Αναιμία και ΙΦΝΕ. Ιωάννης Ε. Κουτρουμπάκης Αναπληρωτής Καθηγητής Γαστρεντερολογίας Ιατρικής Σχολής Πανεπιστημίου Κρήτης

Transcription

1 Αναιμία και ΙΦΝΕ Ιωάννης Ε. Κουτρουμπάκης Αναπληρωτής Καθηγητής Γαστρεντερολογίας Ιατρικής Σχολής Πανεπιστημίου Κρήτης 1

2 Αναιμία και ΙΦΝΕ Ορισμός, αιτιολογία, κλινικά χαρακτηριστικά Επιδημιολογία Παθοφυσιολογικοί μηχανισμοί Διαγνωστική προσέγγιση Θεραπευτική αντιμετώπιση 2

3 Minimum Hemoglobin and Hematocrit Levels Used to Define Anemia in People Living at Sea Level 3

4 Επιπολασμός αναιμίας σε ασθενείς με ΙΦΝΕ Gisbert AJG

5 5

6 Επιπολασμός αναιμίας σε ασθενείς με ΙΦΝΕ 6 Koutroubakis et al J Clin Gastroenterol 2015

7 Παράγοντες κινδύνου για ανάπτυξη αναιμίας σε 1821 ασθενείς με ΙΦΝΕ 7 Koutroubakis et al J Clin Gastroenterol 2015

8 Anemia a complication of IBD Quality of life Hb >12/13g/dl Hb <12/13g/dl Cognitive functions Ability to work Hospitalization and mortality 8

9 Etiology of Anemia in Inflammatory Bowel Diseases Gasche et al IBD

10 Σιδηροπενία στις ΙΦΝΕ Χαμηλή πρόσληψη Πλημμελής απορρόφηση Σχετιζόμενη με νόσο Crohn Σχετιζόμενη με την φλεγμονή Συνεχής απώλεια αίματος Εμφανής (ελκώδης κολίτις) Μη εμφανής (νόσος Crohn) Lomer MC, Br J Nutr Semrin G, Inflamm Bowel Dis Kulnigg S, APT 2006

11 Why is Deficiency Anemia Important? Central Nervous System Fatigue and depression Impaired cognitive function Immune System Impaired ROS production Alterations in T cell and macrophage function Gastrointestinal System Anorexia Nausea Motility disorders Vascular System Hypothermia Pallor of skin Cardiorespiratory System Exertional dyspnea Tachycardia, palpitations Cardiac hypertrophy Systolic ejection murmur Risk of cardiac failure Genital Tract Menstrual problems Loss of libido Goodnough TL et al. Available at:

12 Anemia as a marker of disease severity Koutroubakis et al Clin Gastroenterol Hepatol

13 The burden of anemia in IBD Koutroubakis et al Clin Gastroenterol Hepatol

14 Persistent or Recurrent Anemia Is Associated With Severe and Disabling IBD 14 Koutroubakis et al Clin Gastroenterol Hepatol 2015

15 Impaired Intestinal Absorption in IBD (with elevated IL-6 levels) Interleukin

16 Hepcidin is a Critical Regulator of Homeostasis and is Increased in Inflammation 25-aa peptide Principal regulator of iron absorption and distribution to tissues Synthesized predominantly in hepatocytes Binds to ferroportin, causes internalization and degradation Hepcidin increased in inflammatory states Nemeth E, Ganz T. Acta Haematol. 2009;122:78-86.

17 Hepcidin: The Master Regulator of Absorption Fe 2+ Ferroportin Stein J, Dignass AU. Ann Gastroenterol. 2012;26:1-10.

18 Hepcidin: The Master Regulator of Absorption Ferroportin Hepcidin Stein J, Dignass AU. Ann Gastroenterol. 2012;26:1-10.

19 Hepcidin: The Master Regulator of Absorption Hepcidin export through ferroportin Hepcidin Ferroportin degradation: locked in cell Ferroportin Hepcidin Stein J, Dignass AU. Ann Gastroenterol. 2012;26:1-10.

20 Serum Hepcidin and Prohepcidin in IBD 20 Oustamanolakis P, Eur J Gastroenterol Hepatol. 2011

21 Πιθανά μονοπάτια στα οποία η έκφραση και η ενεργότητα της hepcidin μπορούν να τροποποιηθούν φαρμακολογικά 21 Bartnikas TB, J Clin Invest. 2010

22 ECCO Guidelines on anaemia in IBD ECCO Statement 1D ( Deficiency) Diagnostic criteria for iron deficiency depend on the level of inflammation. In patients without clinical, endoscopic or biochemical evidence of active disease serum ferritin <30 µg/l is an appropriate criterion. [EL 2] ECCO Statement 1E (Anaemia of Chronic Disease) In the presence of biochemical or clinical evidence of inflammation, the diagnostic criteria for ACD are a serum ferritin >100 µg/l and TfS <20%. If the serum ferritin level is between 30 and 100 µg/l, a combination of true iron deficiency and ACD is likely. [EL 2] Dignass et al ECCO guidelines 2015

23 Anemia Evaluation Screening Parameter: Hemoglobin, ferritin, CRP every 6-12 months Anemia work up Ferritin, transferrin saturation, CRP transferrin, vitamin B12, folic acid, haptoglobin, LDH, creatinin, reticulocytes, differential WBC count Gasche C, Inflamm Bowel Dis 2007 (Guidelines) 23

24 IDA and ACD Typically Overlap Serum ferritin <30 µg/l (no inflammation) <100 µg/l (inflammation) Or: TSAT <16% IDA ACD - Serum ferritin >100 µg/l - TSAT <16% - Serum ferritin µg/l - TSAT <16% 24

25 stfr & stfr-f 7 stfr (mg/l) P<0.0001) 12 stfr-f P< IDA Non IDA 0 IDA Non IDA Κατανομή των επιπέδων stfr & stfr-f σε ασθενείς με ΙΦΝΕ και ΣΠΑ (IDA, n=30) και ασθενείς χωρίς ΣΠΑ (Non IDA, n=70). Τα ορθογώνια αναπαριστούν την τιμή median με το εύρος 25-75%. Οι άξονες δείχνουν το εύρος 5-95%. 25 Oustamanolakis P, Inflamm Bowel Dis Oustamanolakis P, Ann Gastroenterol 2011

26 Sensitivity Specificity Hepcidin MCV RDW RSF stfr stfrf Oustamanolakis P, Inflamm Bowel Dis Oustamanolakis P, Ann Gastroenterol 2011 Hepcidin Cut-off value <79.4 ng/ml Sensitivit y (%) Specificit y (%) PPV (%) NPV (%) AUC MCV < RDW >14% RSF <98.6 fl stfr >1.8 mg/l stfr-f >

27 Αλγόριθμος διαφορικής διάγνωσης ΣΠΑ από ΑΧΝ 27 Oustamanolakis P, J Crohn s Colitis. 2011

28 Treatment of Anemia Triggers of treatment: Treatment to be considered if HB is below normal Targets of treatment: Hb normalization or increase >2g/dl within 4 weeks supplementation: The preferred route is intravenous Absolute i.v. indications : severe anemia, intolerance or inappropriate response to oral iron, severe disease activity, EPO therapy, patients' preference EPO therapy: For anemia of chronic disease 28 Gasche C, Inflamm Bowel Dis 2007 ; Dignass et al ECCO guidelines 2015

29 Υπολογισμός αναγκών σιδήρου Ganzoni Equation Total Deficit = Weight {kg} x (Target Hb Actual Hb) {g/l} x stores {mg 500 if W > 35kg} 29

30 Oral Boosts Intestinal Inflammation mg Fe 2+ 10% absorbed Fenton Reaction: 30 Fe 2+ + H 2 O 2 Fe 3+ + OH + OH -

31 Oral vs intravenous 31

32 Oral vs. Sucrose 32 Erichsen, Scand J Gastroenterol 2005

33 Intravenous Compounds dextran (LMW) gluconate sucrose carboxymaltose Ferumoxyt ol Isomaltoside Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd 731 kd 150 kd Complex stability High Low Moderate High High High Test dose required Yes No Yes No No No Maximum approved dose 20 mg/kg BW 62.5 mg 200 mg* 7 mg/kg BW 1000 mg > 66 kg 15mg/kg b 510 mg 20 mg/kg BW Maximum Infusion period Maximum single dose on injection Minimum Infusion period 360 min 30 min 210 min 15 min 17 sec 15 min 200 mg 62.5 mg 200 mg 200 mg 510 mg 200 mg 2 min 10 min 10 min Bolus 17 sec Bolus Dose-related reactions Hypotension, oedema Hypotension, oedema Hypotension, oedema None reported None reported None reported RR of severe side effects Moderate Low Very low None reported Very low 33 None reported

34 Intravenous Compounds dextran (LMW) gluconate sucrose carboxymaltose Ferumoxyt ol Isomaltoside Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd 731 kd 150 kd Complex stability High Low Moderate High High High Test dose required Yes No Yes No No No Maximum approved dose 20 mg/kg BW 62.5 mg 200 mg* 7 mg/kg BW 1000 mg > 66 kg 15mg/kg b 510 mg 20 mg/kg BW Maximum Infusion period Maximum single dose on injection Minimum Infusion period 360 min 30 min 210 min 15 min 17 sec 15 min 200 mg 62.5 mg 200 mg 200 mg 510 mg 200 mg 2 min 10 min 10 min Bolus 17 sec Bolus Dose-related reactions Hypotension, oedema Hypotension, oedema Hypotension, oedema None reported None reported None reported RR of severe side effects Moderate Low Very low None reported Very low 34 None reported

35 Intravenous Compounds dextran (LMW) gluconate sucrose carboxymaltose Ferumoxyt ol Isomaltoside Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd 731 kd 150 kd Complex stability High Low Moderate High High High Test dose required Yes No Yes No No No Maximum approved dose 20 mg/kg BW 62.5 mg 200 mg* 7 mg/kg BW 1000 mg > 66 kg 15mg/kg b 510 mg 20 mg/kg BW Maximum Infusion period Maximum single dose on injection Minimum Infusion period 360 min 30 min 210 min 15 min 17 sec 15 min 200 mg 62.5 mg 200 mg 200 mg 510 mg 200 mg 2 min 10 min 10 min Bolus 17 sec Bolus Dose-related reactions Hypotension, oedema Hypotension, oedema Hypotension, oedema None reported None reported None reported RR of severe side effects Moderate Low Very low None reported Very low 35 None reported

36 Intravenous Compounds dextran (LMW) gluconate sucrose carboxymaltose Ferumoxyt ol Isomaltoside Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd 731 kd 150 kd Complex stability High Low Moderate High High High Test dose required Yes No Yes No No No Maximum approved dose 20 mg/kg BW 62.5 mg 200 mg* 7 mg/kg BW 1000 mg > 66 kg 15mg/kg b 510 mg 20 mg/kg BW Maximum Infusion period Maximum single dose on injection Minimum Infusion period 360 min 30 min 210 min 15 min 17 sec 15 min 200 mg 62.5 mg 200 mg 200 mg 510 mg 200 mg 2 min 10 min 10 min Bolus 17 sec Bolus Dose-related reactions Hypotension, oedema Hypotension, oedema Hypotension, oedema None reported None reported None reported RR of severe side effects Moderate Low Very low None reported Very low 36 None reported

37 Intravenous Compounds dextran (LMW) gluconate sucrose carboxymaltose Ferumoxyt ol Isomaltoside Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd 731 kd 150 kd Complex stability High Low Moderate High High High Test dose required Yes No Yes No No No Maximum approved dose 20 mg/kg BW 62.5 mg 200 mg* 7 mg/kg BW 1000 mg > 66 kg 15mg/kg b 510 mg 20 mg/kg BW Maximum Infusion period Maximum single dose on injection Minimum Infusion period 360 min 30 min 210 min 15 min 17 sec 15 min 200 mg 62.5 mg 200 mg 200 mg 510 mg 200 mg 2 min 10 min 10 min Bolus 17 sec Bolus Dose-related reactions Hypotension, oedema Hypotension, oedema Hypotension, oedema None reported None reported None reported RR of severe side effects Moderate Low Very low None reported Very low 37 None reported

38 g/dl - mean % Responders Ferric carboxymaltose for treatment of anemia in IBD [Response: increase >2g/dl Hb] W0 W2 W4 W8 W12 Log-rank test 0.03 W0 W2 W4 W8 W12 Ferinject FeSulf Kulnigg et al AJG

39 µg/l - median TfS (%) - median Ferric carboxymaltose for treatment of anemia in IBD Ferritin Tf-Saturation W0 W2 W4 W8 W12 0 W0 W2 W4 W8 W12 Woche Ferinject FeSulf Eisen-carbox Kulnigg et al AJG Eisen-sulfat

40 FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease ** FCM IS *p=0.004 **p=0.019 Evstatiev R et al. Gastroenterology 2011;141(3):

41 The gut environment in patients with IBD versus control anaemic subjects is more sensitive to overtime changes associated with iron replacement therapy (IRT) Thomas Lee et al. Gut doi: /gutjnl Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

42 PO iron treatment is associated with specific features in faecal samples Copyright BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved. Thomas Lee et al. Gut doi: /gutjnl

43 The influence of anti-tnf on anemia in IBD Koutroubakis et al Inflam Bowel Dis

44 The influence of anti-tnf on anemia in IBD 44 Koutroubakis et al Inflam Bowel Dis 2015

45 Algorithm for IBDassociated anemia Stein, J. et al. Nat Rev Gastroenterol Hepatol