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Metabolic changes in COPD Metabolic changes in COPD and its clinical implication.and its clinical implication.
Dr. Benjamin J Tanuwihardja, SpP, FCCP.Fakultas Kedokteran-Universitas Kristen Maranatha
Konsultan Balai Pengobatan Penyakit Paru-Paru (BP-4) Bandung
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Pathogenesis of COPDPathogenesis of COPD
NOXIOUS AGENT(tobacco smoke, pollutants, occupational agent)
Genetic factorsRespiratory infectionOther
COPDwww.GOLDCOPD.com
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Inflammatory cells and mediators Inflammatory cells and mediators involved in the pathogenesis of COPDinvolved in the pathogenesis of COPD
Adapted from GOLD workshop report 2001
Cells
MacrophagesNeutrophilsCD8+ lymphocytesEosinophilsEpithelial cellsFibroblasts
Mediators
LTB4, IL-8GRO-1αMCP-1MIP -1αGM-CSFEndothelinSubstance P
Proteinases
Neutrophil elastaseMatrix-metalloproteinasesCathepsinsProteinase-3
EffectsMucus secretion, fibrosis, alveolar wall destruction
Oxidative stress
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COPDCOPD
Chest X-Ray PA
Pulmonary EmphysemaPulmonary Emphysema(pink puffer)(pink puffer)
Chronic BronchitisChronic Bronchitis(Blue Bloater)(Blue Bloater)
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COPDComplications
COPDComplications
SYSTEMICEFFECTSIN COPD
SYSTEMICEFFECTSIN COPD
CARDIOVASCULARDISORDER
CARDIOVASCULARDISORDER
HANDICAP / DISABILITYHANDICAP / DISABILITY
NUTRITIONALDISORDER
NUTRITIONALDISORDER
OsteoporosisEndocrine
disturbances
OsteoporosisEndocrine
disturbances
SYSTEMICINFLAMMATORY
RESPONSE
SYSTEMICINFLAMMATORY
RESPONSE
RESPIRATORYMUSCLE
DYSFUNCTION
RESPIRATORYMUSCLE
DYSFUNCTION
Wouters,EMF. Eur Respir J 2003; 22, Suppl. 46
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NUTRITIONAL DISORDER
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Malnourished COPD Malnourished COPD patientpatient
Body Mass Index(BMI = weight / height= weight / height22)
Body Mass Index (BMI)
Underweight : BMI < 18.5
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Measurement of Nutritional DepletionMeasurement of Nutritional Depletion
l Body Weight <90% IBW (ideal body weight)l BMI (body mass index) = weight/height2 is <20
kg·m-2 or 18.5 kg·m-2
l Fat mass (FM). l Fat -free mass (FFM)
– Bioelectrical impedance (BIA) is a simple method to assess FFM
– Dual-energy X-ray absorptiometry (DEXA) : first measures the bone mass and the soft tissue mass independently, then separates the soft tissue mass into lean tissue mass and FM
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DexaDexa scanscan
SkinfoldsSkinfolds
Bioelectrical Bioelectrical impedanceimpedance
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Prevalence of FFM depletion in Prevalence of FFM depletion in stable moderatestable moderate--toto--severe COPDsevere COPD
l Outpatients : 20 %l Eligible for pulm. rehabilitation : 35 %l Lung transplant candidates : 45 %
Engelen, MP. Eur Respir J 1994,7:1793– 1797
Schols,AM. Am Rev Respir Dis 1993,147:1151– 1156
Schwebel,C. Eur Respir J 2000,16:1050– 1055
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9%26%
10%55%
Underweight Muscle wasting
Underweight Normal muscle mass
Normal weight Muscle wasting
Normal weightNormal muscle mass
Body composition in COPD
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Impact of nutritional depletion Impact of nutritional depletion on COPD out comeon COPD out come
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Nutritional status and mortality in Nutritional status and mortality in COPDCOPD
l 348 severe COPD patients was studied in a cohort of Canadian men and women followed for 3 to 5 yr
l evaluated for lung function and body weightl In conclusion, low body weight was
associated with respiratory mortality in severe COPD
Gray-Donald,K. Am. J. Respir. Crit. Care Med., 1996,153:961-966.
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Prognostic Value of Nutritional Status in COPDPrognostic Value of Nutritional Status in COPD
l Prospective study: whether BMI is an independent predictor of mortality in subjects with COPD from the Copenhagen City Heart Study.
l 1,218 men and 914 women, aged 21 to 89 yr, with airway obstruction defined as an FEV1 / FVC ratio < 0.7
l Spirometric values, BMI, smoking habits, and respiratorysymptoms were assessed at the time of study enrollment, and mortality from COPD and from all causes during 17 yr of follow-up
LANDBO, C. Am. J. Respir. Crit. Care Med., 1999,160:1856-1861
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Results Results
l Low BMI is an independent risk factor for mortality in subjects with COPD, andthat the association is strongest in subjects with severe COPD
LANDBO, C. Am. J. Respir. Crit. Care Med., 1999,160:1856-1861
COPDCOPD--related mortality by BMI related mortality by BMI in subjects with mild, moderate in subjects with mild, moderate
and severe COPD.and severe COPD.
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Weight Loss Is a Reversible Factor in Weight Loss Is a Reversible Factor in the Prognosis of COPDthe Prognosis of COPD
l (1) a retrospective study, 400 patients with COPD none of whom had received nutritional therapy; done in theNetherlands.
l (2) a prospective study, 203 patients with COPD who had participated in a randomized placebo-controlled trial.
l The results:l body weight has an independent effect on survival in COPDl the negative effect of low body weight can be reversed
by appropriate therapy in some of the patients with COPD
SCHOLS,AMWJ. Am. J. Respir. Crit. Care Med., 1998, 157: 1791-1797
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Survival was significantly decreased in both underweight and normal weight patients as compared with overweight and obese patients. (p < 0.0001).
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FEV1 was significantly lower in the underweight and normal weight patients compared with the overweight and obese patients
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Nutritional support consisted of a daily high caloric liquid supplement and combinedwith Anabolic steroid treatment consisted of four injections with Decadurabolin
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Respiratory muscle strength was measured as mouth pressure during maximal static inspiratory (PImax) maneuvers from RV
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Treatment with Growth Treatment with Growth Hormone Hormone
l Growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in COPD
l Randomized placebo control studyl the daily administration of 0.15 IU/kg rhGH during 3 wk
increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.
BURDET, L. Am. J. Respir. Crit. Care Med., 1997, 156: 1800-1806
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MegestrolMegestrol Acetate Stimulates Weight Gain Acetate Stimulates Weight Gain and Ventilation in Underweight COPD Pts.and Ventilation in Underweight COPD Pts.
l Prospective, double-blind, randomized, placebo-controlled trial conducted on an outpatient basis at 18 sites
l Underweight (< 95% ideal body weight) COPD patients > 40 years old
l MA, 800 mg/d oral suspension, or placebo at a 1:1 ratio for 8 weeks
l Of 145 randomized patients (63% men), 128 patients completed the trial
Weisberg,J. Chest. 2002;121:1070-1078
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Body weight ± 1 SE in each group at each Body weight ± 1 SE in each group at each assessment is shownassessment is shown
Weisberg,J. Chest. 2002;121:1070-1078
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PaCOPaCO22 Values in Values in HypercapnicHypercapnic PatientsPatients**
0.020-0.3-4.5Change from baseline50.3 (7.2)44.8 (6.3)Week 8
0.026-1.3-4.6Change from baseline49.3 (5.5)44.7 (6.0)Week 4
0.1650.4-4.4Change from baseline51.0 (12.2)44.9 (6.5)Week 250.6 (5.2)49.3 (3.5)Baseline
p ValuePlacebo Group (n = 12)
MA Group (n = 15)
PaCO2 Values, mm Hg
Weisberg,J. Chest. 2002;121:1070-1078
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PaOPaO22 Values in Hypoxic PatientsValues in Hypoxic Patients**
0.1762.75.7Change from baseline61.2 (11.5)66.5 (11.3)Week 8
0.0052.39.9Change from baseline60.8 (9.9)70.7 (14.1)Week 4
0.0062.37.7Change from baseline60.8 (9.9)68.5 (10.7)Week 258.5 (8.3)60.8 (6.6)Baseline
p ValuePlacebo Group (n = 29)
MA Group (n = 35)
PaO2 Values, mm Hg
Weisberg,J. Chest. 2002;121:1070-1078
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Nutritional Support for Nutritional Support for Individuals With COPDIndividuals With COPD
( A Meta( A Meta--analysis)analysis)
l From 272 references, 9 RCTs were ultimately included.Six articles were considered as high quality.
l Only 2 studies were double blinded.l Conclusion: Nutritional support had no effect
on improving anthropometric measures, lung function, or functional exercise capacity amongpatients with stable COPD.
Ferreira,I.M. Chest. 2000;117:672-678
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SYSTEMIC INFLAMMATIONIN COPD
Oudijk,EJD. Eur Respir J 2003; 22: Suppl. 46, 5s-13s
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Chronic inflammation in the lungChronic inflammation in the lung
Sensory nerves
Cigarette smoke
Alveolar macrophage
Neutrophil
Inhibited byα1-antitrypsin
Neutrophil elastaseAnd other proteolytic enzymes
Mucus secretion(chronic bronchitis)
Alveolar wall destruction(emphysema)
Cytokines and chemotactic factors(TNFα, IL-8, LTB4, etc)
LUNGS
-–
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Crapo,J. 1st ERS lung Science Conference, Taormina, 2003.
Oxidative stress as an initiator of cytokine
release and cell damage.
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muscle wastingimpairment
health status
exercise intolerancedyspneadisability
handicap
skeletal muscle dysfunction
respiratory musclefunction
inflammation
lung impairment
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è spill over from lungs?èenhanced by hypoxia?
inflammation
Elevated circulating levels of:
- TNFα, sTNF-R55, sTNF-R75- IL-8, IL-6, sIL-6R- acute phase proteins
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Inflammation in the airways Inflammation in the airways lead to systemic effects.lead to systemic effects.
Local / lung Systemic effects
Acute
Chronic
Damage of lung tissue / COPD
Leucocytes activation in PB
Cytokines TNF α
Muscle wasting
Weight loss
↓ Prognosis
Ouddijk,EJD. Systemic inflammation in COPD Eur Respir J 2003;22:Suppl. 46, 5s-13s
Effect of smoke
ROS
Mø, PMN
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Model for disease progression in COPDModel for disease progression in COPD
Switch to chronicitySubclinical Clinical
Reversible inflammation
Irreversible inflammation
Mononuclear cells
PMN PMN
Systemic response
Oudijk,EJD. Eur Respir J 2003; 22: Suppl. 46, 5s-13s
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Thank You for your attentionThank You for your attention
Cigarette: A pinch of tobacco rolled in paper
with fire at one end and a fool on the other.
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