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Hypochromic Microcytic Anaemias in Children

Hypochromic Microcytic Anaemias in Children. Mariane de Montalembert, MD Service de Pédiatrie Hospital Necker Paris, France

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Hypochromic Microcytic Anaemias in Children

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  1. Hypochromic Microcytic Anaemias in Children Mariane de Montalembert, MDService de PédiatrieHospital NeckerParis, France Adlette C. Inati, MDHeadDivision of Pediatric Hematology-OncologyMedical DirectorChildren's Center for Cancer and Blood DiseasesRafik Hariri University HospitalBeirut, Lebanon 

  2. Diagnosis and Causes of Hypochromic Microcytic Anaemias in Children Mariane de Montalembert, MDService de PédiatrieHospital NeckerParis, France

  3. Hypochromic Microcytic Anaemias The most common forms of anaemia in childrenand adolescents Constitute a very heterogeneous group of diseasesthat may be acquired or inherited Nutritional iron deficiency and β-thalassaemia trait are the primary causes in paediatrics, while bleeding disorders and anaemia of chronic disease are quite commonin adulthood

  4. Causes of Hypochromic Microcytic Anaemias Blood losses Inadequateintake Enterocyte Erythroidprecursor Defects in heme synthesis or iron acquisition Malabsorption • Breastfeeding with inadequate • supplementary food • Preterm, low birth weight • Growth spurt • Inadequate calorie intake • Vegetarian diet • Polymenorrhea • Parasitic infestations • Peptic ulcer • Inflammatory bowel • disease • Meckel diverticulum • Celiac disease • Helicobacter pylori gastritis • Autoimmune atrophic gastritis • IRIDA (TMPRSS6 mutation) • Chronic inflammation • Haemoglobinopathies • Sideroblastic anaemia • Erythropoietic porphyria • DMT1 mutations • Ferroportin disease • Hereditary atransferrinaemia • Hereditary aceruloplasminaemia Graphic courtesy of Dr. Mariane de Montalembert.

  5. Diagnostic Tree

  6. Tests for Assessing Iron Status Serum iron Total iron binding capacity (TIBC) Transferrin saturation = serum iron/TIBC x 100 Serum ferritin Serum transferrin receptor (sTfR)/serum ferritin [R/F ratio] Reticulocyte haemoglobin content Stainable iron in bone marrow

  7. Iron Deficiency Stages Abbreviations: IDA, iron deficiency anaemia; MCH, mean corpuscular haemoglobin;MCV, mean corpuscular volume; TIBC, total iron binding capacity. Slide courtesy of Dr. Adlette C. Inati, MD.

  8. Laboratory Indicators of Iron Deficiency There is a significant overlap between iron-sufficient and iron-deficient segments of a population, making the diagnosis of iron deficiency unclear Thus, it is necessary to combine several laboratory indicators

  9. Serum Ferritin Levels • Serum ferritin is raised during acute infection and inflammation and liver disease, irrespective of the iron stores, but iron deficiency is the only cause of a low concentration • A normal serum ferritin level doesn’t exclude an iron deficiency, but a low serum ferritin level necessarily means iron deficiency

  10. Iron Deficiency DiagnosisCenters for Disease Control and Prevention • Proper anaemia screening requires not only sound laboratory methods and procedures but also appropriate haemoglobin and haematocrit cut-off values to define anaemia • ≥2 of the following tests are abnormal: • Free erythrocyte protoporphyrin (≥1.24 μmol/L red blood cells) • Transferrin saturation (<14% for 12- to 15-year-olds or <15% for 16- to 39-year-olds) • Serum ferritin (<12 μg/L)

  11. Cut-Off Values for Iron Status by Age and Gender NHANES Survey in the United States • Transferrin saturation (%) • 1–2 y: 9 • 3–5 y: 13 • 6–15 y: 14 • Serum ferritin (μg/L) • 1–5 y: 10 • 6–15 y: 12 • Mean corpuscular volume (fl) • 1–2 y: 77 • 3–5 y: 79 • 6–11 y: 80 • 12–15 y, male: 82 • 12–15 y, female: 85 • Reference haemoglobin values (g/dL): Mean – 2DS • 1–2 y: 10.7 • 3–5 y: 10.9 • 6–11 y: 11.5 • 12–15 y, male: 12 • 12–15 y, female: 11.5 Dallman PR. In: Iron Nutrition in Health and Disease. John Libbey & Company; 1996:65-71. Looker AC, et al. JAMA. 1997;277:973-976. Cogswell ME, et al. Am J Clin Nutr. 2009;89:1334-1342.Slide courtesy of Dr. Mariane de Montalembert

  12. Finding Microcytic Anaemia in a Child Lead intoxication Verify the bloodsmear Check the ironstatus Normal Abnormal Hg electrophoresis, HPLC Iron deficiency Defect in iron utilisation • Abnormal: • β-thalassaemia • HbC disease • HbE disease • HbH disease • β-thal/sickle cell • disease • Normal: • Check forα-thalassaemia(molecular study) Abbreviations: HbC, haemoglobin C; HbE, haemoglobin E; HbH, haemoglobin H; Hg, haemoglobin; HPLC, high performance liquid chromatography. Graphiccourtesy of Dr. Mariane de Montalembert.

  13. Iron Deficiency Anaemia vs β-Thalassaemia Trait Abbreviations: FEP, free erythrocyte porphyrin; HbA2, haemoglobin A2; HbF, haemoglobin F; MCV, mean corpuscular volume; RBC, red blood cells; RDW, red blood cell distribution width;TIBC, total iron binding capacity. Slide courtesy of Dr. Adlette C. Inati.

  14. Hypochromic Microcytic Anaemias in Children Iolascon A, et al. Haematologica. 2009;94:935-948. Graphic of blood smears courtesy of Dr. C. Brouzes.

  15. Inadequate Iron Intake

  16. Iron Deficiency Anaemia (IDA) Pollitt E. Annu Rev Nutr. 1993;13:521-537. Lozoff B, et al. J Nutr. 2007;137:683-689. McCann JC, et al. Am J Clin Nutr. 2007;85:931-945. The most common nutritional disorder worldwide Prevalence varies with age, gender, race, dietary intake, and socioeconomic factors Low serum iron concentration causes insufficient synthesis of haemoglobin and other iron-containing proteins, such as cytochromes, myoglobin, catalase, and peroxidase Associated with psychomotor and cognitive abnormalities and poor school performance in children in the first years of life with haemoglobin ≤10.5 g/dL but a causal relation has not been demonstrated as yet

  17. Children <5 years old Preterm/low birth weight babies Children of immigrants >6 months of age: exclusively breast-fed and/or non–iron-fortified formulas with no iron supplement Introduction of cow’s milk <1 year of age Parasitic infestation (developing countries): hookworm Poverty Adolescents History of heavy menstrual blood loss (>80 mL/mo) Significant physical activity Vegetarian diet Strict fad dieting, especially in females Malnutrition Parasitic infestation (developing countries): hookworm Risk Factors for IDA

  18. Increasing Prevalence of Iron Deficiency Among Adolescent Females High iron needs Tendency of girls to eat less high iron-containing foods (such as meat) Many adolescents are asymptomatic andpresent with only anaemia

  19. Decreased Iron Absorption

  20. Main Causes of Decreased Iron Absorption Celiac disease Autoimmune atrophic gastritis H. pylori gastritis Iron Refractory Iron Deficiency Anaemia (mutation of the serine protease matriptase-2 [TMPRSS6]) Chronic inflammation Herschko C, Skikne B. Semin Hematol. 2009;46:339-350.

  21. Defects in Heme Synthesis or Iron Acquisition

  22. Decisional Tree for the Identification of Candidate Genes in Microcytic Hypochromatic Anaemia • Biologic assays • Iron and haematologic status, including serum transferrin receptor • Diagnostics to be ruled out • Iron deficiency (nutritional, Pica, lead intoxification) • Haemoglobinopathies • Spherocytosis, elliptocytosis • Other haemolytic anaemias (red blood cells enzyme defect…) (complementary investigations: haptoglobin and birilubin assay) • Atransferrinaemia, aceruloplasminaemia Iolascon A, et al. Haematologica. 2009;94:935-948.

  23. Decisional Tree for the Identification of Candidate Genes in Microcytic Hypochromatic Anaemia With permission from Iolascon A, et al. Haematologica. 2009;94:935-948.

  24. Blood Loss

  25. Main Causes for Blood Loss • Polymenorrhea (>80 mL/mo) • Parasitic infestations (hookworm) in developing countries • Peptic ulcer • Inflammatory bowel disease • Meckel’s diverticulum

  26. Epidemiology, Prevention, and Treatment of Iron Deficiency and Iron Deficiency Anaemia Adlette C. Inati, MDHeadDivision of Pediatric Hematology-OncologyMedical DirectorChildren's Center for Cancer and Blood DiseasesRafik Hariri University HospitalBeirut, Lebanon 

  27. Epidemiology of Iron Deficiency and Iron Deficiency Anaemia

  28. Prevalence (%) of Iron Deficiency and Iron Deficiency Anaemia, United States, Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994 (Both Genders) 9% 3% 3% 2% <1% <1% Age (years) Iron deficiency defined on basis of 2 of 3 abnormal values for erythrocyte protoporphyrin concentration, serum ferritin concentration, and transferrin saturation Looker AC, et al. JAMA. 1997;277:973-976.

  29. Prospective Survey of Prevalence of Anaemia and Iron Deficiency Anaemia in Healthy 1-Year-Old Lebanese Children (N = 3052) • ID defined as: MCV <70 μg/mL, SF <12 ng/mL • IDA defined as Hg ≤11 g/dL plus ID Abbreviations: Hg, haemoglobin; ID, iron deficiency; IDA, iron deficiency anaemia; MCV, mean corpuscular volume. Dr. Adlette C. Inati. Unpublished data, 2010. Graphic courtesy of Dr. Adlette C. Inati.

  30. Prospective Survey of Prevalence of Anaemia and Iron Deficiency Anaemia in Healthy 1-Year-Old Lebanese Children Dr. Adlette C. Inati. Unpublished data, 2010. Graphic courtesy of Dr. Adlette C. Inati.

  31. Iron Deficiency Anaemia in Healthy 1-Year-old Lebanese Children Dr. Adlette C. Inati. Unpublished data, 2010. Slide courtesy of Dr. Adlette C. Inati.

  32. Percentages of Causes of Iron Deficiency Status in Italy • Retrospective study in 238 children 7.5 months to 16 years of age with ID • Most common cause of ID • 7.5 months to 2 years: blood loss (57%)* • 3–10 years: malabsorption (78%) • 11–15 years, boys: blood loss (55%) • 11–16 years, girls: blood loss (48%) * Often linked to cow’s milk intolerance. Ferrara M, et al. Hematology. 2006;11:183-186.

  33. Causes for Iron Deficiency and Iron Deficiency Anaemia in Children in Taiwan • Retrospective study in 116 children, age <18 years, diagnosed with ID, 100 of whom had IDA • Peak incidence of childhood ID occurred in children <2 years old and 10–18 years old • Most common cause of ID • <2 years (n = 45): inadequate intake (55.6%) • 2–10 years (n = 13): blood loss (46.1%) • >10 years, male (n = 18): inadequate intake (38.9%) • >10 years, female (n = 40): blood loss (37.5%) Huang SH, et al. J Pediatr Hematol Oncol. 2010;32:282-285.

  34. Adverse Effects of Iron Deficiencyand Iron Deficiency Anaemia

  35. Adverse Effects of Iron Deficiency and Iron Deficiency Anaemia Data equivocal due to many confounding factors and difficulties in obtaining relevant tests of infant development  Anaemic schoolchildren have decreased motor activity, social inattention, and decreased school performance1 Delayed maturation of auditory brain system responses in 6-month-old Chilean infants2 1. Grantham-McGregor S, et al. J Nutr. 2001;131:666S-668S. 2. Roncagliolo M, et al. Am J Clin Nutr. 1998;68:683-690.

  36. Effect of IDA in Infancy on Developmental Tests at 5 Years of Age Difference in results of developmental tests at 5 years of age between children with moderate iron deficiency anaemia in infancy and control group adjusted for a comprehensive set of background factors With permission from Lozoff B, et al. N Engl J Med. 1991;325:687-694.

  37. Treatment of Iron Deficiency and Iron Deficiency Anaemia

  38. Treatment of IDADietary Measures • Iron-containing dietary sources • Heme: fish, poultry, meat • Non-heme: grains, fruits, vegetables, cereals, bread • Iron from heme sources has a higher bioavailability (3x more) than that from non-heme sources but comprises a small portion of dietary iron in most diets • Ascorbic acid, meat, orange juice, and fish enhance iron absorption of non-heme sources • Calcium, phytates, cereals, milk, bran foods rich in phosphates, and tannates (teas) in food impair iron absorption to a variable degree

  39. Treatment of IDAIron Replacement Therapy • Not always required and should be prescribed only if diagnosis is certain • When indicated, treatment with a cost-effective oral iron preparation with minimal side effects will suffice • The cheapest preparation is iron sulfate liquid/tablets • Iron dose: 3–6 mg/kg/d for infants and children and 60–120 mg/d for school-age children and adolescents → increase in haemoglobin of 0.25–0.4 g/dL/d or 1%/d rise in haematocrit • Duration: 3–4 months after reversal of anaemia to replenish body iron stores

  40. Response to Iron • Failure of response after 2 weeks of oral iron requires re-evaluation for • Poor compliance with oral iron • Other acquired causes associated with gastrointestinal blood loss, such as celiac disease, autoimmune atrophic gastritis, H. pylori, inflammatory bowel disease • Genetic anaemias 4–7 days: reticulocytosis 1–4 week: increase in haemoglobin level 1–4 months: repletion of iron stores

  41. Treatment of IDAParenteral Iron Therapy Indications – Poor tolerance to iron tablets (nausea, diarrhoea) – Poor iron absorption – Continued iron loss – Need for quick management (haemodynamic instability) Dose: 50–100 mg/d IVand only in hospital (risk of anaphylactic shock) Iron to be injected (mg) = (15-Hg/g%) x body weight(kg) x 3 Use with caution (anaphylaxis and bioactive iron reactions)

  42. Treatment of IDA Blood Transfusion • Rarely necessary even for severe IDA with haemoglobin concentrations of 4–5 gm/dL • Should be reserved for patients in cardiorespiratory distress, lethargy, and very poor nutritional intake • Needs to be given slowly to avoid heart failure

  43. IDA Diagnosticand Treatment Algorithm Hg/Hct Low Hgapparentlyhealthy child Normal Reassurefamily Treat with oral iron andrepeat Hg in 2–4 wk Counsel parentsabout diet An ↑ in Hg ≥1g/dL after 2–4 wk of iron replacement confirms IDA diagnosis Failure of responseafter 2–4 wk ofiron replacement Re-evaluate for poor compliance, inadequate iron dose, or other causes Do additional lab tests Recheck Hg/Hctat end of treatment and 6 mo later Continue iron replacement for 3–4 mo Reinforcedietarycounseling Abbreviations: Hct, haematocrit; Hg, haemoglobin; IDA, iron deficiency anaemia. Graphic courtesy of Dr. Adlette C. Inati.

  44. Benefits of Correcting Iron Deficiency and Iron Deficiency Anaemia in Early Childhood  Increase in haemoglobin concentration, related to  Baseline status • Exposure to anaemia risk factors in addition to iron deficiency (ie, malaria…)  Decrease in the number of upper respiratory tract infections in a controlled study in children age5–10 years in Sri Lanka  Controversial results on development; effect, if present, is modest  In most studies, no significant growth effect or limited to anaemic children Martin S, et al. Cochrane Data Base of Systematic Reviews. 2001;2. Iannotti LL, et al. Am J Clin Nutr. 2006;84:1261-1276. Domellof M. Nestle Nutr Workshop Ser Ped Program. 2010;65:153-162. de Silva A, et al. Am J Clin Nutr. 2003;77:234-241.

  45. Risks of Correcting Iron Deficiency and Iron Deficiency Anaemia in Early Childhood  Adverse growth effect in iron-replete children (inhibition of other growth-promoting nutrients?)  Increased risk for severe malaria infections in children who are iron sufficient Martin S, et al. Cochrane Data Base of Systematic Reviews 2001;2. Iannotti LL, et al. Am J Clin Nutr. 2006;84:1261-1276. Domellof M. Nestle Nutr Workshop Ser Ped Program 2010;65:153-162. de Silva A, et al. Am J Clin Nutr. 2003;77:234-241.

  46. Prevention and Screening

  47. Prevention • The key to reducing the morbidity associated with iron deficiency includes prevention of iron deficiency and the identification and treatment of children who are iron deficient • Primary prevention means ensuring an adequate intake of iron, which can meet an infant’s and child’s nutritional requirements for optimal growth and development • Secondary prevention entails screening for, diagnosing, and treating iron deficiency anaemia

  48. Primary Prevention American Academy of Pediatrics (AAP) Recommendations (2005) CDC Criteria for Anemia in Children and Childbearing-Aged Women American Academy of Pediatrics. Pediatrics. 2005;115:496-506. Wall CR, et al. Arch Dis Child. 2005; 90:1033-1038. MMWR. 1993;47 (RR-3):1-29. • Continuing breastfeeding for at least the first 4–6 months of life and beyond • Introducing iron-rich solid foods at around 6 months of age • Iron supplementation before 6 months of age for preterm and low birth weight infants and infants with haematologic disorders and/or inadequate iron stores at birth • Giving iron-fortified infant formula, and not cow's milk, for infants weaned before 12 months of age • Encouraging adolescent girls to eat iron-rich foods and foods that enhance iron absorption

  49. Recommendations for Composition of Infant FormulaESPGHAN Coordinated InternationalExpert Group (IEG) • The IEG strongly recommends breastfeeding for infants • Proposed iron composition of infant formula • 0.3–1.3 mg/100 Kcal (cow’s milk protein and protein hydrolysate-based formula) • 0.45–2.0 mg/100 Kcal (soy protein isolate-based formula) • After the age of 6 months • Introducing foods containing highly bioavailable iron • Introducing fortified formula with iron content from 0.3 mg/100 Kcal to 1.3 mg/100 Kcal (for populations with a high risk of iron deficiency) • Practicing caution with iron supplementation since regulation of iron absorption is immature before the age of 9 months Koletzko B, et al. J Pediatr Gastroenterol Nutr. 2005;41:584-599.

  50. Impact of Milk Formula and Iron Supplements on Prevalence of Iron Deficiency Anaemia N = 3052 FF = iron fortified formula NF+ = non-iron fortified formula + iron supplement NF- = non-iron fortified formula and no iron supplements BF+ = breast milk plus iron supplement BF- = breast milk and no iron supplement Dr. Adlette C. Inati. Unpublished data, 2010. Graphic courtesy of Dr. Adlette C. Inati.

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