2. Definition
• Group of disorders caused by
Impaired DNA Synthesis leading to
ineffective hematopoiesis and
distinctive morphologic changes
including abnormally large erythroid
precursors and red cells.
• Megaloblasts are due to Maturational
asynchrony between nucleus and the
cytoplasm of erythrocytes.
• They are often accompanied by
leukopenia and thrombocytopenia.
6. Vitamin B12 - Nutrition
• Produced only by microorganisms
• Humans receive it solely from diet
• Animal protein especially parenchymal meat is a major dietary source
of vitamin B12 for non-vegetarians (mcg/100 gm dry wt).
• Milk and milk products and eggs contain 1 to 10 mcg/100 gm dry
weight.
• While an average non-vegetarian diet contains 5–7 mcg/day of
cobalamin, the average vegetarian consumes only 0.25–0.5 mcg/day
10. Transport
• Following absorption by ileal mucosal cells , vitamin B12 is carried in
plasma by transporting protein Transcobalmine II.
• Cobalamine is converted into the two required co enzyme forms –
Adenosylcobalmine(AdoCbl) and Methylcobalamine (MeCbl)
• Humans recycle Vitamin B12 by enterohepatic circulation. It is
secreted in bile and reabsorbed in the terminal ileum.
• Liver stores 2-3mg of Vitamin B12.
11. Function of Vitamin B12
The primary role of
Vitamin B12 is serving
as co factor for two
major metabolic
reactions.
12. Causes of Vitamin B12 deficiency
1. Decreased Intake
• Inadequate diet
• Vegetarians
• Breastfed infants of Vitamin B12 deficient mothers due to pernicious
anemia or GI disorders – H. pylori, celiac disease, Crohn disease or
pancreatic insufficiency, strict vegetarians, previous gastric bypass
surgery. Associated megaloblastic anemia often appears during first
year of life.
• However, due to Active placental cobalamine transport in utero,
children of deficient mothers maintain CBl levels sufficient to support
adequate prenatal development but are born with low stores.
13. 2. Impaired absorption
• Intrinsic factor deficiency
• Pernicious anemia
• Gastrectomy
• Pancreatic insufficiency due to impaired cleavage and IF complex formation
• Neonatal Necrotising enterocolitis, Inflammatory Bowel Disease, celiac
disease, removal of terminal ileum.
• Malabsorption states
• Diffuse intestinal disease
• Ileal resection, ileitis
• Competition for Vitamin B12
• Infestation with Diphyllobothrium latum, Giardia lamblia
• Bacterial over growth in blind loops and diverticula of bowel
14. Immerslund-Grasbeck Syndrome
• Recessively inherited, rare
• Selective B12 malabsorption in the ileum
• Clinically apparent in first 6 years of life
• Mutation in CUBN or AMN-proteins that form the cubam receptor for
ileal IF-Cbl complex. CUBN is also a receptor for protein reabsorption
in the kidney proteinuria
• In addition to megaloblastic anemia the patient may have neurologic
defects(hypotonia, developmental delay, brain atrophy, movement
disorders and dementia) and/or proteinuria.
15. Hereditary Intrinsic factor deficiency
• Rare, autosomal Dominant
• Mutation in IF gene lack of gastric IF or functionally abnormal IF
• Symptoms become prominent at an early age(6-24 months) with
exhaustion of vitamin B12 stores acquired inutero.
• Weakness, Irritability, anorexia and listlessness.
• Tongue is smooth, red and painful.
• Neurologic manifestations – ataxia, paresthesia, hyporeflexia,
Babinski responses & clonus.
16. Classic Pernicious Anemia
• Genetic predisposition
• Juvenile pernicious anemia usually presents during adolescence.
• Immunologically mediated, autoimmune destruction of gastric mucosa
• Antibodies against multiple self antigens including those against IF and
H+K+ ATPase pump in gastric parietal cells.
• Chronic Atrophic gastritis – marked loss of parietal cells
3 types of antibodies
1. Type I – blocks vitamin B12 and IF binding
2. Type II – prevents binding of IF-B12 complex with ileal receptors
3. Type III –against specific structures in the parietal cell
17. Pathology
• Pathological changes are infiltration by
mononuclear cells in submucosa and lamina
propria of fundus and body of stomach,
progressive loss of parietal and chief cells
and their replacement by intestinal type of
mucous cells.
• Associated with other autoimmune disorders
like Hashimoto’s, graves’, vitiligo, Diabetes
mellitus, primary hyperparathyroidism,
Addison’s and Myasthenia gravis, cutaneous
candidiasis.
• Atrophy of the gastric mucosa and
achlorhydria.
• Parenteral Vitamin B12 should be
administered regularly.
18. Absence of Vitamin B12 transport protein
• Transcobalmine deficiency is a Rare, autosomal recessive condition
• Failure to absorb and transport Vitamin B12.
• Manifests in first few weeks of life
• Failure to thrive, diarrhoea, vomiting, glossitis, neurological abnormalities
and megaloblastic anemia.
• Diagnosis: Presence of severe megaloblastic anemia in the face of normal
folate levels and no evidence of any other inborn errors of metabolism.
• Plasma homocysteine and/or methylmalonic acid is elevated.
• Definitive diagnosis: Plasma Transcobalamine levels
• Serum B12 levels must be kept high to force enough Cbl into cells to allow
normal function. Oral Cobalamine 500-1000mcg twice a week, or im
Hydroxycobalamine 1000mcg per week for initial therapy.
19. Disorders of Vitamin B12 metabolism
a)Congenital
a) Adenosylcobalamine deficiency
CblA and CblB diseases
b) Deficiency of methylmalonyl
COA mutase
c) Methylcobalamine deficiency
CblE and CblG
d) Combined adenosylcobalamine
and methylcobalamine
deficiency.
20. • In CblE and CblG, defective N5-methylTHF-homocysteine methyltransferase fails to
produce MeCbl.
• Patients present in infancy with megaloblastic anemia, vomiting and mental retardation
and are found to have homocystinuria and hyperhomocysteinemia.
• They do not have methylmalonic aciduria or methylmalonic acidemia.
• Good response to Cyanocobalamine.
• CblC, CblD, CblF – AdoCbl and MeCbl are both affected
• Patients can present in early infancy through adolescence.
• Newborns have lethargy, failure to thrive and neurological problems.
• Older patients-Neurological and psychological problems, dementia.
• Homocysteine and Methylmalonic acid are elevated in both urine & blood.
• Partial response to hydroxycobalmine or Cyanocobalalmine
• CblA, CblB and CblH – Methymalonic aciduria & a variety of serious symptoms
21. b) Acquired
• Liver Disease
• Protein malnutrition(Kwashiorkar and Marasmus)
• Drugs associated with impaired absorption or utilisation of Vitamin B12 –
Colchicine, Paraaminosalicylic acid, Neomycin, Ethanol and oral
contraceptives, Metformin
23. Sources of folic acid
• The main dietary sources of folic acid are green vegetables,
such as asparagus, broccoli, spinach and lettuce.
• It is also found in fruit, such as lemons, oranges, bananas and
melons, and in cereals, grains, nuts, beans, beef, fish, liver and
kidneys.
• Prolonged storage or over-cooking in abundant water can
significantly reduce the folate content of food.
24. Absorption and transport
• Folic acid derivatives(folates) are acceptors and donors of one carbon
units for all oxidation levels of carbon.
• Folate in food occurs in Polyglutamate form which should be
hydrolysed by conjugase in the brush border to folate
monoglutamates.
• Monoglutamates are absorbed in duodenum and upper small
intestine, transported to the liver becoming 5-methyltetrahydrofolate
– principal circulating free form.
• RDA of folic acid: 150-400mcg/day from 1-18 years.
25. Function
• The active coenzyme form of folic acid is Tetrahydrofolate(THF)
• In folate deficiency, THF production is depleted causing slowing of
DNA synthesis –> pancytopenia due to defective hematopoiesis
• The cells that are produced have immature nuclei compared to the
degree of maturation of cytoplasm leading to Nuclear cytoplasmic
asynchrony.
• The biosynthetic pathways of Methionine, Homocysteine, Purines and
Thymine all rely on one carbon units being provided by THF.
26. Function
Folate acts as co enzyme for 2 important reactions involving one
carbon transfer
• Thymidylate Synthase
• Methylation of homocysteine to Methionine
27.
28. The Folate Trap
• The conversion of Methylene THF into methyl
THF catalysed by Methylene Tetrahydrofolate
reductase is irreversible.
• The only way to make use of methylTHF & to
maintain the folate cycle is B12 dependant
remethylation of homocysteine to Methionine.
• In case of B12 deficiency it is possible that
inspite of sufficient availability of folates, an
intracellular deficiency of biologically active
THF arises.
• This situation is called folate trap because on
hand methyl THF continues to rise but on the
other hand since it is prevented from releasing
methyl groups a metabolic dead end situation
arises causing blockage of methylation cycle.
29.
30. • The main problem is decreasing activity
of Methionine Synthase under B12
deficiency with secondary disorders
affecting folate metabolism & insufficient
de-novo synthesis of purines and
pyramidines.
• The deficiency in active folate first affects
the quickly dividing and highly
proliferating haematopoietic cells in the
bone marrow and can even lead to
pancytopenia.
• Hence when only folic acid is
supplemented in B12 deficiency cell
division is induced and the subsequent
consumption of methionine in protein
synthesis impairs methylation of myelin
and precipitates or exacerbates Subacute
Combined Degeneration.
31. RDA of Folic acid
Recommended Daily allowance
Adult men and non pregnant women 400mcg/day
Pregnant women 600mcg
Lactating mother 500mcg
Children 9-18years 400mcg
4-8 years 200mcg
1-3 years 150mcg
7-12 months 80mcg
0-6months 65mcg
32. Causes of Folate deficiency
Decreased dietary intake
• Poverty, ignorance, faddism
• Method of cooking (sustained boiling loses 40% folate)
• Goat’s-milk feeding (6 µg folate/L)
• Malnutrition (marasmus, kwashiorkor)
• Special diets for phenylketonuria or maple syrup urine disease
• Prematurity
• Post bone marrow transplantation (heat-sterilized food)
Decreased absorption:
• Idiopathic steatorrhea, Tropical Sprue, Partial/total gastrectomy, jejunal resection,
ileitis, Whipple’s disease, Intestinal lymphoma, Broad spectrum antibiotics
• Drug induced – Methotrexate, Phenytoin, Primidone, Phenobarbitol, Metformin,
Cycloserine
• Post bone marrow transplantation (total body irradiation, drugs, intestinal GVH
disease)
33. Increased requirements of folic acid
• Rapid growth (e.g., prematurity, pregnancy)
• Chronic hemolytic anemia, especially with ineffective erythropoiesis (e.g.,
thalassemia major)
• Dyserythropoietic anemias
• Malignant disease (e.g., lymphoma, leukemia)
• Hypermetabolic states (e.g., infection, hyperthyroidism)
• Extensive skin disease (e.g., dermatitis herpetiformis, psoriasis, exfoliative
dermatitis)
• Cirrhosis
• Post bone marrow transplantation (bone marrow and epithelial cell
regeneration
35. Acquired
1. Impaired utilization of folate
• Folate antagonists (drugs that are dihydrofolate reductase inhibitors, e.g.,
methotrexate, pyrimethamine, trimethoprim, pentamidine)
• Vitamin B12 deficiency
• Alcoholism
• Liver disease (acute and chronic)
• Other drugs
Increased excretion (e.g., chronic dialysis, vitamin B12 deficiency, liver
disease, heart disease)
36. Clinical Manifestations
• Nonspecific manifestations: weakness, lethargy, easy fatiguability, feeding
difficulties, failure to thrive and irritability.
• Other common findings include pallor, glossitis, vomiting, diarrhoea and
icterus.
• Infants may have regressions of milestones and Infantile tremor syndrome
• On examination: Pallor, Sallow yellow complexion
• Hyperpigmentation of knuckles & nail bed
• Neurological complications: Paresthesia,
Sensory deficits, hypotonia, seizures &
Neuropsychiatry changes.
38. Vitamin B12 deficiency
INFANTS:
• Developmental delay
• Apathy
• weakness
• irritability
• evidence of neurodevelopmental delay
• loss of developmental milestones particularly motor achievements(head
control, sitting and turning).
• Athetoid movements, hypotonia and loss of reflexes occurs.
39. OLDER CHILDREN:
• Subacute Combined Degeneration of spinal cord occurs Degeneration of
posterior and lateral columns with peripheral nerve loss.
• Loss of vibration and position sense with an ataxic gait and positive
Rhomberg’s Sign are signs of posterior column & peripheral nerve loss.
• Spastic paresis may occur with knee and ankle reflexes increased because
of lateral tract loss but flaccid weakness may also occur when these
reflexes are lost (secondary to peripheral nerve loss) but Babinski signs
remains extensor.
• Paresthesia in hands and feet, difficulty in walking may occur due to
peripheral neuropathy.
• MRI findings– increased signals on T2 weighted images of spinal cord, brain
atrophy and retarded myelination.
40. Skin changes
• The skin may be diffusely pigmented
or have abnormal blotchy tanning.
• A macular hyperpigmentation with
follicular accentuation may be
observed in the axilla and groin;
hyperpigmentation can also involve
the dorsal acral distal
interphalangeal joints with special
emphasis on pigmentation of the
nail beds and skin creases.
• Premature greying of hair is
reversible within 6 months of
starting treatment
41. • Glossitis with a smooth (depapillated), beefy red tongue
with occasional ulceration of the lateral surface or gingival
hyperplasia are found on oral examination.
• Increased jugular venous distention along with gallop,
cardiomegaly (with or without pericardial effusions),
pulmonary basal crepitations, pleural effusion, tender
hepatomegaly, and pedal edema should alert the clinician
towards a cardiac failure due to severe anemia.
• Very rarely nontender hepatomegaly, but more often
splenomegaly may hint towards extrameduallary
hematopoiesis.
• Also look for signs of associated hypo-or hyperthyroidism
like neck swellings and loss of lateral one third of eyebrow
42. Systemic Manifestations
• Hematologic - Pancytopenia with megaloblastic marrow
• Cardiopulmonary - Congestive heart failure
• Gastrointestinal – Beefy red tongue. Malabsorption
• Dermatologic - Melanin pigmentation and premature graying
• Genital - Cervical or uterine dysplasia
• Psychiatric Depressed affect and cognitive dysfunction
• Neuropsychiatric - Unique to cobalamin deficiency with cerebral,
myelopathic, or peripheral neuropathic disturbances, including optic and
autonomic nerve dysfunction
43. Approach to diagnosis
• Careful and detailed history regarding Dietary faddism, family induced
diet restrictions, exclusive goat milk feeding.
• Maternal vitamin B12 or folate deficiency. Maternal folate deficiency
results in neural tube defects, prematurity, fetal growth retardation &
fetal loss.
• Document presence or absence of malabsorption syndrome, sprue
• History of surgery involving stomach, jejunum or ileum
• History of bone and joint pain(Leukemia)
• History of drug intake – sulfa exposure, use of chemotherapeutic
agents(Methotrexate or Azathioprine), anticonvulsants
44. Investigations
The goal is to confirm the diagnosis of megaloblastic anemia,
distinguish between folate or Cobalamine or combined deficiency and
to determine the underlying cause – dietary, sociocultural or disease
related.
45. 1. Peripheral Blood Examination
• Haemoglobin: decreased
• Red cells: Characteristic
Macrocytes and macro-
ovalocytes is seen. Marked
anisocytosis, poikilocytosis with
tear drop cells. Basophilic
stippling may be seen.
• Cells containing remnants of
DNA (Howell Jolly Bodies),
arginine rich Histone and
nonhemoglobin iron (Cabot
rings) may be observed.
46. • Retic count is low to normal
• Red cell Indices:
• MCV is increased for age and
may be raised to levels of 110-
140fl.
• MCHC is normal.
• Patients with associated iron
deficiency or thalassemia may
have normal or low MCV.
• RDW is increased
47. White blood cells
• Leucopenia: counts reduced to 1500-
4000/mm3
• Neutrophils show hypersegmentation
(>5lobes) and atleast 4-5% of neutrophils
have more than 5 lobes or a single PMN
with more than 6 lobes.
• Platelet count: Moderately reduced
48. Bone Marrow
• Megaloblastic appearance
• Marrow is hyperplastic due to
increased levels of erythropoietin
acting on erythroid progenitor cells.
• Myeloid: Erythroid ratio decreased
or reversed from 3:1 to 1:1
• Cells are large and nucleus has an
sieve-like, open, stippled or lacy
appearance due to its retarded
condensation. Nuclear cytoplasmic
dissociation is best seen in more
mature erythroid red cell
precursors.
49. • Mitoses are frequent and sometimes
abnormal. Nuclear remnants, Howell
Jolly bodies, bi and trinucleated cells
and dying cells are evident of gross
dyserythropoiesis
• Metamyelocytes are abnormally giant
and have a horse-shoe shaped
nucleus.
• Hypersegmented polymorphs may be
seen
• Megakaryocytes show an increase in
nuclear lobes.
50. A, B: Bone marrow aspirate smears
showing severe megaloblastic
changes: nuclear-cytoplasmic
dyssynchrony, binucleation, nuclear
irregularity, and basophilic stippling
in erythroid lineage cells, and also
hypersegmentation, nuclear-
cytoplasmic dyssynchrony, and
giant metamyelocytes or band
forms in granulocytes (Wright-
Giemsa, × 1, 000).
C: Bone marrow core biopsy
showing hypercellularity, erythroid
hyperplasia, left shift in maturation,
and small dysplastic
megakaryocytes (arrow)
(hematoxylin and eosin, × 400).
D: Small dysplastic megakaryocytes
highlighted by CD61
immunohistochemistry on the core
biopsy.
E, F: Increased ring
sideroblasts in iron stain on
the aspirate smears.
51. • Functional pathophysiology of megaloblastic anemia is ineffective erythropoiesis
in all cell lines
• Increased LDH, indirect bilirubin, ferritin, serum iron and transferrin saturation
and low serum haptoglobin levels due to programmed cell death or apoptosis of
megaloblastic cells during maturation rather than when they are mature resulting
in a predominance of younger erythroid cells in the bone marrow.
52. Blood Investigations
• Serum vitamin B12 levels<80pg/ml are almost indicative of Vitamin B12
deficiency (Normal: 200-800pg/ml)
• Serum and red cell folate levels:
• Serum levels <3ng/ml indicate low level, 3-5ng/ml – borderline level,
>5-20ng/ml : normal
• Red cell folate levels<160ng/ml – low. (Normal: 150-600ng/ml)
• Homocysteine levels are markedly increased in both b12 and folate
deficiency.
• Methylmalonic acid increases in serum and urine in B12 deficiency but not
in folate deficiency and hence is more specific for B12 deficiency.
53. Serum and Urine assessment
• Serum LDH is elevated s/o increased turnover of cells in the marrow
due to ineffective eryhthropoiesis.
• Measurement of IF and urinary proteins detects Immerslund
Grasbeck Syndrome
• Urinary excretion of orotic acid to exclude orotic aciduia
• Deoxyuridine suppression test: to differentiate folate and B12
deficiency
• Schillings and FIGLU test were used in the past to detect Vitamin B12
assay and folic acid deficiency but not used now.
54.
55. Schillings Test
• For absorption of Vitamin B12 in GIT
• Performed in 2 parts
Part 1:
• 0.5-1microgram of radiolabelled Vitamin B12 is given orally
• After 2 hours im dose (1000mcg) of unlabelled vitamin B12 of given(to saturate binding
sites of TC I and II and displace unbound radiolabelled vitamin B12 thus permitting
urinary excretion of absorbed radiolabelled vitamin B12)
• Radioactivity is measured in subsequently collected 24hr urine sample and expressed as
% of total oral dose
• In normal persons, >7% of oral dose is excreted in urine.
• If less than normal is excreted it indicates impaired absorption which is due to lack of
either IF or small intestinal malabsorption
56. Part 2
• Patient is orally administered radiolabelled vitamin B12 along with IF
while remainder of test is carried out as in part I
• If excretion is normal – lack of IF
• Excretion remains below normal – defective absorption in small intestine
• INTERPRETATION
• Part I normal – Dietary deficiency
• Part I abnormal, Part II normal – Pernicious anemia and
gastrectomy
• Part I abnormal, Part II abnormal – Malabsorption in small
intestine
57.
58. Treatment of Vitamin B12 deficiency
• Daily dose of 25-100mcg may be used to start therapy
• Monthly im injection in a dose of 200-1000mcg can be started as maintenance therapy.
• Vitamin B12 deficiency can be treated with intramuscular injections of cyanocobalamin or oral vitamin
B12 therapy. Approximately 10% of the standard injectable dose of 1 mg is absorbed, which allows for
rapid replacement in patients with severe deficiency or severe neurologic symptoms.
• Conventional therapy has been
• 1000 μg of CyanoCbl or HydroxyCbl by injection daily for 1 week, followed by
• 100 μg of CyanoCbl weekly for 1 month
• 100 μg of CyanoCbl monthly thereafter. This therapy is believed to replete and sustain body
cobalamin stores.
• Physiological requirement is 1-3mcg/day
• Patients with dietary insufficiency should receive nutritional counselling.
• Lifelong B12 supplementation if diet cannot be altered.
59. Response to treatment
• A single injection of cyanocobalamin is given and disappearance of
megaloblastoid changes in the bone marrow is looked for in the next 48
hours besides two of the following, in order to call the test positive.
• 50 percent decrease in serum iron or LDH within 48 hours.
• Increase in retic count 5 to 10 days after treatment.
• Correction of neutropenia and thrombocytopenia over a period of 2 weeks.
• Once reticulocytosis subsides MCV is decreased by 5 fL or more.
• Plasma MMA and homocysteine in 2 weeks.
• Correction of anemia of 2 to 4 weeks.
• Decrease in the neutrophil lobe count to normal over a 4 weeks period
60. ABNORMALITY EXPECTED TIME UNTIL IMPROVEMENT
Homocysteine or methylmalonic acid level,
or reticulocyte count
One week
Neurologic symptoms Six weeks to three months
Anemia, leukopenia, mean corpuscular
volume, or thrombocytopenia
Eight weeks
Time to Improvement of Abnormalities in Vitamin B12 Deficiency After Initiation of Treatment
61. Treatment of folate deficiency
Successful treatment of patients with folate deficiency involves:
• Correction of the folate deficiency
• Treating the underlying causative disorder
• Improvement of the diet to increase folate intake
• Folate deficiency is typically treated with oral folic acid 1 to 5 mg per day. This dosage is more than
the recommended dietary allowance of 400 μg per day, thereby allowing for adequate repletion
even in the setting of malabsorption. Treatment is continued for the duration of hematologic
recovery or until the cause of deficiency is addressed. In patients with malabsorption, treatment is
continued indefinitely. Before folic acid is given, it is necessary to exclude vitamin B12 deficiency.
• Correct the cause of the deficiency, e.g.
• improved diet, a gluten-free diet in celiac disease, treatment of an inflammatory disease
such as tuberculosis or Crohn’s disease.
• In other situations, it is advisable to continue the folic acid to prevent recurrence,
• e.g. chronic hemolytic anemia such as thalassemia or in patients with malabsorption who do
not respond to a gluten-free diet
62. Response to treatment
• Bone marrow may totally revert in 24 hours
• Patient starts feeling well in days
• Retic response will peak at 5‐7 days
• Hb starts rising after 1‐2 weeks
• Hb normalizes by 3 months
• PS becomes normal after 1‐2 months as old macrocytic RBCs will
persist till their life
63. Prophylaxis with Cobalamin
• 5 to 10 mcg for nutritional causes and
1000 mcg/day for problems of malabsorption
• Infants on specialized diets
• Premature infants
• Infants of mothers with pernicious anemia
• Infants and children of mothers with nutritional
cobalamin deficiency
• Vegetarianism and poverty-imposed near-
vegetarianism
• Total gastrectomy.
64. Prophylaxis with Folic acid
• All women, from the moment they begin trying to conceive until 12 weeks of
gestation, should take a folic acid supplement (400 μg folic acid daily) to prevent
neural tube defects.
• Pregnancy and lactation, premature infants
• Mothers at high risk/previous history for delivery of infants with neural tube
defects – 4mg/day
• Hemolytic anemias/hyperproliferative hematologic states
• Patients with rheumatoid arthritis or psoriasis on therapy with methotrexate
• Patients on antiepileptic drugs
• Patients with ulcerative colitis
65. Infantile Tremor Syndrome
• Infantile tremor syndrome (ITS) is a self limiting condition characterized by pallor,
developmental delay/regression, skin pigmentation, brown scanty scalp hair,
hypotonia
• Tremors are coarse in character, decreased or disappeared in sleep and resolves
within 4–6 weeks in its natural course
• ITS occurs in exclusively breastfed infants of strictly vegetarian mothers.
• As a result, these infants are predisposed to develop vitamin B12 deficiency.
• Clinically, symptoms and signs of ITS are similar to those of vitamin B12 deficiency
in infants.
• Several studies have consistently demonstrated low serum vitamin B12 in these
infants.
• Additionally, in some studies from India, infants with megaloblastic anemia due to
vitamin B12 deficiency displayed symptoms and signs consistent with ITS .
66. • Response to treatment with vitamin B12 in ITS is rapid with
improvement in general activity and responsiveness within 48-72
hours.
• This is followed by the return of social smile and improved appetite.
• Lost developmental milestones are gradually regained.
• The tremors begin to subside by the end of first week and disappear
completely by 3-4 weeks.
• It follows that infants with vitamin B12 deficiency can present with
predominantly hematological (megaloblastic anemia) or
predominantly neurological (infantile tremor syndrome)
manifestations.
• Some infants may have purely neurological or purely hematological
presentations.
67. Thiamine-responsive anemia in DIDMOAD (Wolfram)
syndrome:
• It is a rare autosomal recessive disorder of thiamine transport,
possibly deficient thiamine pyrophosphokinase activity, due to
mutations in a gene on chromosome 1q23.
• Megaloblastic anemia and sideroblastic anemia with ringed
sideroblasts may be present.
• Neutropenia and thrombocytopenia are present.
• It is accompanied by diabetes insipidus (DI), diabetes mellitus (DM),
optic atrophy (OA) and deafness (D).
• Treatment: Anemia responds to 100 mg thiamine daily but
megaloblastic changes persist. Insulin requirements decrease.
68. Hereditary orotic aciduria:
• Rare autosomal recessive defect of pyrimidine synthesis with failure
to convert orotic acid to uridine and excretion of large amounts of
orotic acid in the urine, sometimes with crystals. Appears in 1st year
of life.
• It is associated with severe megaloblastic anemia with normal serum
B12 & folate levels and no evidence of TC deficiency. Neutropenia,
failure to thrive and physical and mental retardation are frequently
present.
• Treatment: Oral uridine in a dose of 100–200 mg/kg/day. The anemia
is refractory to vitamin B12 and folic acid.
69. Lesch-Nyhan syndrome:
• Mental retardation, self-mutilation and choreoathetosis result from
impaired synthesis of purines due to lack of hypoxanthine
phosphoribosyltransferase.
• Some patients have megaloblastic anemia.
• Treatment: Megaloblastic anemia responds to adenine therapy (1.5 g
daily).
70. Malignancy
• Megaloblastic anemia can also mimic malignant conditions.
• Cytopenias, combined with severe megaloblastic findings in the
bone marrow, overlap with the neoplastic processes of low-
grade myelodysplastic syndrome or acute myeloid leukemia
• Diagnostic considerations include myelodysplastic syndrome
with excess blasts and erythroid predominance, as well as pure
erythroid leukemia (ie, a neoplastic proliferation of immature
erythroid cells with > 80% erythroids and > 30%
proerythroblasts) without increased myeloid blasts.
71. Dysplastic features characteristic
of myelodysplastic syndrome
that are not typical of
megaloblastic anemia include
the following:
• Hyposegmentation or
hypogranulation of
granulocytes
• Hypolobation or small forms of
megakaryocytes
• Hypogranular platelets
• Increased blasts.
Hyperpigmentation results from decreased glutathione which induces tyrosinase activity which in turn mobilizes melanocytes to keratinocytes, causing increased melanin synthesis.