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

Obesity

Coroner Arter Diseases

Diabetes MellitusHypertension

Asthma

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 :

1. Genetic effects of obesity

2. Immune modification by obesity

3. Direct mechanical effects of obesity

1. 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

concentration was 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 cellsof a human cell line through its spesific leptin receptor

It was projected leptin may provide a link between inflammationand 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

Asthma Obesity

Kentaro M et al. J Allergy Clin Immunol 2006; 117:705- 6

Leptin and atopy

Beuther AD et al. Am J Respır Crıt Care Med 2006; 174:112-119

Asthma, obesity, atopy and LEPTIN

Obesity-asthma control (1)

Obesity also appears to play a role in asthma severity andcontrol, and alters the efficacy of standard asthma medications.

It was determinated that obese or overweight subjects accountfor 75% of emergency department visits for asthma

It was noted an increase in asthma severity with obesity in apopulation 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 oradults

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, IL6and 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)

ObeseMean±S.D (Min.-Maks.)

NonobeseMean±S.D

(Min.-Maks.)p

Age (year)

53,90±10,19 (33-76) 47,30±15,65 (20-83) 0,027

Duration of asthma (year)

8,94±8,79 (1,0-45) 8,30±8,68 (0-45) 0,743

BMI (kg/m²) 34,87±4,26 (30-47) 25,5±2,84 (18-29,1) 0,000

FEV1 (%) 93,10±18,83 (67,20-106,) 145,47±20,4 (67,2-106,) 0,115

FEV1 (ml) 2054,63±528,46 (820-3040) 2447±698,98 (710-3820) 0,006

PEF (lt/sn) 5,01±1,34 (2,42-8,15) 5,79±1,41 (2,90-8,95) 0,013

PEF (%) 89,63±24,16 (42,2—142) 95,81±19,29 (66,7-150,) 0,207

T.IgE (IU/ml) 134,46±201,8 (1,03-1034)

117,09±218,0 (2,60-1226)

0,711

Allerjik Rinitispresense (%)

63,40 57,50 0,58

Sinusitis presense (%)

53.70 40.00 0,21

Nazal Polyppresense (%)

7,30 0 0,24

Pulmonary function tests and characteristics of the study population

Signs

 Obese atopis

Mean±S.D(Min.-Maks.)

Obese nonatopic

Mean±S.D(Min.-Maks.)

P.

Age (year) 53,65±11,15 (33-71) 54,14±9,460 (41-76) 0,176

Duration ofasthma (year)

9,48±10,22 (1,0-45) 8,43±7,39 (1-30) 0,948

BMI (kg/m²) 35,81±5,03 (30-47) 33,97±3,26 (30-41,6) 0,354

FEV1 (ml) 2182,50±551,86 (820-3040) 1932,86±487,13 (1090-2870) 0,109

FEV1 (%) 97,13±18,49 (55,-142,) 89,26±18,7 (42,2-131,) 0,201

PEF (ml) 5,17±1,54 (2,42-8,1) 4,86±1,13 (2,91-7,69) 0,273

PEF (%) 96,17±21,11 (45-121) 83,43±25,7 (42,2-131,) 0,083

T.IgE IU/ml195,80±254,49 (11,10-

1034,00)76,04±112,34 (1,03-500) 0,007

Allerjik Rinitis presense

(%)50 76,2 0,08

Sinüsitis presense

(%)60 47,6 0,42

Nazal Polyppresense (%)

5 9,5 1

Pulmonary function tests and characteristics of in obese cases

Obese

Median (Min.-Maks.)

Nonobez

Median (Min.-Maks.)

p

Leptin levels (pg/ml) 22,60 (4,80- 100,00) 16,70 (2,32- 92,10) 0,050

FENO levels (ppb) 21,00 (11,00- 52,00) 22,50 (6,00-297,00) 0,532

ACT 19,00 (7,00-25,00) 23,00 (9,00-25,00) 0,090

The study parameters in obese and non-obese cases

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)

R2 = 0,1378

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45 50

Leptin düzeyi (pg/ml)

VK

İ (kg

/m²) Leptin

düzeyi

The relation between BMI and serum leptin levels in all cases

r=0,394, p<0,001

Asthma control was evaluated in obese group

39%

61%

AKT<20

AKT≥ 20

38%

62%

AKT<20

AKT≥ 20

61% of obese patients had ACT<20 where, the ratio was 38% in non-obese patients (p:0,035).

Asthma control was evaluated in non-obese group

0

10

20

30

40

50

60

AKT

F EN

O d

üzey

i (pp

b)

FENO

<20 ≥20

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 FENO levels in obese group (n:41);

p:0,799

0

20

40

60

80

100

120

AKT

Lep

tin d

üzey

i (pg

/ml)

leptin

<20 ≥20

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 ACT and serum leptin levels in obese group (n:41);

p:0,371

The relation between serum leptin levels and FENO levelsin obese group (n:41);

R2 = 0,0684

0

10

20

30

40

50

60

0 20 40 60 80 100 120

Leptin düzeyi (pg/ml)

F EN

O d

üzey

i (pp

b)

FENO

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 totalimmunglobulin 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)

Obese atopic

Median(Min.-Maks.)

Obese nonatopic

Median (Min.-Maks.)

p

Leptin Levels (pg/ml )

25,77 (8,40- 100,00) 20,39 (4,80- 100,00) 0,23

FENO Levels (ppb) 21,50 (11,00- 52,00) 20,00 (12,00- 49,00) 0,43

ACT 19,00 (7,00-25,00) 18,00 (7,00-25,00) 0,33

Study parameters of according to atopy in obese group

R2 = 0,0001

0

20

40

60

80

100

120

0 200 400 600 800 1000 1200 1400

T.IgE (IU/ml)

Lept

in d

üzey

i (pg

/ml)

Leptin düzeyi

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).

Premenstruel semptom

MENSVAR

varyok

Me

d L

EP

TIN

50

40

30

20

10

Premenstruel semptom

Serum leptin düzeyi pg/ml

p:0,005

Serum leptine levels in patients who complained of

premenstrual asthma

Serum leptin levels were positively correlated with BMI in all cases (p:0,05)

Total immunoglobulin E levels 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 bothindicators increased in a correlation may be related with that theleptin synthesized in little amount in lungs bridged between T cellsand inflammatory cells and released inflammatory cytokins. It wasalso found that the İNOS increase stimulated by inflammatorycytokins like TNFα, IL1, IFNγ resulted in an increase in level ofFENO. Therefore, an increase in ‘Leptin and FENO’ levels actslike ‘cause and result’ in the chronic inflammations observed inassembly of asthma and obesity.

It was found that release of inflammatory cytokins related withhigh levels of leptin contributed to increased premenstrualsymptoms in asthmatic patients.

Besides, it was displayed that obesity affects AKT scoresoffered today for evaluating the control of asthmasignificantly, 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

hadnon-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’tstatistical 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 stateof chronic inflammation. So it was thougt of sistemic inflammation that was occured byadipokines and cytokines were to taken part ofimportance in the pathogenesis of asthma andobesity

It has shown that obesity complicates the control of the asthma