Oxford Inflammatory Bowel Disease & Hepatology MasterClass

Managing Anaemia in IBD

Dr Alex Kent

Senior Research Fellow

Disclosures

WHO Classification of Anaemia

Normal haemoglobin and haematocrit levels

WHO/UNICEF/UNU. Iron deficiency anemia: Assessment, prevention and control. Report of a joint WHO/UNICEF/UNU consultation. Geneva; World Health Organisation, 1998

Population group Haemoglobin Haematocrit

g/dL Mmol/L %

Children 6 mo – 5 years 11.0 6.83 33

Children 5-11 years 11.5 7.13 34

Children 12-14 years 12.0 7.45 36

Non-pregnant women 12.0 7.45 36

Pregnant women 11.0 6.83 33

Men 13.0 8.07 39

Impact of anaemia

“asymptomatic”

Reduced quality of life: equalling cancer1

Higher disease activity2: reduced hct & general well-being

Chronic fatigue

Impaired cognitive performance3

Reduced mood

Increased incidence of and morbidity from infectious diseases4

Thyroid dysfunction & impaired thermoregulation5

Pregnancy: preterm delivery, low birth weight, reduced neonatal health6

References: 1. Leitgeb C et al. Cancer 1994: 2535-2542 2. Schreiber S et al. NEJM 1996:619-623 3. Beard JL et al. Am J Clin Nut 2007:778-787 4. Basta SS et al. Am J Clin Nut1979: 916-925 5. Dillman E et al. Am J Physio 1980:R377-381 6. Allen LH et al. Am J Clin Nut 2000:1280S-4S

Causes of anaemia in IBD

Iron Deficiency Anaemia

Anaemia of Chronic Disease

Vitamin B12 / folate deficiency1

Haemolysis2

Myelodysplastic syndrome3

Drug-induced:

Thiopurine4

Sulfasalazine5

Methotrexate6

References: 1. Fernandez-Banares F et al. Am. J. Gastroenterol 1989;84(7):744-8. 2. Bell DW et al. South Med. J., 1981;74(3):359-61. 3. Wang, Z et al. Dig. Dis. Sci.2008;53(7):1929-32. 4. Corominas H et al. Med. Clin. (Barc.) 2000;115(8):299-301 5. Dunn AM et al. Lancet 1981;2(8258):1288. 6. Bellaiche G et al. Gastroenterol. Clin. Biol. 1999;23(10):1102-3.

Screening bloods

Full blood count

MCV

Serum ferritin

Transferrin saturation

CRP

Vitamin B12

Folate

Haptoglobin

Lactate dehydrogenase

Creatinine

Reticulocyte count

Distribution of iron in adults

3-4 kg iron in human body

Iron absorption

Maximum absorption: 20mg per day

Iron deficiency anaemia

Prevalence 45%1

Causes:

Blood loss 1 ml blood = 0.5 mg iron

daily losses >4ml = iron deficiency

Poor nutritional uptake2

Impaired iron absorption3 SB Crohn’s disease

References: 1. Gisbert JP et al. Am J Gastro 2008:1299-1307 2. Lomer MC et al. Br J Nutr 2004:141-148 3. Semrin G et al. Inflamm Bowel Dis 2006:1101-1106

Iron deficiency anaemia: Treatment

Aims:

Hb rise of 2g/dL in 4 weeks

Normalisation of Hb, ferritin and TF saturation Greatest improvement in QoL at 11→12 g/dL1

Options:

Oral iron

Parenteral iron

References: 1. Crawford J et al. Cancer 2000:888-895.

Oral iron

Iron requirements

(Body weight (kg) x (target Hb* (g/dL) – actual Hb) x 2.4) + mg iron for stores#

*Target Hb: for body weight below 35 kg = 13 g/dL; for body weight 35 kg and above = 15 g/dL #Depot iron: for body weight below 35 kg = 15 mg/kg body weight; for body weight 35 kg and above = 500 mg

Oral iron (cont)

References: 1. Micromedex Healthcare Series, 2007. Thomson Healthcare Inc 2. 1. Kerr DN et al. Lancet 1958;489-492

Maximum absorption of elemental iron is 20mg per day

Concerns:

Side effects / intolerance2: 21-52%

Toxic reactive oxygen species

Slow response

Elemental iron content of iron salts

Iron salt Dose Iron content (%) Iron content Cost

Ferrous sulphate 200mg 30 65mg £1.07 (28)

Ferrous fumarate 200mg 33 65mg £2.30 (84)

Ferrous gluconate 300mg 11.6 35mg £1.93 (28)

Parenteral iron

Iron gluconate

Less stable, leading to labile iron release

higher risk of A/E

Maximum dose 125mg

Iron dextran (low molecular weight)

Dextran-related anaphylaxis; test dose required

Long infusion time; large doses

Long time interval before bioavailibility

Iron sucrose (venofer)

95% of iron utilised within 2-4 weeks

Maximum dose 600mg/week in 200mg infusions

Iron carboxymaltose (ferrinject)

Rapidly infused (1000mg in 15 mins); no test dose

Iron utilised within 6-9 days so lower risk of A/E

Summary of parenteral iron preparations

LMW iron dextran

Cosmofer

Iron sucrose Venofer

Iron carboxymaltose

Ferrinject

Iron isomaltose

Monofer

Blood

Maximum single dose

20mg/kg 200mg 1000mg (20mg/kg)

20mg/kg

Rapid infusion No Yes (bolus) Yes Yes

Test dose? Yes Initial No No

Iron concentration

50 mg/ml 20 mg/ml 50 mg/ml 100 mg/ml 200mg per unit

Vial volumes 2 & 10 5 2 & 10 1, 5 & 10

Cost £7.97 / £39.85

£9.35

£19.10 / £95.50 £16.95 / £84.75 / £169.50

Parenteral iron (cont.)

Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel disease. Gasche C et al. Inflamm Bowel Dis. 2007 Dec;13(12):1545-53. Statement 4A: “The preferred route of iron supplementation in IBD is intravenous, even though many patients will respond to oral iron. Intravenous iron is more effective, better tolerated, and improves the quality of life to a greater extent than oral iron supplements.” (Grade A)

Indications for intravenous iron

Haemoglobin <10g/dL

Intolerance to oral iron

Poor response to oral iron

Moderate-severe disease activity

Concomitant treatment with erythropoietic agent

Patient preference

Anaemia of Chronic Disease

Causes:

Functional iron deficiency1 Up-regulation of ferritin

Reduced transferrin

Inhibition of erythropoiesis2 IL-1 & TNF-α produce toxic radicals

damage erythropoietin-producing cells

Inhibition of differentiation/proliferation of erythroid precursors3 Interferon-α, -β, -γ, TNF-α and IL-1

Uptake and retention of iron in the reticulo-endothelial system4 Interferon-γ, TNF-α and IL-6

Hepcidin

References: 1. Macdougall IC et al. BMJ 1992:225-226 2. Faquin WC et al. Blood 1992:1987-1994 3. Theurl I et al. Blood 2006:4142-4148 4. Weiss G et al. NEJM 2005:1011-1023

Iron absorption

Maximum absorption: 20mg per day

Ferritin (μg/L) Transferrin

saturation

(%)

MCV

MCH

sTR Active

inflammation

No

inflammation

IDA <100 <30 <16 ↓ ↓ ↑

ACD >100 >100 <16 Normal Normal Normal

or ↓

Identifying the cause of anaemia

Take home message

Ask carefully for symptoms of anaemia

Anaemia should raise concerns about disease activity

Oral iron only in mild anaemia and inactive disease

Do not overtreat with oral supplements

Early treatment

Intravenous iron is preferable