Serum Leptin Levels and Lipid Profiles in Patients with Allergic Rhinitis and Mild Asthma
Niveles de leptina sérica y perfiles lipidicos en pacientes con rinitis alérgica y asma leve
a Department Internal Medicine & Division of Allergy. Gülhane Military Medical Academy and Medical School. Ankara. Turkey.
b Department of Biochemistry. Gülhane Military Medical Academy and Medical School. Ankara. Turkey.
c Department of Public Health. Gülhane Military Medical Academy and Medical School. Ankara. Turkey.
d Department of Radiology. Gülhane Military Medical Academy and Medical School. Ankara. Turkey.
KeywordsAllergic. Asthma. Leptin. Rhinitis. Steroid. United airway disease.
AbstractAntecedentes: A pesar de la mejor comprensión de la patofisiología de la rinitis alérgica y del asma, el efecto del nivel sérico de la leptina (hormona proteica 16-kDa) todavía es controvertido. Solamente unos pocos estudios se han llevado a cabo para investigar los niveles séricos de lectina en rinitis alérgica y asma, habiéndose observado resultados contradictorios. Objetivo: Investigar la asociación entre leptina, perfiles lípidos y rinitis alérgica y asma, así como determinar si los esteroides inhalados o intranasales afectan a los niveles de leptina. Pacientes y métodos: 43 pacientes con rinitis (10 de ellos con asma leve) (edad entre 18-45 años, media 29,81) y 32 voluntarios como grupo control (edad entre 20-45 años, media 30,65). Resultados: los niveles de leptina en los pacientes fue de 8,49±10,76 ¿6/ml, sin diferencia con los voluntarios: 5,42±6,63 ¿g/ml (p>0.05), Encontramos una relación directa entre el incremento del índice de masa corporal (IMC) y los niveles de leptina (p=0.008). No se observó ninguna asociación entre la leptina y triglicéridos, HDL-colesterol, VLDL-colesterol, eosinofilia o IgE total (p>0.05); excepto para el colesterol total y el LDL-colesterol (p>0.05). Aunque no se encontró correlación entre la rinitis alérgica y asma leve con los niveles de leptina, la correlación de estos parámetros y la edad fueron más marcados para las mujeres que para los hombres (p=0.39 en los varones y p=0.011 en las mujeres), encontrándose así una relación directa entre el incremento del IMC y el sexo en el grupo de pacientes (p=0.008 en varones y p=0.0001 en mujeres). También se comprobó que esto no fue efecto de los esteroides inhalados o intranasales. Conclusión: nuestros datos demuestran que los niveles séricos de leptina y el perfil lipídico en la rinitis alérgica y el asma leve no difiere del de los controles sanos.
ResumenBackground: Despite improved understanding of the pathophysiology of allergic rhinitis and asthma, the effect of serum leptin level is still controversial. Only a few studies have been performed to investigate the serum leptin levels in allergic rhinitis and asthma, and contradictory results have been observed. Objective: We aimed to investigate the association between leptin, lipid profiles and allergic rhinitis and mild asthma, and to determine whether inhaled and/or intranasal steroids affect the leptin levels. Patients and methods: We studied 43 patients with allergic rhinitis (10 of with mild asthma) (mean age 29.81, range 18-45 yr) and 32 volunteers as a control group (mean age 30.53, range 20-45 yr). Results: Serum leptin levels in patients were 8.49 ± 10.76 μg/ml, and did not differ from volunteers 5.42 ± 6.63 μg/ml. (p > 0.05). We found a direct link between increased body mass index (BMI) and serum leptin levels (p = 0.008). No association was seen between leptin and triglyceride, HDL-cholesterol, VLDL-cholesterol, eosinophil, total IgE (p > 0.05); except for total cholesterol and LDL-cholesterol (p < 0.05). Although, no correlation between allergic rhinitis and mild asthma and serum level of leptin was shown, these parameters and age correlations were stronger in female than in male (p = 0.39 for male and p = 0.011 for female), and also found direct link between increased BMI and sex and patients group (p = 0.008 for male and p = 0.0001 for female). We also determined that there was no effect of inhaled and/or intranasal steroids statistically on serum leptin levels. Conclusion: Our data demonstrate that the serum levels of leptin and lipid profiles on allergic rhinitis and mild asthma were not different than those in controls.
Leptin, 16-kDa protein hormone, is produced by white adipose tissue. Structurally, it is a member of the IL-6 family of cytokines. Leptin is an anorexic peptide that is primarily known for its role as a hypothalamic modulator of food intake, body weight and fat stores1.
In addition to its effect on the hypothalamus, leptin is a modulator of the immune and proinflammatory responses. Leptin acts directly on T cells where it enhances the production of Th1 cells promoting inflammation2,3. Leptin also plays a significant role in, e.g., reproductive processes, angiogenesis, hematopoiesis and oxidation of lipids.
On the other hand, leptin had already been shown to be associated with asthma, and there have been reports that asthma and obesity are related4-7. The mechanisms by which leptin may be a risk factor for allergic rhinitis and asthma are not entirely understood, although a few recent studies have addressed this question4-9.
There is a close link between allergic rhinitis and allergic bronchial asthma. The lining of the airway from the nose to the lungs is similar in structure and therefore similarly affected by the allergic process - so what affects the nose also can affect the lungs. And often what happens in one part of the airway has an impact on the other. Although some patients with do not have asthma, inflammatory changes can still be evident in their lower airway. Up to % 30 of allergic rhinitis (AR) patients, with no past history of asthma, will show bronchial hyperreactivity to methacholine10.
A report from the American Academy of Allergy, Asthma, and Immunology estimated that up to 78 % of patients with asthma have nasal symptoms and 38 % of patients with allergic rhinitis have asthma11. Adequate treatment of rhinitis might positively affect the course of asthma, and worsening of rhinitis was associated with persistence of asthma symptoms10.
Because of these relations, various researchers, especially in the last ten years, have referred to allergic rhinitis and asthma as allergic united airway disease10,12-14 and recently as combined AR and asthma syndrome (CARAS)15.
Since, AR and asthma are both mediated by similar allergic inflammatory mechanism, we aimed to evaluate changes of serum leptin concentration and answer the question whether there exists a relationship between leptin levels and allergic rhinitis and asthma or not, and the effect of an inhaler and/or intranasal administered corticosteroid (budesonide) on it.
PATIENTS AND METHODS
This was a prospective study enrolling 43 patients with allergic rhinitis (10 of with mild asthma) (mean age 29.81, range 18-45 yr) and 32 volunteers as a control group (mean age 30.53, range 20-45 yr). All patients and control groups accepted to participate in the study. Patients were recruited during the symptomatic period in GATA Allergy Clinic, Ankara, Turkey.
Demographic characteristics were recorded and body mass index (BMI) values were calculated ( = weight [kg]/height2 (m2)] for all patients (table I). After a 12-hour overnight fast, venous blood samples were collected after 10 to 15 minutes of rest to measure serum leptin, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), eosinophil and total IgE levels. Samples were centrifuged at 4 °C; serum samples were stored at 70 °C until analysis. Low-density lipoprotein-cholesterol (LDL-C) and very low-density lipoprotein-cholesterol (VLDL-C) values were calculated with the Friedewald formula. The principle of the Friedewald formula is based on two assumptions: Firstly, that since very low-density lipoprotein (VLDL) carries most of the circulating triglycerides, VLDL-C can be estimated reasonably well as TG concentrations divided by constant (i.e. 5 for mg/dL and 2.2 for mmol/L). Secondly, that TC is distributed among the three major lipoprotein subclasses [namely HDL, LDL and VLDL. There are though some limitations as to the calculation of LDL-C according to the LDL-F formula, the two most common being that the patient needs to be fasting for at least 12 hours and that TG levels have to be < 400 mg/dL16 Serum leptin levels were measured by a commercially available kit (BIOSOURCE LEPTIN EASIA [BioSource Europe S.A., Nivelles, Belgium]) according to the manufacturer's instructions. (Reference interval in healthy lean adult: lean male 2.4 ± 1.1ng/ml, lean female 6.6 ± 3.0 ng/ml.)
Skin prick tests were performed on the forearms using extracts of grass mix, tree mix, cockroach, mould mix, weed mix, dermatophagoides pteronyssinus, dermatophagoides farinae, dander of dog and cat, negative and positive (histamine) control (Allergo, Stuttgart, Germany). Besides, ultrasonographic examinations performed to evaluate parenchymal changes of liver before and after treatment.
Allergic rhinitis was classified according to the 4 classes of ARIA (mild intermittent, mild persistent, moderate/severe intermittent, moderate/severe persistent), and defined as having a score of 2 or more on a 0 to 3 point scale (0, no symptoms and 3, severe symptoms) regarding to sneezing, itchy nose, running nose, stuffy nose, and eye symptoms17. All patients received nasal budesonide one month (in daily dose of 400 μ g).
Asthma was defined and severity was classified according to GINA guidelines and 10 asthmatic patients were additionally treated with a low dose of inhale corticosteroids (400 μ g inhale budesonide, daily) and rapid acting β 2-agonist, if needed18-20. Asthma symptoms, the number of symptom-free days, use of rescue medication were assessed from asthmatic patients during one month and the rate of asthmatic score was determined. Pulmonary function tests such as forced vital capacity (FVC), forced expiratory volume/1 second (FEV1) and FEV1/FVC were performed to all patients before and after treatment.
Inclusion Criteria for Study Entry was shown on table II. The University Bioethics Committee approved the study protocol and informed consent was obtained from each patient and volunteer.
The statistical analyses were performed using a statistical software package SPSS for windows, SPSS Inc. USA). Independent samples test statistical analysis was used to compare demographic findings of the subjects. In the analyses of presence of asthma, sex and age differences, comparison of serum leptin levels before and after treatment were used Pearson correlation test.
There were no differences between the two groups (patients and volunteers) with respect to demographic characteristics and laboratory analyses (including pulmonary function test), but clear significant differences were noted concerning the eosinophils, an indicator of allergic inflammation (table III). We found a direct link between increased BMI and serum leptin levels (p = 0.0001) (table IV). No association was seen between leptin and triglyceride, HDL-cholesterol, VLDL-cholesterol, eosinophil, total IgE (p > 0.05); except for total cholesterol and LDL-cholesterol (p < 0.05) (table IV).
There is no effect to the leptin levels on the severity of allergic rhinitis and asthma existence or not (tables V, VI). Although the allergenic sensitivity seems to be no effect on serum leptin concentrations (p > 0.05) (table VII), leptin level is found higher in pollen sensitivity than house dust mite sensitivity after separating from mix group (p = 0,026). When distributing the patients by bipartite of BMI (as normal and high weight or obese), the leptin levels were found an increase in high weight or obese (p = 0.008) (table VIII). A significant correlation was found between leptin and sex in two groups, in favor of female (p < 0.05) (table IX).
Although, no correlation between allergic rhinitis and mild asthma and serum levels of leptin was shown, these parameters and age correlations were stronger in female than in male, particularly in pre-menopausal women (p = 0.39 for male and p = 0.011 for female), and also found direct link between increased BMI and sex in patient group (p = 0.008 for male and p = 0.0001 for female) (table X). Serum leptin level distribution related to age and BMI were shown in graphic 1 and 2. There was no association between serum leptin level and patient symptoms (table XI).
Figure 1.--Serum leptin level distribution related to age.
Figure 2.--Serum leptin level distribution related to BMI.
We also determined that there was no effect of intranasal and/or inhaled steroids statistically on serum leptin levels (table XII). It was shown that while asthma score was improving with inhaled and intranasal steroids in allergic rhinitis and mild asthma (p = 0.017), serum leptin level was a little decreased, but not found statistically meaningful (p = 0.735) (table XIII). Lastly, all of ultrasonographic examinations (parenchymal changes of liver) were found normal.
Our results indicate that the serum leptin levels in allergic rhinitis and mild asthma are similar to normal groups. Our results also indicate that leptin levels show stronger correlation with BMI, particularly in pre-menopausal women. This result is concordant with literature5,6,21.
We found a significant positive correlation between serum leptin concentrations, cholesterol and LDL. A similar association between leptin levels and cholesterol and triglycerides was observed by Bedir et al. in healthy men22.
Previous studies have demonstrated that, increases in BMI and consequently obesity, have been associated with increased prevelance of asthma. But the mechanisms of this association are not fully understood4,5,23.
Some authors declared that, leptin shares structural and functional homology with IL-6 and it may be directly involved in the regulation of the humoral inflammatory response, stimulating the pro-inflammatory Th1 cytokine pathway and suppressing Th2 cytokine production7,24-29. In other words, leptin influences cytokine production from T lymphocytes, generally switching the phenotype toward a TH1 response30. It's known that leptin stimulates the release of proinflammatory cytokines such as interleukin-6, interferon- g and tumor necrosis factor from the adipose tissue and promotes Th1 immune responses, consequently29.
When we look at the mechanism of allergy, we can see that Th2 cells are responsible for allergic immune responses that they preferentially produce the cytokines IL-4 (that promotes IgE production and inhibits Th1), IL-5 (a growth and differentiation factor for eosinophils) and IL-13 (involved among other pro-allergenic processes in the bronchial tissue re-modulation that occurs in asthma). On the other hand, Th1 cells produce interferon-γ , and IL-2, which inhibit Th2 lymphocytes in experimental models such as in vitro cell cultures30. Actually, a shift from Th2-polarized immune response toward Th1-oriented pattern has been reported after SIT30,31. As a result, leptin may not be involved in allergic pathway, unlike obesity. Our results show the concordant to this situation. On the contrary to our results, some literatures support the hypothesis that leptin plays a key role in allergic process5,8,9.
Systemic administration of exogenous glucocorticoids has been found to increase circulating leptin levels32. But, nasal and/or inhaled budesonide up to 800 micrograms per day does not influence circulating leptin levels. This result is also concordant with literature33.
These results indicate that, the effect of leptin on allergic rhinitis and mild asthma was still unclear and to explain these mechanistic pathways need further large studies.
Bibliography1.Otero M, Lago R, Gomez R, et al. Towards a pro-inflammatory and immunomodulatory emerging role of leptin. Rheumatology 2006;45:944-50.
2.Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 2005;42:880-5.
3.Matarese G. Leptin and the immune system: how nutritional status influences the immune response. Eur Cytokine Netw 2000;11:7-14.
4.Shore SA, Fredberg JJ. Obesity, smooth muscle, and airway hyperresponsiveness. J Allergy Clin Immunol 2005;115: 925-7.
5.Matsuda K, Nishi Y, Okamatsu Y, Kojima M, Matsuishi T. Ghrelin and leptin: A link between obesity and allergy? J Allergy Clin Immunol 2006;117:705-6.
6.Sood A, Ford ES, Camargo CA. Association between leptin and asthma in adults. Thorax 2006;61:300-5.
7.Mai X-M, Böttcher MF, Leijon I. Leptin and asthma in overweight children at 12 years of age. Pediatr Allergy Immunol 2004:15;523-30.
8.Guler N, Kirerleri E, Ones U, Tamay Z, Salmayenli N, Darendeliler F. Leptin: does it have any role in childhood asthma? J Allergy Clin Immunol 2004;114:254-9.
9.Unal M, Eskandari G, Muslu N, Pata YS, Akbas Y. Serum leptin levels in patients with allergic rhinitis. Otolaryngol Head Neck Surg 2006;134:331-3.
10.Taramarcaz P, Gibson PG. The effectiveness of intranasal corticosteroids in combined allergic rhinitis and asthma syndrome. Clin Exp Allergy 2004;34:1883-9.
11.The Allergy Report. Overview of allergic diseases: diagnosis, management, and barriers to care. Vol 1. Milwaukee: American Academy of Allergy, Asthma, and Immunology, 2000.
12.Leynaert B, Neukirch F, Demoly P, et al. Epidemiologic evidence for asthma and rhinitis comorbidity. J Allergy Clin Immunol 2000;106:201-5.
13.Bugiani M, Carosso A, Migliore E, et al. Allergic rhinitis and asthma comorbidity in a survey of young adults in Italy. Allergy 2005;60:165-70.
14.Koh YY, Kim CK. The development of asthma in patients with allergic rhinitis. Curr Opin Allergy Clin Immunol 2003;3:159-64.
15.Passalacqua G, Canonica GW. Impact of rhinitis on airway inflammation: biological and therapeutic implications. Respir Res 2001;2:320-3.
16.Gazi I, Tsimihodimos V, Filippatos TD, et al. LDL cholesterol estimation in patients with the metabolic syndrome. Lipids Health Dis 2006;5:8.
17.Bousquet J, Neukirch F, Bousquet PJ. Severity and impairment of allergic rhinitis in patients consulting in primary care. J Allergy Clin Immunol 2006;117:158-62.
18.Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Workshop Group; World Health Organization. Allergic rhinitis and its impact on asthma.J Allergy Clin Immunol 2001;108: 147-334.
19.Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention NIH Pub. No 02-3659, January 1995. Updated 2005. [Cited 2006 Oct 24]. Available from: www.ginaasthma.com
20.Bousquet J, Clark TJ.H, Hurd S, et al. GINA guidelines on asthma and beyond. Allergy 2007;62:102-12.
21.Doniec Z, Pierzchala-Koziec K, Tomalak W, et al. Serum level of leptin and neuropeptide Y in children with mild asthma. Pneumonol Alergol Pol 2004;72:9-13.
22.Bedir A, Topbas¸ M, Tanyeri F, Alvur M, Ark N. Leptin might be a regulator of serum uric acid concentrations in humans. Jpn Heart J 2003;44:527-36.
23.Tantisira KG, Litonjua AA, Weiss ST, Fuhlbrigge AL. Association of body mass with pulmonary function in the Childhood Asthma Management Program. Thorax 2003;58:1036-41.
24.Wanamethee SG, Tchernova J, Whincup P et al. Plasma leptin: Associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis 2007;191:418-26.
25.Lord GM, Matarese G, Howard JK, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998;394:897-901.
26.Lord GM. Leptin as a proinflammatory cytokine. Contrib Nephrol 2006;151:151-64.
27.Bernotiene E, Palmer G, Gabay C. The role of leptin in innate and adaptive immune responses. Arthritis Res Ther 2006;8: 217.
28.Shore SA, Schwartzman IN, Mellema MS, et al. Effect of leptin on allergic airway responses in mice. J Allergy Clin Immunol 2005;115:103-9.
29.Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005;115:911-9.
30.Jayasekera NP, Toma TP, Williams A, Rajakulasingam K. Mechanisms of immunotherapy in allergic rhinitis. Biomed Pharmacother 2007;61:29-33.
31.Erel F, Karaayvaz M, Çals¸kaner Z, et al. Effect of allergen immunotherapy on the nazal mucosa in patient with allergic rhinits. J Invest Allergol Clin Immunol 2000;10:14-19.
32.Larsson H, Ahren B. Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. J Clin Endocrinol Metab 1996;81:4428-32.
33.Heuck C, Wolthers OD. Serum leptin in children with asthma treated with inhaled budesonide. Respir Med 1999;93: 268-71.