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2. disease

Hypochromic Microcytic
Anaemias in Children
Mariane de Montalembert, MD
Service de Pédiatrie
Hospital Necker
Paris, France
Adlette C. Inati, MD
Head
Division of Pediatric Hematology-Oncology
Medical Director
Children's Center for Cancer and Blood Diseases
Rafik Hariri University Hospital
Beirut, Lebanon
1
Diagnosis and Causes of
Hypochromic Microcytic
Anaemias in Children
Mariane de Montalembert, MD
Service de Pédiatrie
Hospital Necker
Paris, France
2
Hypochromic Microcytic
Anaemias
• The most common forms of anaemia in
children and adolescents
• Constitute a very heterogeneous group of
diseases that 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 common in adulthood
3
• Breastfeeding with inadequate
supplementary food
• Preterm, low birth weight
• Growth spurt
• Inadequate calorie intake
• Vegetarian diet
Enterocyte
Malabsorption
• Celiac disease
• Helicobacter pylori gastritis
• Autoimmune atrophic gastritis
• IRIDA (TMPRSS6 mutation)
• Chronic inflammation
Graphic courtesy of Dr. Mariane de Montalembert.
Erythroid
precursor
Defects in heme synthesis
or iron acquisition
• Haemoglobinopathies
• Sideroblastic anaemia
• Erythropoietic porphyria
• DMT1 mutations
• Ferroportin disease
• Hereditary atransferrinaemia
• Hereditary aceruloplasminaemia
Blood losses
Inadequate intake
Causes of Hypochromic
Microcytic Anaemias
• Polymenorrhea
• Parasitic infestations
• Peptic ulcer
• Inflammatory bowel
disease
• Meckel diverticulum
4
Diagnostic Tree
5
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
6
Iron Deficiency Stages
Stage
Prelatent
Latent
IDA
Reduced iron
stores with normal
serum iron levels
Exhausted iron
stores with normal
haemoglobin
Low haemoglobin
Haemoglobin
Normal
Normal
Decreased
MCV/MCH
Normal
Normal
Decreased
Serum iron
Normal
Decreased
Decreased
TIBC
Normal
Increased
Increased
Transferrin
saturation
Normal
Decreased
Decreased
Serum ferritin
Decreased
Decreased
Decreased
Marrow iron
Decreased
Absent
Absent
Parameter
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.
7
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
8
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
9
Iron Deficiency Diagnosis
Centers 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-yearolds or <15% for 16- to 39-year-olds)
– Serum ferritin (<12 μg/L)
10
Cut-Off Values for Iron Status by Age and Gender
NHANES Survey in the United States
•
Transferrin saturation (%)
–
–
–
•
Serum ferritin (μg/L)
–
–
•
1–5 y: 10
6–15 y: 12
Mean corpuscular volume (fl)
–
–
–
–
–
•
1–2 y: 9
3–5 y: 13
6–15 y: 14
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
11
Finding Microcytic Anaemia in a
Child
Lead
Verify the blood smear
intoxication
Check the iron status
Normal
Abnormal
Hg electrophoresis, HPLC
Iron deficiency
Defect in iron utilisation
Abnormal:
• β-thalassaemia
Abbreviations: HbC, haemoglobin C; HbE, haemoglobin E;
HbH, haemoglobin H; Hg, haemoglobin; HPLC, high
performance liquid chromatography.
Graphic courtesy of Dr. Mariane de Montalembert.
• HbC disease
• HbE disease
• HbH disease
• β-thal/sickle cell
disease
Normal:
•Check for
α-thalassaemia
(molecular study)
12
Iron Deficiency Anaemia vs
β-Thalassaemia Trait
Iron Deficiency
β-Thalassaemia Trait
>13
<13
RDW
Increased
Normal
Fe/TIBC
Decreased
Normal
Ferritin
Decreased
Normal
FEP
Increased
Normal
HbA2
Decreased
Increased
Normal
Increased
Pencil forms
Fine basophilic
stippling, target cells
Test
MCV/RBC
HbF
RBC morphology
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.
13
Hypochromic Microcytic Anaemias in Children
Blood
smear
Serum iron
Iron Deficiency
Defects in Iron
Utilisation1
Thalassaemia
Lead
Intoxication
Chronic Disease
Microcytosis, anisocytosis,
Poikilocytosis,
elliptocytosis,
hypochromia
Hypochromia
Microcytosis, target
cells, helmets,
dacryocytes
Coarse basophilic
stippling
Microcytosis,
hypochromia
Normal or
Transferrin
saturation
Serum
transferrin
receptor
Normal
Serum
ferritin
Other
diagnostic
tools
Normal
Bone marrow: ringed
sideroblasts
Iolascon A, et al. Haematologica. 2009;94:935-948.
Graphic of blood smears courtesy of Dr. C. Brouzes.
High-performance
liquid
chromatography
Blood lead level
Erythrocyte
sedimentation rate
C-reactive protein
14
Inadequate Iron Intake
15
Iron Deficiency Anaemia (IDA)
• 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
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.
16
Risk Factors for IDA
Children <5 years old
• Preterm/low birth weight
babies
• Children of immigrants
• >6 months of age: exclusively
breast-fed and/or non–ironfortified 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
17
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 and
present with only anaemia
18
Decreased Iron Absorption
19
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.
20
Defects in Heme Synthesis
or Iron Acquisition
21
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.
22
Decisional Tree for the Identification of Candidate
Genes in Microcytic Hypochromatic Anaemia
With permission from Iolascon A, et al. Haematologica. 2009;94:935-948.
23
Blood Loss
24
Main Causes for Blood Loss
• Polymenorrhea (>80 mL/mo)
• Parasitic infestations (hookworm) in
developing countries
• Peptic ulcer
• Inflammatory bowel disease
• Meckel’s diverticulum
25
Epidemiology, Prevention, and
Treatment of Iron Deficiency
and Iron Deficiency Anaemia
Adlette C. Inati, MD
Head
Division of Pediatric Hematology-Oncology
Medical Director
Children's Center for Cancer and Blood Diseases
Rafik Hariri University Hospital
Beirut, Lebanon
26
Epidemiology of Iron Deficiency
and Iron Deficiency Anaemia
27
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.
28
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.
29
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.
No. of
children
3052
No. of
males
1654
No. of
females
1398
30
Iron Deficiency Anaemia in Healthy
1-Year-old Lebanese Children
Degree of Anaemia Hg (g/dL)
Number (%)
Severe (<8)
18 (3)
Moderate (8–9.99)
210 (35)
Mild (10–10.99)
376 (62)
Total
604 (100)
Dr. Adlette C. Inati. Unpublished data, 2010.
Slide courtesy of Dr. Adlette C. Inati.
31
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.
32
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.
33
Adverse Effects of
Iron Deficiency
and Iron Deficiency Anaemia
34
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.
35
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.
36
Treatment of Iron Deficiency
and Iron Deficiency Anaemia
37
Treatment of IDA
Dietary 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
38
Treatment of IDA
Iron 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
39
Response to Iron
• 4–7 days: reticulocytosis
• 1–4 week: increase in haemoglobin level
• 1–4 months: repletion of iron stores
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
40
Treatment of IDA
Parenteral 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 IV and 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)
41
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
42
IDA Diagnostic
and Treatment Algorithm
Hg/Hct
Low Hg
apparently
healthy child
Normal
Treat with oral iron and
repeat Hg in 2–4 wk
An ↑ in Hg ≥1g/dL after 2–4 wk of
iron replacement confirms IDA
diagnosis
Continue iron
replacement
for 3–4 mo
Reinforce
dietary
counseling
Abbreviations: Hct, haematocrit; Hg, haemoglobin;
IDA, iron deficiency anaemia.
Graphic courtesy of Dr. Adlette C. Inati.
Counsel parents
about diet
Reassure
family
Failure of response
after 2–4 wk of
iron replacement
Recheck Hg/Hct
at end of
treatment and
6 mo later
Re-evaluate for
poor compliance,
inadequate iron
dose, or other
causes
Do additional lab
tests 43
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 age
5–10 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. 44
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.
45
Prevention and Screening
46
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
47
Primary Prevention
American Academy of Pediatrics (AAP)
Recommendations (2005) CDC Criteria for Anemia in Children
and Childbearing-Aged Women
• 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
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.
48
Recommendations for Composition of
Infant Formula
ESPGHAN Coordinated International
Expert 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.
49
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.
50
Screening
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.
51
Iron Deficiency and 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
52
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