Transcript Clinical Classifcation of b-thalassemia b

Approach to
Childhood Anemia
H. Tamary
Hematology, Schneider Children’s
Medical Center of Israel
Normal Hemoglobin and MCV Values
in Term Infant
Day 1
12 weeks
Hb
(g/dL)
MCV
(fl)
19.0±2.2
11.3 ±0.9
119 ±9.4
88 ±7.9
Regulation of Erythropoiesis
Hemoglobin ConcentrationDifferent Gestational Age
Globin Synthesis in Embryo, Fetus
and Adult
Decline in Fetal Hemoglobin
Criteria for Identifying Children with
Low Hemoglobin Values
Age
6ms –11 years
>11 male
>11 female
Hemoglobin
(g/dL)
<11
<13
<12
Etilogical Classification of Anemia
(I)
A. Blood loss
B. Excessive blood destruction
1. Intrinsic factors
a. Defects of membrane: spherocytosis,
elliptocytosis
b. Defects of hemoglobin
– Structural anomaly: HbS
– Synthesis anomaly: thalassemia
Etilogical Classification of Anemia
(II)
c. Enzymatic defect: G6PD deficiency,
pyruvate kinase
2. Extrinsic factors
a. Immune mechanisms: Rh, ABO
incompatibility, autoimmune
hemolytic anemia
b. non-immune mechanisms:
infections
Etilogical Classification of Anemia
(III)
C. Decreased production
1. Deficiency of substance: iron, Vit B12, folic
acid
2. Mechanical interference: malignant
replacement
3. BM failure
a. Primary: aplastic anemia
b. Secondary: renal, liver disease
Etiological Classification of Neonatal
Anemia
• A. Blood loss-fetal to fetal, feto-maternal,
traumatic delivery
• B. Increased blood destruction-Rh, ABO
or minor blood group incompatibility,
enzymopathy, hemoglobinopathy athalassemia
• C. Decreased production-pure red cell
aplasia
Anemia Historical Factors
• Age-Neonatal period initial manifestation of
hemolytic disease, 6 m-iron deficiency, bthalassemia
• Ethnic group-Thalassemia syndromes, G6PD def
• Diet- documented sources of iron
• Drugs- oxidant-induced hemolytic anemia, drug
induced aplastic anemia
• Inheritance-family history of anemia, jaundice, gall
stones
Anemia Physical Findings
Skin
Facies
Eyes
Hands
Spleen
Hyperpigmentation Fanconi
Anemia (FA)
Frontal bossing
Thalassemia
Prominence malar Major
&maxillary bone
Microphthalmia
FA
Abnormal thumb
FA
Enlargement
Hemolytic
anemia,
infection,
leukemia
Features of Ineffective
Erythropoiesis
FA Congenital Anomalies
Complete Blood Count
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Hemoglobin
MCV
WBC and differential count
PLT
RDW- red cell distribution width
CHr - hemoglobin concentration in
reticulocytes
Microcytic Anemias
MCV<80fl
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Iron deficiency anemia
Thalassemia syndromes
Chronic inflammation
Siderblastic anemias
Lead poisoning
Normocytic Anemias
MCV 80-90fl
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Congenital hemolytic anemia
Acquired hemolytic anemia
Acute blood loss
Splenic pooling
Chronic disease
Macrocytic Anemias
MCV>90fl
With megaloblastic bone marrow
• Vitamin B12 deficiency
• Folic acid deficiency
• Hereditary orotic aciduria
Without meglaoblastic bone marrow
• Aplastic anemia
• Pure red cell aplasia
• Liver disease
• Congenital Dyserythropoietic Anemia
Direct antiglobulin test (Coombs’)
Bone Marrow Aspiration
Acute Lymphoblastic Leukemia
Bone Marrow Biopsy
Normal
Aplastic anemia
Erythroid BM Colonies
Iron Deficiency Anemia
in Children
Human Hemoglobin
Distribution of Iron in Man
Cytochromes
Myoglobin
3%
10%
Ferritin &
Hemosiderin
22%
Hemoglobin
65%
Nutritional Iron Deficiency
Increment of RBC Mass as
Function of Age
Stages of Iron Depletion
Absorption of Food Iron
Iron Absorption in Infants
Mental &Psychomotor Development
According to Hb Concentration
Prevention of Nutritional Iron
Deficiency Anemia
• Encourage breast feeding for the first 6
months
• Avoid cow’s milk at least for the first year
of life
• Iron fortified formula (12mg/l)
• Solid food: cereals, meat
• Oral iron 2mg/kg 4-12months
• CBC: 9-12 months and 15-18 months
Iron Doses for Low Birth Weight
Infants Starting at 1 Month of Age
Iron
mg/kg/day
Birth weight
(g)
4
3
2
1000
1000-1500
1500-2500
“The tragedy of iron deficiency during
infancy and early childhood”
• Brain injury as a result of iron deficiency
caused by improper nutrition
• Iron deficiency affects mental development and
motor functioning
• Reduced activity of iron-containing enzymes in
CNS, appear to be irreversible
Buchanan G, J of Ped 135:413, 1999
Nutritional Iron Deficiency
• No iron prophylaxis
• No introduction of meat products
• Increased tea consumption
Stages of Iron Depletion
Iron Depletion
• Hb, MCV, RDW, CHr-Normal
• SI, TIBC-Normal
• Serum Ferritin- Low
Iron Deficiency – No Anemia
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Hb, MCV- Normal
RDW- High
CHr- Low
Serum Ferritin- Low
Serum Iron – Low
TIBC- High
Iron Deficiency Anemia
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Hb-Low
MCV- Low
RDW- High
CHr –Low
Serum Iron –Low
TIBC – High
Serum Ferritin - Low
Iron Deficiency-Biochemical Markers
• Serum iron concentrationInfluenced by iron absorption from meals, infection,
inflammation and diurnal variation
• Total iron-binding capacity (TIBC)-Increases in iron
deficiency.
Decrease in malnutrition, chromic infection and cancer.
• Ferritin-Correlates with total iron stores.
Acute phase reactant
Iron Deficiency- Serum Transferrin
Receptor
• Serum transferrin receptor- in iron
deficiency there is increased number of
receptors
Unlike ferritin, increases in iron
deficiency but not in chronic infection
Iron Deficiency-Treatment
• Elemental iron 5-6mg/Kg/d
• Reticulocytosis in one week
• After 1 month the Hb should increase by
at least 1gr%
• Iron therapy continued 2-3 months after
Hb returned to normal
• No improvement after a month other
cause for iron deficiency
Etiologic Factors in Iron Deficiency (1)
Increased physiologic requirements
• Rapid growth
• Menstruation
Decreased iron assimilation
• Iron-poor diet
• Iron malabsorption: Celiac disease
Etiologic Factors in Iron Deficiency (2)
Blood loss
• Gastrointestinal bleeding
• Milk induced enteropathy
• Peptic disease
• Inflammatory bowel disease
• Parasite bowel infection
Hemoglobinuria due to prosthetic valve
Idiopathic pulmonary hemosiderosis
Intense exercise
Thalassemia Syndromes &
Hemoglobinopathies
• a-thalassemia
• b-thalassemia
• Sickle cell anemia
b-thalassemia
Geographical Distribution of Thalassemia
and Hemoglobin Disorders
Globin Synthesis in Embryo, Fetus
and Adult
b-thalassemia -Location and Type
of Mutations
Clinical Classification of
b-thalassemia

b-thalassemia trait
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Homozygous b-thalassemia
Thalassemia Major
Thalassemia Intermedia
b-thalassemia minor
Differential Diagnosis of
Microcytosis
Iron deficiency
Anemia
Serum Iron
Transferrin
Ferritin
Hemoglobin
electrophoresis
Low
High
Low
Normal
Carriers of
b Thalassemia
Normal
Normal
Normal
High A2
b-thalassemia Minor –
HPLC Hb Electrophoresis
Hb A
b-thalassemia Carrier
Detection
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Microcytic anemia
MVC <78fl, MCH<27pg
HbA2>3.5%
b-thalassemia Major
Thalassemia Major at Diagnosis
Peripheral Blood Smear
Normal
Beta-thalassemia Homozygote
Homozygous b-thalassemia
Hb Electrophoresis
Hb F
Decline in Fetal Hemoglobin
Pathogenesis of b-thalassemia Major
Free excess of a-globin chains
Hemolysis
Ineffective erythropoiesis
Severe anemia
Skeletal deformities
Increased iron absorption
Transfusion Program-Suppression of
Ineffective Erythropoiesis
Clinical Manifestations of
Iron Overload
• Cardiac: arrhythmias, CHF
• Endocrine: growth failure, delayed sexual
maturation, hypoparathyroidism,
hypothyroidism, DM
• Skin: bronze discoloration
• Liver: cirrhosis
Important studies of Deferoxamine
Therapy in Thalassemia
Year
1974
1978
1981
1985
1989
Finding
IM therapy stabilize hepatic iron
12h portable infusion for iron balance
Therapy reduces hepatic iron
Reduction of cardiac disease in
compliant patients
Extended survival in young patients
Compliance with DFO Treatment
and Survival
Combination of L1and DFO
• L1 not as powerful as DFO
• Two chelators given on the same day
have additive affect on urine iron
loss
BMT in Thalassemia
Prognostic Criteria
• Hepatomegaly
• Liver fibrosis
• Quality of iron chelation
Prognostic Categories
• Class I-none of the above
• Class II One of the above
• Class III two or three of the above
BTM Class I
Prevention of b-thalassemia
• Carrier screening
• Prenatal diagnosis
CVS and DNA analysis
Pre-implantation diagnosis (PGD)
DNA extracted form fetal
erythroblasts in maternal
circulation
a-thalassemia
a-globin Cluster
a-thalassemia-Abnormal Hbs
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 2 2
Hb Bart’s
b
b
b2b2
Hb H
Gene Deletion in a-thalassemia
Hydrops Fetalis Syndrome
• Most Hb- Hb Barts, unable to deliver O2
to tissues
• Tissue hypoxia & anemia
Massively enlarged palcenta
Heart failure, edema anasarca
Interferes with organogenesis,
-congenital malformations
Extramedullay erythropoiesis
Hydrops Fetalis Syndrome
Hemoglobin H Disease
• Genotype --/-a
• On cord blood: 10-20% Bart’s
hemoglobin
• Moderate microcytic anemia
• Hb electrophoresis 5-30% Hb H
a-thalassemina Trait
• Genotype: - -/aa,-a/-a
• Hb electrophoresis on cord blood:
2-10% Hb Bart’s
• On adult blood: microcytic, with or
without anemia
• Diagnosis by exclusion of b-thalassemia
minor & iron deficiency
a-thalassemia Silent Carrier
 -a/aa
• Hb electrophoresis on cord blood:
traces to 2% Hb Bart’s
• No anemia or microcytosis on adult
blood
Deletions in the a-globin Gene
Cluster
Categories of a-thalassemia
Mutations
Non-deletion a-thalassemia
Mutations
a2
aNco
aHph
aTSaudi
a-thalassemia
Genotype-Spectrum
a-thal Trait
• --/aa
• -a/-a
aTa/aa
aTa/-a
Hb H Disease
• --/-a
aTa/aTa
aTa/--
Strategy for a-thalassemia
Multiplex PCR Analysis
Anemia of Chronic Infection
Anemia of Chronic Infection
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Serum Iron- Low
TIBC- Low
Serum ferritin- High
Reduced release of iron form
macrophages and reduced intestinal iron
absorption
Anemia of Chronic Disease