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