Prof Dr Berrin CeyhanMarmara University School of Medicine
Definition of anemia
WHO (World health organisation) describes anemia as
Hgb< 13g/dl or Htc<39% in malesHgb<12 g/dl or Htc<36% in females
AnemiaDisabilityImpaired physical performanceLower muscle strengthIncreased mortalityFatigueCachexiaImpaired moodLower cognitive functionQuality of life
Anemia in COPDIt can be the result ofSystemic inflammationNutritional disordersOccult blood lossDrugs (theopylline, ACE, Phenoterol via
direct, RAAS, and EPO secretion)Oxygen therapyDecreased renal flow (EPO is sytnthesized in
kidney)Hypogonadism in COPD (androgens stimulates
erythropoiesis via direct stimulation or RAAS )
Chronic disease anemiaChronic infectionsChronic inflammationNeoplasmsHeart failure
Mechanisms of chronic disease anemia
IL-6 Interferon gammaShortened RBC survival (IL-1 and TNF)Slight increase RBC productionImpaired proliferation of erythroid
precursors (IFN-gamma, free radicals)
Bone marrow can not respond to increased demand and relative erthropoietin resistance (IL-1, TNF-alpha, and IFN- gamma)
Impaired RES iron stores, sequestration of iron in macrophages, dysregulation of iron homeostasis, impaired iron utilisation and mobilisation (IL-1 and INF-gamma)
Alterations in hematopoiesis in COPDIncrease in mean corpuscular volume (MCV)29%-37% in COPD (MCV>94 fL)No correlation between MCV and PaO2mmHgRenin angiotensin aldosterone system (RAAS)
activationIncreased EPO with renin or aldosterone in
animal modelsACEI decreseases EPO and hematocritIn this group of COPD patients renin
aldosteron level 3 times higher when compared hypoxemic COPD patients
Anemia and cystic fibrosis
Inflammatory mediators IL-1, Il-8 and TNF-alpha
Nutritional factors
Iron kinetics are lower
Anemia and pulmonary fibrosis• Inflammatory cytokinesTNF-alpha, IL-6, IL-8 levels are high
• Erythroid colony forming unit is inhibited
• Ineffective erythropoiesis
• Lower hgb and EPO levels than COPD
• Tsantes A Med Sci Monit 2005
Anemia and pulmonary fibrosisN=9Hgb and serum EPO did not differ from
controlsTNF-alpha, IL-6 and IL-8 significantly raisedProliferating capacity of RBCs higherRate of differentiation of RBCs slower
Tsantes A Chest 2003
Epidemiology of COPD and anemia
7337 COPD patients between 1996-2003 23.1 % anemia(%23.3 % in heart failure patients)
John M Int J Cardiol 2006
177 COPD patients 31% anemic
58% normochrom normocytemic41% chronic disease anemia25 iron deficiency anemia34% other causes
Portillo K Rev Clin Esp 2007
COPD pts n=683 Cote C ERJ 2007
COPD pts n=683 Cote C ERJ 2007
2524 COPD patients receiving LTOT (ANTADIR)Anemia is seen 12.6% of males and 8.2% of females
Polycythaemia htc>54% (8.4% of patients)
Anemia is associated withSurvival rateHospital admission rateLonger duration of hospital stay
Polycythemia is associated with higher survival rates
If Htc>55% , 3 year survival rate is 70%If Htc <35%, 3 year survival rate is 24%
Chambellan A et al Chest 2005
Htc was the strongest predictor of mortality
Htc was inversely correlated with the hospital admission rate and duration of hospitalisation
Negative correlation with PaCO2 level
Other survival predictors• Age• Htc• BMI• PaO2• Sex • FEV1 Chambellan A et al Chest 2005
Markers of COPD severityBMIAirflow obstructionDyspneaExercise capacity
BODE indexPredictor of mortality due to respiratory or all other causes
Htc 42+/_5% for surviversHtc 39+/_5% for those who died
Celli Br NEJM 2004
Negative correlation between rate of hospitalisation and anemia
John M Int J Cardiol 2006
NETT Study .Increased mortality in anemic patients
Other mortality predictors: Age,oxygen use, higher residual volume, higher
BODE index Martinez et al Am J Respir Crit Care Med 2006
Clinical relevance of anemia of COPD
Blood cell transfusion leades to Reduction in minute ventilationReduction of work of breathingImproved pulmonary gas exchangeImproved exercise capacity
Ventilator dependent COPD pts after transfusion (hgb>12 g/dl) weaned in 1-4 days
Schoneofer B Anesthesia 1998
Anemia and economic implications2404 COPD patients 33% had anemiaAnnual costs 17240$ versus 6492 $
Shorr AF Curr ed Rev Opin 2008
132. 424 COPD patients21% had anemia mortality rate 262 vs 133 death/1000 person-
yearAnnual medicare payment 1466 $ vs 649$
Halpern MT Cost Eff Resour Alloc 2006
Osteoporosis and COPDEtiologyInflammatory lung diseaseReduced physical activityReduced skeletal muscle massSystemic inflammationTreatment (steroids )Ageing (hypogonadism, reduced muscle
mass, inactivity)
Diagnosis
Dual energy X-Ray absorptiometry (DXA)
T score; a standart deviation compared to a young adult sex matched control population
Z score ; a standard deviation compared to an age and sex matched control population
Epidemiology15 pre-transplantation COPD pts 45% had bone Z scores of >2SD
Pre transplantation cystic fibrosis pts75%
Other pulmonary disease pts15%
Aris RM Chest 1996
29% vertebral fractures in pre-transplantation COPD patients
Shane E Am J Med 1996
Epidemiology 44 elderly female patients (ICS treatment)
20 pts with COPD 50%(correlated with BMI)
24 pts with asthma 21% have osteoporosis (288 vs 743 miligram ICS)
Total cumulative BDP dose did not correlate with BMD
BMD is high even higher BDP dose in asthma Katsura H Chest 2002
Epidemiology412 COPD patients, 1200 mcg taking
triamcinoloneGreater lumbar spine and femoral neck
osteoporosis in triamcinalone group in 3 years, no increased fracture risk
LHSR NEJM 2000
102 smoker COPD patients with mild COPD, taking budesonide
A modest reduction at the trochanteric site BMD in 3 years (13.4% versus 11.5% vertebral fracture)
Pauwels RA NEJM 1999
Osteoporosis risk factors
Smoking ( lung low attenuation area correlated with reduced bone density)
Olvara T Chest 2008
Increased alcohol intake (RR: 2.4)Low Vitamin D level (It regulates the absorption of calcium,
PTH, bone resorption)Genetic factors(COLIA1 gene
polymorphism encodes type I Collagen)
Osteoporosis risk factors Treatment with corticosteroidsReduces the absorption of calcium in the gut Increases the renal excretion of calciumStimulates the bone resorption (through the
effect of parathormone)Inhibits the osteoblastic lineEspecially in trabecular bone(proximal femur,
Ward’s triangle) and cortical rim of the vertebral bodies
Mecran K Am J Respir Crit Care Med 1995
A reduction of osteocalcin after first week (42% of pts with oral steroid and 17% of pts with beclamethasone Mecran K Am J Respir Crit Care Med 1995
Mild to moderate COPD 1.2 mg/day triamcinolone for 40 months. BMD reduction in lumbar spine and femoral neck
Scanlon PD Am J Resp Crit Care Med 2004
Mild COPD pts 800 ug budesonide 3 years no reduction in BMD
800 ug beclomethasone and budesonide and 750 ug flixotide had limited effects on bone metabolism
LHSRG NEJM 2000,Goldstein MF Chest 1999, Pauwels RA NEJM 1999
Osteoporosis risk factorsReduced skeletal muscle mass and strength
which is related to BMDThe greater the stress on a bone area, the greater
the bone mass
In COPD, Reduced mobility due to shortness of breath steroid myopathy metabolic factors may cause osteoporosisBMD at femoral neck was up to 10% greater in those
who exercised regularlyValimaki MJ BMJ 1994
Osteoporosis risk factorsWeight loss and Low BMI are predictors of
mortality
FFM( fat free mass) is associated with exacerbations and hospital admission rate
FFM are related to bone density
Load of soft tissue preserves the bone mass
Mostert R Respir Med 2000
Osteoporosis risk factorsHypogonadism and reduced IGF
Oestrogen regulates bone resorption and formation
Testesterone regulates bone formation
Ageing causes low eostrogen and testerone levels
Steroid treatment decreases LH and circulating oestrogen and testerone levels
IGF-1 stimulate the differentiation and proliferation of osteoblasts
Osteoporosis risk factors Chronic systemic inflammationIL-1 alpha and TNF-alpha stimulate bone
resorptionIL-6 stimulates the formation of osteoclasts
Raisz LG NEJM 1988
Consequences of osteoporosis in COPDSteroid treatment increases the risk of
fractures RR: 1.33-1.61Risk disappeared within 1 year after stopped
Van Staa TP J Bone Miner Res 2001
Consequences of osteoporosis in COPD312 male COPD pts , prevalance of at least one
vertebral fracture
48.7% pts never used steroid 57.1% pts received inh. steroids63.3% pts receiving systemic steroids
McEvoy CE Crit Care Med 1998
Consequences of osteoporosis in COPDThoracic vertebral fracture and hyperkyphosis
causes10% reduction FVC in lung function
Mortality after hip fracture is 20% in first year
Morbidity; 19% requires residential careHigh economic burden
UK, 108745 patients (9100 asthma and 5500 COPD) OR;
Asthma 1.28COPD 1.611500 microgm BDP increases fracture risk 1.95(hip
1.77 and vertebra 3.78)OCS risk 1.75Smoking 1.57-1.79Fracture risk disappeared after adjustment was
made for disease severity in pts using ICS (1.47-1.48 F De Vries ERJ 2005
Severity of obstructive airway disease and risk of osteoporotic fracture
F De Vries ERJ 2005
Therapeutic interventions
Low VitD concentration linked to ;
Osteoporosis HT İschemic heart disease Cancer Tip I diabetes FEV1 and FVC
Calcium and Vitamin D supplement reduce bone loss rate
Minimum daily intake;1200 mg calcium >50 yrs1500 mg calcium and VitD3 400IU/day
steroid induced osteoporosis
Black PN Chest 2005 Lane NE Endocrinol Metab Clin Nort Am 1998
Hormone replacement
In postmenopausal femalesOest+prog reduce the speed of bone loss
Testerone improve the BMD in pts with long term steroid treatment
Reid IR Arch Intern Med 1996
Calcitonine
A peptide hormone secreted by the C cells of the thyroid
It has inhibitory effect on the osteoclasts1/3 pts stopped the treatment with
exacerbation of asthma
Luengo M Thorax 1994
BiphosphonatesAnalogue of pyrophosphate has affinity for
hydroxyapatite in the bone (etidronat, alendronat ve risedronat )
They inhibit the action of osteoclasts, and therefore inhibit bone resorption
BTS placebo controlled study in 700 asthmatic oral and/or inhaled steroid ; 5 year study
Effect of etidronate and/or calcium supplement?1 year treatment with biphosphonate 524$
ParathormonIt increases bone formation in small dosesRaloksifen“Selektif oestrogen receptor modulator”.
Prevention and treatment after menopauseStronsiyum RanelatIt increases bone formation and decreases
bone resorption
PreventionTraning program and conditioningHormone replacement therapyIntake of calcium and vitamin D (1200-1500
mg/day calcium and 400 IU vit D/day
In pts on long term inhaled steroids and systemic steroids
REGULAR BMD by DXA should be undertaken