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The Factors Involved In The Relation Between Asthma And Obesity Hatice Bakir Kilic*, I.Kivilcim Oguzulgen*, Fatih Bakir** ve Haluk Turktas* *Department of Biochemistry, Ankara Numune Hospital, Ankara **Department of Pulmonary Medicine, Gazi University Faculty of Medicine,
BACKGROUND • More than one billion people around the world are overweight or obese with a body mass index (BMI) of 25 kg/m² or more. • More than 50% of the United States (US) population is obese. • In the US in 2000 it was responsible for approximately 400.000 deaths and accounted for about 7% of health care expenditures *Poulain M et al. CMAJ April 25, 2006;112: 174- 179.
Asthma-obesity (1) • The documented increase in asthma prevelance over the last 20 years Coroner Arter Diseases Diabetes Mellitus Hypertension Asthma Obesity Vollmer WM et al. Am J Respir Crit Care Med 1998; 157:1079- 84. Shore SA et al. J Allergy Clin Immunol 2005;115: 925- 7 Vieira VJ et al. Am J Clin Nutr 2005;82: 504- 9
Asthma-obesity (2) • The influence of obesity on asthma : • Genetic effects of obesity • Immune modification by obesity • Direct mechanical effects of obesity • Sex specific effects of obesity Tanitisira KG et al. Thorax 2001;56: 64- 74
Leptin and obesity • In obese cases genetic mutation was been → leptin or leptin receptor deficiency →leptin resistance → serum leptin concentrationwas increased • In addition to its effects on the regulation of body fat mass, leptin is also proinflammatory Shore SA et al. J Allergy Clin Immunol 2005;115: 925- 7 Sinn DD et al. Arch Intern Med 2002; 162: 1477- 1481 Sood A et al. Thorax 2006; 61: 300- 5
Leptin and asthma • Leptin receptors also exist in human lung tissue • Leptin may have stimulatory effects on the proliferation of cells of a human cell line through its spesific leptin receptor • It was projected leptin may provide a link between inflammation and T-cell function in asthma • Although there is evidence of a positive association between asthma and obesity in adults and children, very little is known about the role of leptin in asthma. Guler N et al.J Allergy Clin Immunol. 2004;114:254-9.
Leptin TNF-α IL-6 IL-1β Obesity Asthma Kentaro M et al. J Allergy Clin Immunol 2006; 117:705- 6
Leptin and atopy Asthma, obesity, atopy and LEPTIN Beuther AD et al. Am J Respır Crıt Care Med 2006; 174:112-119
Obesity-asthma control(1) • Obesity also appears to play a role in asthma severity and control, and alters the efficacy of standard asthma medications. • It was determinated that obese or overweight subjects account for 75% of emergency department visits for asthma • It was noted an increase in asthma severity with obesity in a population of over 4000 adolescents Weiss ST et al. Am J Respir Crit Care Med 2004; 169:963- 8. Akerman MJ et al. J Asthma 2004; 41: 521- 26. Cassol V et al. J Asthma 2006; 42: 57- 60.
Obesity-asthma control (2) • Varraso et al. found a relationship between BMI and clinical asthma severity score, but only in women. • Mansell et al and Lavoie et al. found no effect of BMI on the prevelance of asthma severity scores in either adeloscents or adults Varraso R et al. Am J Respir Crit Care Med 2005; 171: 334- 339. Lavoie KL et al. Respir Med 2006;100: 648- 57. Mansell Al et al. Pediatr Pulmol 2006; 41: 434- 440.
FENO and asthma • Both iNOS (inducible nitric oxide synthases) expression and FENO (Fractional Exhaled Nitric Oxide) levels was shown to be increased in asthmatic patients • FENO levels have been used as a tool for monitoring the effectiveness of antiinflammatory medications • FENO levels have been positively correlated with eosinophils in bronchial biopsy specimens and with eosinophils in induced sputum Kharitonov SA et al. Gazi Med J 1998; 9 Suppl 1: S25- 30. Jatakanon A et al. Thorax 1999; 54: 108- 114. Jatakanon A et al. Thorax 2000; 55: 184- 188. Oğuzülgen İK. Toraks Dergisi 2000; 1 (3): 65- 70.
FENO and obesity • In obese subjects macrophage numbers in adipose tissue increase, producing significant amounts of TNF-α, IL6 and iNOS • BMI was positively correlated with FENO levels (p:0,0007) in a study that was been with 24 healty nonsmoking subjects. De Winter-de Grot et al. J Allergy Clinic Immunol. 2005;115:419-5.
Aim • In this study we aimed to evaluate the influence of obesity on asthma, to determine the role of leptin in the relationship between obesity and asthma and to show the efficacy of leptin in asthma control and inflammation.
Material and Methods(1) • The asthmatic women (n:81) who were admitted to Gazi Univesity Faculty of Medicine Department of Pulmonary Medicine Polyclinic on April and May 2007 have been received study as prospective. • 41 obese →21 atopic, 20 nonatopic 40 nonobese → 20 atopic, 20 nonatopic • All the study subjects were stable in terms of their asthma and were receiving regularly controller medications
Material and Methods (2) • They were excluded from the study: • The patients who have had asthma attach over a month • The patients who smoker • The patients who have acut or sistemic inflammatory disease • The patients who have been infection of acut lower respiratory system
Material and Methods (3) • Pulmonary function test • Prick test • Serum leptin level • Serum total immunglobulin E level • Fractional Exhaled Nitric Oxide (FENO) • Astım Control Testi (ACT)
Signs Pulmonary function tests and characteristics of the study population
In all cases (n:81); • No relationship is present between BMI and FENO level. (r= -0,025, p:0,82) • As BMI increases, ACT levels decrease as well,but it has been shown that the negative correlation is low (r= -0,116, p:0,301)
The relation between BMI and serum leptin levels in all cases r=0,394, p<0,001
Asthma control was evaluated in non-obese group 61% of obese patients had ACT<20 where, the ratio was 38% in non-obese patients (p:0,035).
The relation between ACT and FENO levels in obese group (n:41); p:0,799 Median FENO levels, • ACT<20 (n:25) → 21,00 ppb (12-51) • ACT≥20 (n:16) → 20,50 ppb (11-52)
The relation between ACT and serum leptin levels in obese group (n:41); p:0,371 Median serum leptin levels, • ACT<20 (n:25)→ 23,19 pg/dl (4,80-100) • ACT≥20 (n:16)→ 19,70 pg/dl (11,14-100)
The relation between serum leptin levels and FENO levels in obese group (n:41); r= 0,439, p:0,004
In obese group (n:41); These correlations is not statistically significant: • The positive correlation that between serum leptin levels and total immunglobulin E (T.IgE) levels (r=0,43, p:0,789) • The negative correlation that between serum leptin düzeyi and ACT (r= -0,138, p:0,390) • In nonobese group (n:40) There was no significant correlation among parameters
In non-obese group (n:40); • Median serum leptin levels, • ACT<20 (n:16)→ 20,69 pg/ml (4,03-35,10) • ACT≥20 (n:24)→ 15,90 pg/ml (2,30-92,11), (p:0,890) • Median FENO levels, • ACT<20 (n:16) → 26,00 ppb (10,00-297,0) • ACT≥20 (n:24) → 19,50 ppb (6-171,0) (p:0,194)
Study parameters of according to atopy in obese group
The relation between serum total immunglobulin E levels and serum leptin levels in atopic group r= 0,329, p:0,038
In atopic subjects (n:41); There was no significant correlation among parameters • Between serum leptin levels and FENO levels (r= -0,006, p: 0,969 ) • Between serum leptin levels and ACT scores (r= -0,081, p: 0,621) • In non-atopic subjects (n:40); There was no significant correlation
When the cases were classified as patients with ACT<20 and ACT≥20; between the asthma related comorbidities, as allergic rhinitis, sinusitis, nasal polyp existence and BMI>30, BMI was found to be the only significant factor that contributed to asthma control badly. • It was found that obesity complicates the control of the asthma at 2,6 times (%95 CI: 1,06- 6,38, p: 0,036).
Serum leptine levels in patients who complained of premenstrual asthma p:0,005 Serum leptin düzeyi pg/ml Premenstruel semptom Premenstruel semptom
Serum leptin levels were positively correlated with BMI in all cases (p:0,05) • Total immunoglobulin Elevels were positively correlated with leptine levels in atopic patients (r=0,329, p:0,038,), which can be interpreted as leptin could be partly affected from atopy
Serum leptin levels were positively correlated with FENO levels in obese group(r=0,439, p:0,004). • In the assembly of asthma and obesity, It is thought that both indicators increased in a correlation may be related with that the leptin synthesized in little amount in lungs bridged between T cells and inflammatory cells and released inflammatory cytokins. It was also found that the İNOS increase stimulated by inflammatory cytokins like TNFα, IL1, IFNγ resulted in an increase in level of FENO. Therefore, an increase in ‘Leptin and FENO’ levels acts like ‘cause and result’ in the chronic inflammations observed in assembly of asthma and obesity. • It was found that release of inflammatory cytokins related with high levels of leptin contributed to increased premenstrual symptoms in asthmatic patients.
Besides, it was displayed that obesity affects AKT scores offered today for evaluating the control of asthma significantly, negative and independent from all other factors. This explains the relation between serum leptin levels and obese FENO levels • In the only study of the literature on the relation of AKT and obesity relation, In asthmatic, ıt was evaluatied the relation between ACT and BMI obese females who had laparoscopic adjustable gastric banding and who had non-operated. preopreative mean BMI→45,2±4,7; ACT scoresı →18,7 postopreative mean BMI→ 34,8±4,2; ACT scores →22,2 Preopreative and postopreative FENO levels → There weren’t statistical significant Maniscalco M. et al. Respir Med Jan 2008; 102 (1):102- 8.
Conclusion • As a result; leptin and other adipokines, elevated in asthma and obesity; have been up- regulated various cytokines, promoting a state of chronic inflammation. So it was thougt of sistemic inflammation that was occured by adipokines and cytokines were to taken part of importance in the pathogenesis of asthma and obesity It has shown that obesity complicates the control of the asthma