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HEMATOLOGY -ONCOLOGY Div.

Child Health Depart.- School of Medicine


University of Sumatera Utara

Anemia
Definition:
reduction in red cell mass or
blood hemoglobin concentration
below 2 standard deviations (SD)

Table 1.Normal red blood cell values in


children
Age
Birth (cord blood)
1-3 days(capillary)
1 week
2 week
1 month
2 month
3-6 month
0.5-2 years
2-6 years
6-12 years
12-18 years, female
12-18 years, male
18-49 years, female
18-49 years, male

Hemoglobin(g/dl)
Mean
-2SD
16.5
13.5
18.5
14.5
17.5
13.5
16.5
12.5
14.0
10.0
11.5
9.0
11.5
9.5
12.0
10.5
12.5
11.5
13.5
11.5
14.0
12.0
14.5
13.0
14.0
12.0
15.5
13.5

MCV(fl)
Mean
-2SD
108
98
108
95
107
88
105
86
104
85
96
77
91
74
78
70
81
75
86
77
90
78
88
78
90
80
90
80
Caroline Hasting,2002
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Anemia
(WHO,1976):
- 6 month <6 year: <11 g/dL
- 6 year 12 year : <12 g/dl
(WHO/UNICEF,1997)
-

6 month <5 year


<11 g/dL
>6 year 14 year
<12 g/dL
adult (man)
<13 g/dL
adult (woman)
<13 g/dL
adult (pregnant woman) <11 g/dL
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IRON DEFICIENCY ANEMIA


Definition :
Anemia resulting from lack of sufficient iron for
synthesis of hemoglobin.

Prevalence :
The most common cause of anemia worlwide
An estimated 30% of the worlds population :
4.5 billion anemic
500 600 million Iron def. anemia

...Prevalence

North American (1970) : 30 - 75% of


child 1 2 years of age
Israelli : 25% females (aged 16 - 17 yrs)
Indonesia : 25 35% (aged 5 yrs)

Prevalence
Prevalence
Anemia
Anemia

Developed countries
0-4 tahun : 20.1%
5-14 tahun: 5.9%

Developing
countries
0-4 tahun: 39.0%
5-14 tahun: 48.1%

WHO, 2001
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Prevalence
Prevalence
ofofIDID&&IDA
IDA
UK Infants:
Asian IDA 39%
Afro-Caribbean 20%
White 16%

USA:
1-2 years ID 9%; IDA 3%
adolescent girls ID 9%; IDA 2%

Indonesia (SKRT 2001):


Developing countries
Adolescent girls 21-35%

<5 years 48.1%


<1 year 55%
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Etiology of iron deficiency

ETIOLOGY
I. Deficiency intake :
Dietary (milk 0,5-1.5 mg iron/L)
II. Increased demand :
Growth (low birth weight, premarurity, low-birth-weight
twins or multiple births, adolescence, pregnancy)
Cyanotic Congenital heart disease
III. Blood loss :
A. Perinatal
1. Placental
Transplacental bleeding into maternal circulation
Retroplacental (e.g,premature placental separatio )
Intraplacental
Fetal blood loss or before birth (e.g, placenta previa)
Fetofetal bleeding in monochrorionic twins
Placental abnormalities
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2.Umbilicus
- Ruptured umbilical cord (e.g, vasa previa) and
other
umbilical cord abnormalities
- Inadequate cord tying
- Postexchange transfusion
B. Postnatal
1.Gastrointestinal tract
- Primary iron deficiency anemia resulting in gut
alteration
with blood loss agravating existing iron deficiency
- Hypersensitivity to whole cows milk?
- Anatomic gut lesions, exudative enteropathy
caused by undelying bowel disease
- Gastritis from aspirin, adrenocortical steroids,
indomethacin, phenylbutazone
- Intestinal parasites( e.g, hookworm /Necator
Americanus)
- Henoch-Scholein Purpura
.

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2. Hepatobililiary system: hematobilia


3. Lung: Pulmonary hemosiderosis, Goodpasture sydrome,
defective iron mobilization with IgA deficiency
4. Nose: recurrent epistaxis
5. Uterus: menstrual loss
6. Heart: intracardiac myxomata, valvular prostheses or patches
7. Kidney: microangiopathic hemolytic anemia, hematuria,
nephrotic syndrome,hemosiderinurias-chronic intravascular
hemolysis
8. Extracorporeal: hemodialysis, trauma
IV. Imparied absorption
Malabsorption syndrome, celiac disease, severe prolonged
diarrhea, postgastrectomy, inflammatory bowel disease,
Helicobacter pylori infection associated chronic gastritis
Lanzkowsky,2005

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Key Functional of Iron

13

Iron Status in Human Body

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Iron cycle

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BLUE OCEAN

16

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BLUE OCEAN

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Pathophysiology
Stages Iron Deficiency

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Diagnostic Approach
Anamnesis
Physical examination findings
Laboratory examination

Korones D, 1999
Glader B, 2007

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History taking

Pallor,floppiness :time of onset


Fatigue,lethargy
Poor feeding
Irritability
Abdominal pain
Headache ,dizziness
Shortness of breath
Arthralgia
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Clinical Manifestation

Pallor ,jaundice
Tachycardia,postural hypotension
Anorexia
Angular stomatitis
Glossitis
Spoon nail
Pica (pagophagia)
Effect on neurologic and intellectual function:
attention span, allertness,learning
Nathan Oski,2003

Lanzkowsky P,2005
Glader B, 2007

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CLINICAL
MANIFESTATIONS

Consequences of anemia :
Mild moderate iron def. ( Hb 6-10 g/dl)
compensatory mechanism (+)
Severe iron deficiency (Hb < 5 g/dl) :
Fatigue, listlessness, irritability, anorexia,
tachycardia, cardiac dilatation & systolic
murmurs.
Advanced iron deficiency :
Pale, plump, & petulant .
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CLINICAL MANIFESTATIONS

Nonhematologic consequence :
Pica :
Phagophagia (compulsive eating of ice)
Geophagia : interest in dirt consumption risk for
parasitic infestation & lead poisoning)
Ephitelial changes : Koilonychia, atrophy of lingual
papil
Exercise intolerance
Behavioral changes
Abnormal thermogenesis
Altered host response

RL,edisi ke 7

Miller Rd,Baehner
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LABORATORIUM FINDINGS
Hemoglobin(Hb) is below the acceptable level for age
Red cell indices :
- / normal MCV,MCHC and MCHC for age
- RDW
Blood smear :
- Red cells : hypochromic, microcytic with
anisocytosis and
poikilocytosis Hb concentration

Reticulocyte count: N/slightly increased


Pleated count : Thrombocytopenia, thrombocytosis
Free erythrocyte protoporphyrin: > 100 g/dl

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Lab.finding
Consentration Ferritin < 12 mg/dl
Serum iron and iron saturation percentage iron
metabolism :
Serum iron :
TIBC :
Transferrin sat. (ratio SI : TIBC) :
Serum transferrin receptor levels ( STfR )
Red blood cell zinc protoporphyrin/ heme ratio
- Bone marrow iron is insufficient to support
heme synthesis
- Zinc protoporphrin relative to heme increases
- Zinc substituses for iron in protoporphyrin IX

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The diagnosis of microcitic anemia


using MCV and RDW
MCV
Low
RDW
Narrow
Hb elektroforesis
MCV on Parents

Wide
FEP*
Ferritin
Trial of Iron

*Also elevated in lead poisonin. Do serum lead level (if clinical indicated)

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Poikylocytosis

Anisocytosis

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DIFFERENTIAL DIAGNOSIS

1.Thalassemia trait
2.Anemia of chronic diseases
3.Lead poisoning

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Diffrential Diagnosis Hypochrom


Microcytic Anemia
Lab findings
chronic disease
MCV

Serum iron

TIBC

Transferrin saturation
FEP

Serum ferritin

IDA Thalassemia Minor

N
N
N
N
N

Anemia

N/

N/

Lukens,1995

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DIAGNOSIS

Criteria of IDA by WHO :


1. Hb concentration < normal (age
dependent)
2. Hematocrit < 31% ( N: 32 - 35%)
3. Serum iron < 50 Ug/dl (N: 80-180 ug/dl)
4. Transferrin sat. < 15 (N: 20-50%)

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Diagnostic Criteia of IDA (Cook dan


Monsen):

Hypochrom microcytic anemia


Transferrin saturation <16%
FEP (free erythrocyte portoporphyrin)
>100 ug/dL
Serum ferritin <12 ug/dL

For diagnosis purpose: it is required


minimum 2 of 3 criteria (TS, serum
ferritin dan FEP)
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...Diagnosis

Alternative way to determine IDA:


Trial of iron supplementation

Important to know subclinical IDA with monitor

hemoglobin respons (increased hemoglobin level).


This procedure is very practical, sensitive dan
economical especially for children at high risk of
IDA
If with iron supplementation 3 mg iron/kgBW/day,
3-4 weeks, Hb level is increased 1-2 g/dL it is
confirmed for IDA.
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Diagnosis

Criteria of IDA by Lanzkowsky :


1. Peripheral smears :
- Microcytic hypochromic
- MCV, MCH, MCHC :
- RDW > 17%
2. FEP :
3. Serum ferritin :
4. Serum ferritin , TIBC , Transferrin sat. <
16%
5. Response to iron preparation
6. Bone marrow : Iron (-) /

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Classification of Anemia
Screening

Hb

CBC:
MCV- MCH

Microcytic,
hypochromic

Normocytic,
normochromic

MCV <80 fL

MCV 80-95 fL

MCH <27 pg

MCH 27 pg

Iron deficiency anemia

Hemolytic anemia

Thalassemia

Anemia chronic disease

Anemia chronic disease

Anemia due to bleeding

Lead poisoning
Sideroblastic anemia

Macrocytic

Peripheral blood
smear
Reticuloyte index

MCV >95 fL

Megaloblastic:
vitamin B12
deficiency or folat

Mixed deficiency

Non-megaloblastic:
alcohol, liver
disease,
myelodysplasia

Bone marrow failure

Aplastic anemia

Renal disease

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Clinical management
Diagnosis
Assessment of underlying cause: dietary
history, birth history, presence of
abnormal bleeding , family history , past
medical/surgery history
Investigation and treatmentof any
underlying cause found : dietary advice
,endoscopy
Iron therapy

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Iron therapy
Oral therapy
Dose: 3 mg/kg/day (2 devided doses)max
180mg
Duration: 6-8 weeks after Hb and the red cell
indices return normal
The following preparations provide 3 mg of
elemental iron: 15 mg of ferrous sulfate,
9 mg of ferrous fumarate,
26 mg of ferrous gluconate,
9 mg of ferrous succinate,
17 mg of ferrous glycine sulfate,
21 mg of sodium iron edetate
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Hematologic response:
a. Reticulocyte increase within 5-10 days following
initiation of iron therapy
b. Hb concentration increase
Failure to respond to oral iron :
The following reasons should be considered:
a. Poor compliance
b. Inadequate iron dose
c. Ineffective iron preparation
d. Persistent or unrecognized blood loss
e. Incorrect diagnosis
f. Coexistent disease (infection ,inflammatory bowel
disease,malignant disease,hepatic or renal disease)
g. Impaired GI absorption

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Parenteral Therapy
1.Intramuscular
Iron dextran ( 50 mg elemental iron/ml) /im , with dose :
Normal Hb - initial Hb x Blood volume(ml)x 3.4 x 1.5
100
It is safe,effective ,well tolerated in infants with acute illness
Indications :
- Noncompliance with oral of iron
- Severe bowel disease(e.g,inflammatory
bowel disease)
- Chronic hemorrhage (e.g, hereditary
telangiectasia, menorrhagia)
- Acute diarrheal disorder in under privileged
populations with iron deficiency anemia

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2.Intravenous
.Sodium ferric gluconate (Ferrlecit)
.Iron(III) hydroxyde sucrose comple (Venofer)
Anemia associated with renal failure and hemodialysis
Dose: 1 4 mg/Kg/week

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Transfusion therapy
Packed red cell
Severe anemia (Hb < 5 g/dl) requiring correction more
rapidly especially when signs of cardiac dysfunction are
present

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Nutritional Counseling
Maintain breast feeding for at least 6 months
iron fortified (6-12mg/L) infant formulas after
weaning from the breast and in non-breast fed
infants until 1 year of age
Iron-fortified cereal from 6 months to 1 year
Suplemental iron
Facilitator of iron absorption: vitamin C-rich
foods(citrus,tomatoes,potatoes),meat,fish,poultry
Eliminated inhibitors of iron absorption such
tea,phosphate ,phytates common in vegetarian diets
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Iron Content of Infant Foods


Food

Iron,mg

Unit

Milk 0.5-1.5
Liter
Eggs 1.2
Each
Cereal,fortified
3.0-5.0
Ounce
Vegetables(starched)
Yellow
0.1-0.3
Ounce
Green
0.3-0.4
Meats(strained)
Beef, lamb, liver
0.4-2.0
Ounce
Pork, liver, bacon
6.6
Ounce
Fruits(strained)
0.2-0.4
Ounce

Lanzkowsky,2005
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Factors affecting iron absorption of nonheme


iron from the gastrointestinal tract

Increased absorption
Vit C: citrus, tomatoes, potatoes,
Solutes
Sugars
meat, fish,poultry
Hydrochloric acid
Decreased absorption
Antacids
Pancreatic secretions
Hypochlorhydria
Phytates
Phosphates

Blackwell,2006

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Prevention
1.Encouragement of breast feeding (BF)
2.Use of iron-fortified infant formula after weaning
BF or non-BF
3.Delay in the introduction of whole cows milk to 1
year of age
4.Use iron fortified infant cereals and ascorbic
acid-rich food solid food are introduced at 6
months
5.Supplemental iron
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..Prevention

Iron supplemental:
Exclusive breast feeding beyond 6 month : 1
mg/Kg/d
Low birth weight infants:
a. 1.5-2.0 kg
: 2 mg/kg/day
b. 1.0-1.5 kg
: 3 mg/kg/day
c. <1 kg
: 4 mg/kg/day

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MEGALOBLASTIC ANEMIA
Definition :
Presences of megaloblasts in the bone marrow
and macrocytes in the blood

Abnormalities of red blood cell (RBC)


morphology and maturation
Etiology :
Deficiency of folic acid
Deficiency Vitamin B12 (Cobalamin)
Inborn errors of metabolism (rarely)
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Causes of Megaloblastosis
I.
II.
III.

Vit B12 (Cobalamin) deficiency


Folate deficiency
Miscellaneous
A. Congenital disorders in DNA synthesis
1. Orotic aciduria(uridine responsive)
2. Thiamine- responsive megaloblastic anemia
3. Congenital familial megaloblastic anemia requiring massive
dose of vit B12 and folate
4. Associated with congenital dyserythropoietic anemia
5. Lesch-Nyhan syndrome (adenine responsive)
B. Acquired defects in DNA synthesis
1. Liver disease
2. Sideroblastic anemias
3. Leukemia, especially acute myeloid leukemia
4. Aplastic anemia (constitutional/acquired)
5. Refractory megaloblastic anemia
C. Drug induced megaloblastosis
1. Purine analogues (e.g, 6 mercaptopurine, azathioprine and
thioguanine)
2. Pyrimidine analogues
3. Inhibitor of ribonucleotide reductase (cytosine arabinoside,
hydroxyurea)
Lanzkwosky,2005

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Megaloblastic anemia

50

Nucleated RBC of megaloblastic anemia

Reticulocytes

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FOLIC ACID
DEFICIENCY

Folic acid : adsorbed in the small intestine


Megaloblastic anemia : occurs after 2 3 mo
on a folate- free diet.

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Causes of Folic Acid Deficiency


I Inadequate intake
A. Poverty, ignorance, faddism
B. Method of cooking (sustained boiling loses 40% folate)
C. Goats milk feeding (6g folate/ L)
D. Malnutrition (marasmus, kwasiokor)
E. Spesial diets for phenylketonuria or maple syrup urine disease
F. Prematurity
G. Post bone marrow transplantion
II. Defective absorption
A. Congenital, isolated defect of folate malabsorption
B. Aquired
1. Idiopathic steatorrhea
2. Tropical sprue
3. Partial or total gastrectomy
4. Multiple diverticula of small intestine
5. Jejunal resection
6. Regional Ileitis

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7.
8.
9.
10.

Whipple disease
Intestinal Lymphoma
Broad spectrum antibiotics
Drugs associated with impaired absorption/utilization of folic
acid (e.g, Dilantin, primidone, metformin, ethanol,barbiturates)
11. Post bone marrow transpntation ( total body irradiation, drugs,
intestinal GVH disease)
III. Increased requirements
A. Rapid growth (e.g, prematurity, pegnancy)
B. Cronic hemolytic anemia ( thalassemia major)
C. Dyserythropoietic anemias
D. Malignant disease(e.g, lymphoma, leukemia)
E. Hypermetabolic states (e.g, infection, hyperthyroidism)
D. Extensive skin disease (e.g, Dermatitis herpetiformis,psosiasis)
G. Cirrhosis
H. Post bone marrow transplantation

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IV. Disorders of folic acid metabolism


A. Congenital
1. Methylenetetrahydrofolate reductase
deficiency
2. Glutamate formiminotransferase deficiency
3. Fuctional N5- methyltetrahydrofolate:
homocysteine methyltransferasedeficiency
4. Dihydrofolate reductase deficiency
5. Methenyl-tetrahydrofalate cyclohydrolase
6. Primary methyl-tetrahydrofolate:
homocysteine methyltransferase deficiency

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B. Acquired
1. Impaired utilization of folate
a. Folate antagonis (drugs that are
dihydrofolate reductase inhibitors,e.g,
methotrexate, pyrimethamine,
trimethoprim, pentamidine)
b. Vit B12 deficiency
c. Alcoholism
d. Liver disease (acute and cronic)
e. Other drugs
V. Increased excretion (e.g, chronic dialysis, vit
B12 deficiency, liver disease, heart disease)

Lanzkowsky,2005
56

VITAMIN B12 DEFICIENCY


ANEMIA
Derived from cobalamin in food
(mainly animal sources) secondary to
production by microorganism
Obtained primarily from :
Animal proteins (ie, red meat, poultry, fish, eggs,
and dairy)
Plants and vegetables lack the vitamin unless
they have been contaminated by soil
microorganisms
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Absorption of vit. B12


58

Cause of vitamins B12 Deficiency


I.

II.

Inadequate vitamins B12 intake


A. Dientary (<2g/day): foods fads, veganism, malnutrition,
poorly controlled PKU diet
B. Maternal deficiency leading to B12 deficiency in breast
milk
Defective vit B12 absorption
A. Failure to secrete intrinsic factor
1. Congenital intrinsic deficiency
a. Quantitative
b. Quantitative (biologically inert)
2. Juvenile pernicious anemia (autoimmune)(gastric
atrophy)
3. Juvenile pernicious anemia ( gastric autoantibodies)
with autoimune polyendocrinopaathies
4. Juvenile pernicious anemia with IgA deficiency
5. Gastric mucosal disease
a. Corrosives
b. Gastrectomy ( partial/ total)
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B. Failure of absorption in small intestine


1. Spesific vit B12 malabsorption
a. Abnormal intrinsik factor
b. Defective cobalamin transport by enterocytes
c. Ingestion of chelating agents
2. Intestinal disease causing generalized
malabsorption, including vit.B12 malabsorption :
a. Intestinal resection
b. Crohnn disease
c. Tunerculosis of terminal ileum
d. Lymphosarcoma of teminal ileum
e. Pancreatic insufficiency
f. Zollinger-Ellison syndrome
g. Celiac disease, topical sprue
h. Other less specific malabsorption syndromes
i. HIV infection
j. Long standing medication that decreases gastric
acidity
k. Neonatal necrotizing enterocolitis
3. Competition for vit B12
a. Small bowel bacterial overgrowth
b. Diplyllobothrium latum, Giardia lamblia, Plasmodium
falcifarum, Strongyloides stercoralis
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III. Defective vit.B12 transport


a. Congenital TC II deficiency
b. Transient deficiency of TC II
c. Partial deficiency of TC II
IV. Disorders of vit.B12 metabolism
A. Conenital
1. Adenosylcobalamin Cb1A and Cb1B diseases
2. Deficiency of methylmalonyl-CoA mutase
3. Methylcobalamin deficiency Cb1E and Cb1G
diseases
4. Combined adenosylcobalamin and
methylcobalamin deficiencies
B. Acquired
1. Liver diseases
2.Protein malnutrition
3. Drugs associated with impaired absorption
and/or utilization of vitB12
Lanzkowsky,2005
61

Clinical Features of cobalamin and folate


deficiency
1.
2.
3.

4.
5.
6.

Pallor, lethargy, fatigability, and anorexia; sore red tounge and


glossitis; episodic or continous diarrhea
History: similarly affected sibling or a sibling who died, maternal
vit B12 deficiency
Vit B12 deficiency: developmental delay, apathy, weakness,
irritability, or evidance of neurodevelopmental delay, loss of
developmental milestones, particulary motor achievements,
hypotonia,loss reflexs,paresthesias
Neurologic complications are increased risk of vascular
thrombosis due to hyperhomocysteinemia
Maternal folate deficiency: neural tube defects, prematurity, fetal
growth retardation, fetal loss
Inborn errors of metabolism: failure to thrive, neurologic disorders,
unexplained anemias, cytopenias
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Diagnosis
1. Red cell changes:
a. Hemoglobulin : reduced
b. Red cell indices: MCV, MCHC normal
c. RDW:
d. Blood smear: macrocytes and macro ovalocytes, anisocytosis,
poikilocytosis, Howell-Jolly bodies
2. White bood cell count: 1500-4000/mm3, neutrophils large and
hypersegmentation
3. Platelet count: 50.000-180.000/mm3
4. Bone marrow : megaloblastic
5. Serum vit.B12 level: <80 pg/mL
6. Serum levels < 3 ng/mL, red cell folate levels: 74-640ng/mL
7. Urinary excretion of orotic acid to exclude orotic aciduria
8. Deoxyuridine suppression test

63

Vit.B12 deficiency suspected :

1. History dietary and previous surgery


2. Schilling excretion test
3. Schilling test is abnormal, repeat with commercial
intrinsic factor.
4. Gastric acidity after histamine stimulation
5. Measure serum holo-transcobalamin II
6. Investigated : Ileal disease
7.Disorders of vitamin B12 metabolism

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Suspect folic acid deficiency :

1. Dietary and drugs (antibiotics,anticonvulsants),


gastroenterologic symptoms
(malabsorption,diarrhea,dietary history)
2. Tests for malabsorption
3. Upper gastrointestinal barium study and follow through
4. Endoscopy and biopsy : upper gut ,jejunal
5. Enzyme assays

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Treatment Folic acid deficiency


1. Folic acid :
Initially corrected : 5 mg (100 g/Kg)daily for 4 months
orally or parenteral
Diagnostic test: smaller dose 0.1 mg/day for a week
2. Underlying causative disorder
3. Improvement of the diet (increase folate intake
4. Prophylactic folic acid: children with severe hemolytic
anemia
5.Transfusion : severe anemia or child is very ill.
6. N-5-formyl tetrahydrofolic acid : Hereditary dihydrofolate
reductase deficiency

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Treatment
Vitamin B12 deficiency
Prevention
Prophylactic vit B12 :total gastrectomy,Ileal resection
Active treatment
- First treated : 6 series im or sc Hydroxocobalamin
- Low doses of Cobalamin 10 g/day o 0.2 g/Kg sc for 2
days reticulocytosis
- Maintenance :1000g Hydroxocobalamin every 3 months
- Food supplemented with Cobalamin

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