1. Presenters:
DR. RENESHA ISLAM
DR. MD IMRAN HABIB
YEAR-3 RESIDENT (PHASE-B)
PAEDIATRIC HAEMATOLOGY & ONCOLOGY
BANGABANDHU SHEIKH MUJIB MEDICAL
UNIVERSITY (BSMMU)
WELCOME
TO
SEMINAR
2. .
⢠In 2018, A 13 years old boy Emon came from
kishoreganj with low socio economic
background was admitted to our department
with a history of fever, pallor, worsening mild
weakness, numbness in bilateral lower limbs &
gait disturbance,Rombergs sign was positive.
On lab. Examination blood count showed
macrocytosis, hypersegmented
neutrophil,reduction in serum vitamin B12
level, bone marrow showed megaloblast.
3.
4. ⢠Megaloblastic anemia is characterized by the presence
of megaloblasts in the bone marrow and macrocytes in
the blood.
⢠In more than 95% of cases, megaloblastic anemia is a
result of folate and vitamin B12 deficiency
10. Causes of Vitamin B12
Deficiency
1. Inadequate vitamin B12 intake
a. Dietary : food fads, lacto-ovo vegetarianism, low animal-
source food intake, veganism, malnutrition.
b. Maternal deficiency leading to B12 deficiency in breast
milk.
11. 2. Defective vitamin B12 absorption
a. Failure to secrete intrinsic factor
i. Congenital intrinsic factor deficiency (gastric mucosa normal)
⢠Quantitative & Qualitative
ii. Juvenile pernicious anemia (autoimmune)
iii. Juvenile pernicious anemia with autoimmune
polyendocrinopathies
iv. Juvenile pernicious anemia with IgA deficiency
v. Gastric mucosal disease
⢠Chronic gastritis
⢠Corrosives
⢠Gastrectomy
12. b. Failure of absorption in small intestine
i. Specific vitamin B12 malabsorption:
Abnormal intrinsic factor
Imerslund Grasbeck syndrome
Ingestion of chelating agents
ii. Intestinal disease causing generalized
malabsorption, including vitamin B12 malabsorption:
Intestinal resection
Crohnâs disease
Tuberculosis of terminal ileum
Pancreatic insufficiencyc
ZollingerEllison syndrome
13. Celiac disease , tropical sprue
Long-standing medication that decreases gastric acidity
Parasites
Neonatal necrotizing enterocolitis
iii. Competition for vitamin B12
Small-bowel bacterial overgrowth
Diphyllobothrium latum, the fish tapeworm , Giardia
lamblia, Plasmodium falciparum.
14. 3. Defective vitamin B12 transport
a. Congenital TC II deficiency
b. Transient deficiency of TC II
c. Partial deficiency of TC I (haptocorrin
deficiency)
15. 4. Disorders of vitamin B12 metabolism
a. Congenital
i. Adenosylcobalamin deficiency CblA and CblB
diseases
ii. Deficiency of methylmalonyl-CoA mutase
iii. Methylcobalamin deficiency CblE and CblG
diseases
iv.Combined adenosylcobalamin and
methylcobalamin deficiencies: CblC , CblD , and CblF
diseases.
⢠.
16. B. Acquired :
i. Liver disease
ii. Protein malnutrition (kwashiorkor,
marasmus)
iii. Drugs associated with impaired absorption
and/or utilization of vitamin B12 (e.g., p-aminosalicylic
acid, neomycin, ethanol, oral contraceptive agents,
Metformin)
17. Nutritional Deficiency :
⢠The recommended dietary allowance of vitamin B12 for
children is 0.9 - 2.4 Îźg/day.
⢠The most common cause of Cbl deficiency in infants is
dietary deficiency in the mother. Mothers following
vegetarian, vegan, macrobiotic, and other special diets
,had previous gastric bypass surgery or short gut syndrome.
18. Defective Absorption
Condition Stomach Schilling Test Serum Antibodies
Histo
logy
IF HCL Without
IF
With IF IF PC Ass
factor
Congenital
pernicious
anemia
N Ab N N Ab Ab
Juvenile pernicious
anemia
(autoimmune
At Ab Achl N P
90%
P
10%
Juvenile pernicious
anemia with
polyendocrinopathi
es
or selective
IgA deficiency
At Ab Achl N P P
Enterocyte vitamin
B12 malabsorption
(Imerslund-
Grasbeck)
N P N A A
19. Intrinsic Factor
Deficiency
⢠Patients with absent or defective IF (also known as S-
binder) have low serum B12 and megaloblastic
anemia.
ď§ autosomal recessive disorder
⢠usually appears early in the second year of life.
⢠The abnormal absorption of cobalamin is corrected by
mixing the vitamin with a source of normal IF.
.
20. Defective Cobalamin Transport by Ileal Enterocyte
Receptors for the Intrinsic Factor-Cobalamin
Complex
(Imerslund-Grasbeck Syndrome)
⢠It is due to a selective defect in cobalamin absorption in the
ileum.
⢠autosomal recessive disorder
⢠ileal receptor for IFcobalamin complex is absent
⢠gastric IF level is normal, they do not have antibodies to IF, and
the ileal intestinal morphology is normal.
,
21. ďś chromosome 10 mutations are found in either of two genes
encoding proteins: cubilin (CUBN) and amnionless (AMN).
ďś Symptoms within the first 2 years
ďś C/F:
o pallor, weakness,
o failure to thrive, delayed development,
o recurrent infections
o gastrointestinal symptoms &
proteinuria.
22. Defective
Transport
defect Age of
presentation
C/F Lab finding
TC I (haptocorrin
or R-binder)
deficiency
Deficiency/
absence of TCI in
plasma, saliva,
leukocytes.
Unclear Neurologic
symptoms
(myelopathy)
Low serum Cbl,
normal TC II-Cbl
levels. No
increase in MMA
or homocysteine
TC II deficiency Defective/ absent
TC II
Early infancy 35
weeks
Failure to thrive,
megaloblastic
anemia later
neurologic
features and
immunodeficienc
y
Usually normal
serum Cbl,
elevated serum
MMA,
homocysteine,
absent/defective
TC II
24. 1.Adenosylcobalam
in Deficiency CblA
and CblB Diseases
impaired
methylmalonyl CoA
mutase activity
methylmalonic
acidemia.
autosomal
recessive
Life-threatening or fatal
ketoacidosis in the first few
weeks or months of life.
⢠Hypoglycemia/
hyperglycinemia.
⢠Failure to thrive
⢠S Cbl - N
2. Methylmalonyl-
CoA Mutase
Deficiency
result in
methylmalonic
aciduria
autosomal
recessive
Infants are well at birth but
become rapidly symptomatic
on protein feeding and
develop lethargy, failure to
thrive, muscular hypotonia,
respiratory distress, and
recurrent vomiting and
dehydration
25. 3 . Methylcobalamin Synthesis Deficiency: CblE and
CblG Diseases
4 . Combined Adenosylcobalamin and Methylcobalamin
Deficiencies CblC CblD , and CblF Diseases
26. Methylcobalamin synthesis Deficiency:
CbIE & CbIG Disease
Result in
⢠Reduced N5-methyltetrahydrofolate: Homocysteine
methyltransferase
⢠And homocysteinuria with hypomethioninemia.,
C/F: Failure to thrive, Megaloblastic anemia,
neurological deficit.
27. Combined Adenosylcobalamin and Methylcobalamin
Deficiencies CblC, CblD and CblF Diseases
MeCbl
homocysteinuria and
hypomethioninemia
AdoCbl
methylmalonic
aciduria
Methylmalonyl
CoA mutase
homocystinuria
hypomethioninemia
methylmalonic aciduria
28. .
C/F:
ď Failure to thrive
ďDevelopmental retardation
ďHydrocephalus
ďSpasticity, delirium, psychosis.
ďMany dies with symptoms in 1st month of life.
29.
30. FOLIC ACID DEFICIENCY
⢠Food folate (polyglutamate form)
⢠hydrolyzed in the brush border of the intestine to folate
monoglutamates.
These are absorbed in the duodenum and upper small intestine
( transported to the liver becoming)
5-methyl tetrahydrofolate, the principal circulating folate form.
31. The recommended dietary allowance of folate
increases from 150 to 400 Îźg/day from age 1
year to 18 years.
32. Causes of Folic Acid Deficiency
o Defective absorption
a. Congenital (isolated defect of folate
malabsorption)
b. Acquired
o Idiopathic steatorrhea
o Partial or total gastrectomy
o Intestinal lymphoma
o Broad-spectrum antibiotics
o Drugs
o Post bone marrow transplantation.
⢠Poverty, ignorance, faddism
⢠Method of cooking
⢠Goatâs-milk feeding
⢠Malnutrition
⢠Special diets for
phenylketonuria or maple
syrup urine disease
⢠Prematurity
⢠Post bone marrow
transplantation.
Inadequate intake
Increased requirement
⢠Rapid growth
⢠Chronic hemolytic anemia
⢠Malignant disease
⢠Hypermetabolic states
Increased excretion
⢠chronic dialysis
⢠vitamin B12 deficiency
33. Acquired Folate
Deficiency
o Rapid growth in the first few weeks
of life, particularly in premature
o Pregnant women
o Goatâs milk diet
o Medication (Antiepileptic
medication)
o Diseases of the small intestine
causing malabsorption.
o Hemolytic anemia with rapid red
cell turnover (Sickle cell anemia)
o Chronic infections (HIV infection in
infants).
ďś Methylene tetrahydro folate
reductase deficiency
ďś Glutamate formimino transferase
deficiency
ďś Functional N5-methyltetrahydro
folate: Homocysteine methyl
transferase deficiency
ďś Dihydrofolate reductase deficiency
ďś Methenyl-tetrahydro folate cyclo
hydrolase
ďś Primary methyl tetrahydro folate:
Homocysteine methyl transferase
deficiency.
Congenital Disorders of
Folic acid Metabolism
Disorders of folic acid metabolism
35. ⢠A rare autosomal recessive trait.
⢠Characterized by an abnormality in the absorption of oral
folic acid or of reduced folates (5-methyltetrahydrofolate
or 5-formyltetrahydrofolate (folinic acid))
⢠Elevated excretion of Formiminoglutamate (FIGLU) and
of Orotic acid.
⢠Manifestation:
-In first few months of life.
-Characterized by megaloblastic anemia associated with
low serum, RBC, & cerebrospinal fluid folate levels.
Hereditary Folate
Malabsorption
36. Clinical features:
⢠Chronic or recurrent diarrhea
⢠Mouth ulcers
⢠Failure to thrive
⢠Usually loss of developmental milestones
⢠Seizures, progressive neurological deterioration.
Treatment :
⢠Oral folic acid (5-40 mg daily) & lower parenteral
doses correct the hematologic abnormality.
⢠Oral doses of folates may have to be increased to 100
mg or more daily if necessary.
Hereditary Folate
Malabsorption
37. o Rare autosomal recessive disorder.
o Cause:
Mutations of MTHFR gene.
plasma homocysteine and homocystinuria and
plasma methionine levels.
o Presents severely in early infancy (first month of life).
Methylene tetrahydro folate Reductase
Deficiency
Deficiency results in
38. Clinical features
ď§ Hypotonia
ď§ Motor and gait abnormalities
ď§ Recurrent strokes
ď§ Seizures
ď§ Mental retardation
ď§ Psychiatric manifestations and microcephaly.
Treatment
⢠Resistant to treatment.
⢠Regimens have included folic acid, methyl
tetrahydrofolate, methionine, pyridoxine, various
cobalamins, carnitine, and betaine.
39. ďą Autosomal recessive inheritance, caused by mutation in
FCTD gene.
ďą Patients with the severe form show mental and physical
retardation, abnormal EEG activity and dilatation of the
cerebral ventricles with cortical atrophy.
ďą Lab finding :
elevated to normal serum folate levels & elevated FIGLU
levels in the blood & urine after a histidine load. Plasma
amino acid levels usually normal, but hyperhistidinemia,
hyperhistidinuria, & hypomethioninemia have been
found.
Glutamate Formiminotransferase
Deficiency (OMIM 229100)
42. History taking
Physical findings
Lab investigations
ď§Dietary
ď§Method of cooking
ď§ Goatâs-milk feeding
ď§ maternal vitamin B12 or folate
deficiency.
ď§ prematurity.
ď§fetal growth retardation, and fetal
loss.
ď§History of similarly affected sibling.
ď§unexplained anemias, or
cytopenias.
ď§Bowel habit alteration.
ď§Surgical history.
ď§Drug history, Long-standing
medication
Approach to patient with megaloblastic anaemia
43. Clinical features
⢠Anemia â
- pallor, lethargy, fatigability, anorexia.
⢠Gastrointestinal symptom-
- Sore red tongue, GI upset, weight loss, diarrhea (episodic
or continuous) or constipation.
⢠Neurological symptom : (infants)
- Apathy, weakness, irritability
- Loss of developmental milestones,
particularly motor achievements
- Athetoid movements
- Hypotonia, and loss of reflexes occur.
44. Clinical feature
⢠In older children
- Subacute combined degeneration of the
spinal cord.
- Loss of vibration and position sense with
an ataxic gait & positive Rombergâs sign .
- Spastic paresis may occur, with knee and
ankle reflexes increased .
- Peripheral nerve loss: flaccid weakness
(may occur but Babinski sign remains
extensor). Paresthesia in the hands or feet
and difficulty in walking and use of the
hands .
- Cognitive and developmental retardation.
⢠Increased risk of vascular thrombosis.
45. Investigation
⢠CBC:
-Hemoglobin: Usually reduced, may be marked.
-Red cell indices: MCV increased for age and may be
raised to levels of 110-140 fl; MCHC normal.
-RDW: Increased.
-WBC count: Reduced to 1500-4000/mm3
:Neutrophils show hypersegmentation.
-Platelet count: Moderately reduced to
50,000 - 180,000/mm3.
:Platelet function is sometimes impaired.
48. DIAGNOSIS OF COBALAMIN AND FOLATE DEFICIENCY
- Lactate dehydrogenase,
- Indirect bilirubin,
- Ferritin,
- S. iron and transferrin saturation
- Low serum haptoglobin levels
⢠Serum vitamin B12 level: 80 pg/ml are almost always
indicative (normal values 200-800 pg/ml).
Serum folate level interpretation
<3 ng/ml low level
3-5 ng/ml borderline
>5-6 ng/ml normal
RBC folate levels<160 ng/ml low
49. ⢠Homocysteine level- rises in both folate and vitamin B12
deficiency.
⢠Methylmalonic acid- increases in the serum and urine in
cobalamin deficiency and is therefore a more specific test
for cobalamin deficiency. (210 -480 nmol/l-normal level)
⢠Deoxyuridine suppression test-To discriminate between
folate and cobalamin deficiencies.
⢠Urine :
-Urinary excretion of orotic acid to exclude orotic
aciduria.
-Urinary methylmalonic acid, proteinuria (If vitamin
B12 deficiency is suspected).
50. vitamin B12 deficiency
⢠Gastric acidity after
histamine stimulation
(establishes a gastric cause).
⢠Barium studies and small-
bowel biopsy (Ileal disease).
⢠Measurement of S. holo-TC II
It falls below the normal
range before total serum
cobalamin does.
⢠Schilling test.
Folic acid deficiency
⢠Tests for GIT diseases with
associated malabsorption:
gluten autoantibodies, 24-hr
stool fat, upper GIT barium
study and follow-through,
upper-gut endoscopy and
jejunal biopsy.
⢠Oral doses of 5 mg
pteroylglutamic acid should
yield a plasma level in excess of
100 ng/ml in 1 h. No rise in
plasma level congenital folate
malabsorption should be
considered.
⢠Enzyme assays.
53. Bone marrow
examinaion
⢠Hyperplastic.
⢠Meyeloid / erythroid : decrease/normal.
⢠Erythroid hyperplasia with large erythroid precursors.
⢠Myeloid precursors may also be large. Giant myelocytes
and giant metamyelocytes may also be observed.
⢠Nuclear cytoplasmic dissociation is best seen in the
more mature erythroid red cell precursors.
⢠Mitoses are frequent and sometimes abnormal. Nuclear
remnants, Howell Jolly bodies, bi- and trinucleated cells
and dying cells are evidence of gross dyserythropoiesis.
55. Antenatal diagnosis
⢠Congenital methylmalonic aciduria has been
diagnosed in utero by measurements of
methylmalonate in amniotic fluid or maternal urine.
56. TREATMENT
⢠Vitamin B12 Deficiency
⢠Active Treatment
-Several daily doses of 25 - 100 mg cyanocobalamin may be
used to initiate therapy as well as potassium supplements.
-Maintenance therapy can be started with monthly I/M in
doses 200-1000 mg cyanocobalamin.
-Intestinal absorption of vitamin B12 (abnormalities of if or
of ileal uptake)-100 mg of B12 injected subcutaneously
monthly
-Complete TC II deficiency-1000 mg IM 2-3 times weekly.
-Methylmalonic aciduria with defects in the synthesis of
cobalamin coenzymes: 1 -2 mg vitamin B12 parenterally
daily.
57. ⢠Cyanocobalamin
- Vitamin B12 deficiency of dietary origin
- âś BY MOUTH âś 50â105 mcg daily in 1â3 divided doses.
⢠Hydroxocobalamin
Macrocytic anaemia without neurological involvement
âś By IM injection âś Initially 0.25â1 mg 3 times a week for
2 weeks, then 0.25mg once weekly until blood count
normal, then 1 mg every 3 months.
- Macrocytic anaemia with neurological involvement
âś By IM injection âś
Initially 1 mg once daily on alternate days until no
further improvement, then 1 mg every 2 months.
58. Reticulocytes
- Begin to increase - on 3rd or 4th days.
- Rise to a maximum on the sixth to eighth days.
- Fall gradually to normal about the 20th day.
⢠Bone marrow reversal from megaloblastic to
normoblastic cells within 6hr and is complete in 72hr.
⢠Improvement of alertness and responsiveness within
48 hr.
⢠Developmental delays may catch up in several months
in young infants.
Response to
Vitamin B12 Treatment
59. Folic Acid Deficiency
⢠Treatment of the cause and Before folic acid is given
vitamin B12 deficiency must be excluded.
âś Neonate: Initially 500 mcg/kg once daily for up to 4m.
âś 1â11 months: Initially 500 micrograms/kg once daily
(max. 5 mg/dose) for up to 4 months, upto 10 mg/day in
malabsorption states.
âś 1â17 years: 5 mg daily for 4 months.
⢠In other situations, folic acid is required life-long, such as
thalassemia or in patients with malabsorption who do not
respond to a gluten-free diet.
⢠Hereditary dihydrofolate reductase deficiency respond to
N-5-formyl tetrahydrofolic acid .
60. Response to
Folic Acid Treatment
Appetite 12 days
Rise in reticulocytes in 24 days
Hemoglobin 26 weeks.
Leukocytes and platelets increase and megaloblastic
changes in the marrow diminish within 24 - 48 h.
⢠However, large myelocytes, metamyelocytes, and band
forms may be present for several days.
⢠Folic acid is usually administered for several months until
a new population of red cells has been formed.
61.
62. Prevention
⢠Interventions that address micronutrient deficiencies.
⢠Biofortification.
⢠Dietary diversification.
⢠Dietary modification.
⢠Industrial fortification.
⢠Ironâfolic acid supplementation in women of
reproductive age.
⢠Maternal, infant, and young child nutrition.
⢠Routine micronutrient interventions for children.