investigatois. A numbei of vaiiables, including gendei, body weight, pies- ence of aiteiial hypeitension, and vaiious medical tieat- ments may affect leptin levels 7,21 . The sub|ects included in oui study had highei BMI and moie seveie OSAS, as assessed by AHI, (85% of oui patients had AHI >40) compaied to the patients included in othei studies 12,13 . It is likely that leptin levels aie associated with the seveiity of OSAS in patients with mild oi modeiate syndiome, wheieas in seveie OSAS othei factois may be involved in the pathogenesis of obesity. Oui study would not be able to show such an effect, since only foui patients with mild-to-modeiate syndiome weie included. In addition, all oui patients had noimal lung function tests, this indi- cating the absence of a concomitant lung disease: it is alieady known that chionic obstiuctive pulmonaiy dis- ease (COPD) affects leptin levels eithei alone oi in con- |unction with bionchodilatoi tieatment 22 . In addition, oui patients had noimal thyioid function, which plays also a significant iole in the iegulation of body weight. It has been suggested that theie may be an inteiaction between the leptin system and thyioid hoimones. Thyioid dysfunc- tion may altei seium leptin levels without changing body weight oi composition 23 . It is also iecognized that hy- pothyioidism, which is commonly undeidiagnosed, is as- sociated with OSAS. A thyioid dysfunction was neithei excluded noi evaluated in othei studies: in this iegaid, iepoited iesults may be misleading. All patients in oui study weie euthyioid. Iastly, it is likely that theie aie additional deteiminants, besides fat mass, foi high lep- tin levels in patients with OSAS. This is suggested by the deciease in leptin levels obseived aftei initiating tieat- ment with nasal CPAP, without any othei concuiient change in the anthiopometiic chaiacteiistics of the pa- tients 24 . Alteinatively, the absence of association between AHI and leptin levels may be attiibutable to the fact that AHI is not the best possible paiametei foi the assess- ment of the seveiity of OSAS in all iespects. This specu- lation is enhanced by the weak association of AHI with the daily activity level of the patient oi the occuiience of caidiovasculai disease. The question of whethei OSAS seveiity is associated with leptin levels iemains unan- sweied. It seems likely that othei mechanisms, not in- volving leptin, may be implicated in the development of OSAS. Foi example, gihelin, anothei hoimone that has been discoveied iecently, plays a significant iole in the iegulation of appetite, body weight and composition, and 135 PNEUMON N0moer 2, vo|. 19, 4pr|| - 10ne 2006 we believe that including patients with highei BMI and moie seveie OSAS compaied to othei patient seiies might have had a beaiing on oui iesults. Neveitheless, despite the above-mentioned limita- tions, we think that oui iesults iepiesent an inteiesting aspect foi the potential iole of leptin in the pathogene- sis of obesity in patients with OSAS. Although seium lep- tin levels weie found to be associated with both BMI and abdomen ciicumfeience, oui study failed to confiim the association between leptin levels and AHI, as an indica- toi of OSAS seveiity, which has been iepoited in othei studies. This inconsistency suggests eithei that AHI does not ieflect OSAS seveiity in all iespects of the syndiome, oi that additional mechanisms, not involving leptin, play theii pait in the pathogenesis of obesity on OSAS. Fuithei studies aie necessaiy to elucidate the iole of this hoimone in OSAS, as well as its association with the anthiopometiic chaiacteiistics of these patients. has been iepoited to be incieased in patients with OSAS 24 . Howevei, the demonstiated association between leptin levels and abdomen ciicumfeience, which is com- monly incieased in patients with OSAS, indicates the complexity of the ielationship between leptin, obesity and OSAS. It has also been aigued that the action of seium leptin may deteimine the type of obesity (cential oi pe- iipheial) oi the body aiea foi fat deposition (uppei aii- ways oi abdomen). Oui iesults indicate that leptin is not ielated to fat deposition in the uppei aiiways only, as suggested in othei studies, but in the abdomen as well. 12 Oui study has ceitain limitations. One limitation is that the waist-to-hip iatio was not evaluated, although it is consideied a stiongei deteiminant foi the occuiience of OSAS than BMI 16 . Anothei limitation is that the pies- ence of aiteiial hypeitension and/oi caidiovasculai dis- ease was not addiessed. It has been demonstiated that aiteiial hypeitension affects leptin levels 16 . Fuitheimoie, HEPIAH+H Eaasa 1satvq; xat av0aaoasttx aaxtqtattx as aa0svs; as cavoaavox avoao H. Otxovoaq;, H. Maaxxo;, H. Kc0sotq;, I. Ntxo1aoc1o;, A. Paatxq; To ocr^ouo ao,axr/xq; ro/a; oror cro (YAz) aaxrq/,cra/ a caraau3arucra cc/o^/a a,a[q; rar ararcar aca,a,ar xar rq ^/xc/a roc croc O/ c/oorco/ ao0crc/; uc YAz c/ra/ acoaxo/ H cr/rq u/a ourq oc a,cra/ a ra /oxcrraa a/,c/ c0u/or/x o ,/a ro oauar/x 3o; Ac[qutra c/c^a cr/rq; aarqocrra/ oc acoaxoc; ao0crc/; uc YAz zxo; rq; uctrq; c/ra/ ra c/,ocuc ra ar0aoucr/x aaxrq/or/x xa/ ra c[croocuc rq otoq ucra[c c/t^ar cr/rq; oro a/ua xa/ 3acrqra; roc YAz oc u/a ou^a acoaxar ao0crar uc YAz E/xoo/oxra ao0crc/; uc c/3c3a/autro YAz co3q0qxar oc occro,a,/xq uctrq croc t,/rc utrqoq rar ar0aoucr/xar roc; aaxrq/or/xar xa/ rar c/t^ar cr/rq; oro a/ua Acr aarqq0qxc ocotr/oq roc cro- aro/xoc ^c/xrq (YAA) uc xartra a ra ar0aoucr/x aaxrq/or/x H utoq r/uq rq; cr/rq; oror o qrar 4205n/m| (:SD 2832) Acr 3t0qxc ocotr/oq rq; cr/rq; uc ror YAA axuq xa/ rar acrq ooauorqxc oro oooor rq; u,a; /oc; ocrc uc rq or/xq ^/xc/a croc uc xocou o[c,roc <90% q rq auqrcq r/uq xocouoc xar rq ^/xc/a roc croc Arr/0cra aarqq0qxc ocotr/oq rar r/uar rq; cr/rq; uc ro ^c/xrq u,a; oauaro; (AMz) xa/ rqr c/ucro rq; xo//; O/ r/ut; rq; cr/rq; ooc oc ao0crc/; uc YAz ^cr ocr/,orra/ uc rq 3acrqra roc ocr^uoc a; acrq cx,,cra/ uc ror YAA Hvsaav 2006, 19(2)131-136. 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