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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

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 


Diagnosis and causes of hypochromic microcytic anaemias in children

Diagnosis and Causes of Hypochromic Microcytic Anaemias in Children

Mariane de Montalembert, MDService de PédiatrieHospital NeckerParis, France


Hypochromic microcytic anaemias
Hypochromic Microcytic Anaemias Children

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


Causes of hypochromic microcytic anaemias
Causes of Hypochromic Microcytic Anaemias Children

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.


Diagnostic Tree Children


Tests for assessing iron status
Tests for Assessing Iron Status Children

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


Iron deficiency stages
Iron Deficiency Stages Children

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.


Laboratory indicators of iron deficiency
Laboratory Indicators of ChildrenIron 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


Serum ferritin levels
Serum Ferritin Levels Children

  • 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


Iron deficiency diagnosis centers for disease control and prevention
Iron Deficiency Diagnosis ChildrenCenters 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)


Cut off values for iron status by age and gender nhanes survey in the united states
Cut-Off Values for Iron Status by Age and Gender ChildrenNHANES 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


Finding microcytic anaemia in a child
Finding Microcytic Anaemia in a Child Children

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.


Iron deficiency anaemia vs thalassaemia trait
Iron Deficiency Anaemia vs Childrenβ-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.


Hypochromic microcytic anaemias in children1
Hypochromic Microcytic Anaemias in Children Children

Iolascon A, et al. Haematologica. 2009;94:935-948.

Graphic of blood smears courtesy of Dr. C. Brouzes.



Iron deficiency anaemia ida
Iron Deficiency Anaemia (IDA) Children

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


Risk factors for ida

Children <5 years old Children

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


Increasing prevalence of iron deficiency among adolescent females
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



Main causes of decreased iron absorption
Main Causes of Decreased Iron Absorption Females

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.



Decisional tree for the identification of candidate genes in microcytic hypochromatic anaemia
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.


Decisional tree for the identification of candidate genes in microcytic hypochromatic anaemia1
Decisional Tree for the Identification of Candidate Genes in Microcytic Hypochromatic Anaemia

With permission from Iolascon A, et al. Haematologica. 2009;94:935-948.


Blood loss
Blood Loss Microcytic Hypochromatic Anaemia


Main causes for blood loss
Main Causes for Blood Loss Microcytic Hypochromatic Anaemia

  • Polymenorrhea (>80 mL/mo)

  • Parasitic infestations (hookworm) in developing countries

  • Peptic ulcer

  • Inflammatory bowel disease

  • Meckel’s diverticulum


Epidemiology prevention and treatment of iron deficiency and iron deficiency anaemia

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 



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.


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.


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.


Iron deficiency anaemia in healthy 1 year old lebanese children
Iron Deficiency Anaemia in Healthy 1-Year-old Lebanese Children

Dr. Adlette C. Inati. Unpublished data, 2010.

Slide courtesy of Dr. Adlette C. Inati.


Percentages of causes of iron deficiency status in italy
Percentages of Causes of Iron Deficiency Status in Italy Children

  • 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.


Causes for iron deficiency and iron deficiency anaemia in children in taiwan
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.


Adverse effects of iron deficiency and iron deficiency anaemia
Adverse Effects of Children in TaiwanIron Deficiencyand Iron Deficiency Anaemia


Adverse effects of iron deficiency and iron deficiency anaemia1
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.


Effect of IDA in Infancy on Developmental Tests Anaemia

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.



Treatment of ida dietary measures
Treatment of IDA AnaemiaDietary 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


Treatment of ida iron replacement therapy
Treatment of IDA AnaemiaIron 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


Response to iron
Response to Iron Anaemia

  • 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


Treatment of ida p arenteral iron therapy
Treatment of IDA AnaemiaParenteral 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)


Treatment of ida blood transfusion
Treatment of IDA AnaemiaBlood 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


Ida diagnostic and treatment algorithm
IDA Diagnostic Anaemiaand 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.


Benefits of correcting iron deficiency and iron deficiency anaemia in early childhood
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.


Risks of correcting iron deficiency and iron deficiency anaemia in early childhood
Risks of Correcting Iron Deficiency and Anaemia in Early ChildhoodIron 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.


Prevention and Screening Anaemia in Early Childhood


Prevention
Prevention Anaemia in Early Childhood

  • 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


Primary Prevention Anaemia in Early ChildhoodAmerican 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


Recommendations for Composition of Anaemia in Early ChildhoodInfant 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.


Impact of milk formula and iron supplements on prevalence of iron deficiency anaemia
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.


Screening american academy of pediatrics recommendations 2005
Screening Iron Deficiency Anaemia American Academy of Pediatrics Recommendations (2005)

Screening haemoglobin or haematocrit between 9 and 12 months of age then 6 months later, and, for patients at high risk, once a year from age 2–5 years

Screening haemoglobin and/or haematocrit in infants age 6-12 months who are living in poverty, or who are black, Native American, or Alaska Native, immigrants from developing countries, preterm and low birth weight infants, and infants whose principal dietary intake is unfortified cow's milk

Annual screening of menstruating girls and screening boys once during the peak growth period by measuring haemoglobin concentration or haematocrit

American Academy of Pediatrics. Pediatrics. 2005;115:496-506.


Iron deficiency and iron deficiency anaemia conclusions
Iron Deficiency and Iron Deficiency Anaemia Iron Deficiency Anaemia Conclusions

  • Causes of childhood ID and IDA are age- and gender-dependent

  • Diet is a reasonable predictor of iron status in late infancy and early childhood

  • Preventing rather than treating iron deficiency is a priority

  • Primary healthcare providers can help prevent and control ID and IDA by counseling individuals and families about diet and iron, and by screening persons for ID risk and treating affected individuals

  • Treatment of ID and IDA should not be undertaken until the actual etiologic diagnosis is ascertained

  • Early initiation of iron replacement therapy will correct IDA but may not prevent its long-term systemic complications

  • Further studies are needed to determine the effects of mild IDA on infant and child neurocognitive development


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