Symposium on Nutritional Anemia
Megaloblastic Anemia: Back in Focus
Jagdish Chandra
Department of Pediatrics, Lady Hardinge Medical College, and Kalawati Saran Children’s Hospital, New Delhi, India
ABSTRACT
Megaloblastic anemia (MA), in most instances in developing countries, results from deficiency of vitamin B12 or folic acid. Over
the last two to three decades, incidence of MA seems to be increasing. Of the two micronutrients, folic acid deficiency
contributed to MA in a large majority of cases. Now deficiency of B12 is far more common. In addition to anemia, occurrence
of neutropenia and/or thrombocytopenia is increasingly being reported. Among cases presenting with pancytopenia, MA stands
out as an important (commonest cause in some series) cause. This article focuses on these and certain other aspects of MA.
Possible causes of increasing incidence of MA are discussed. Observations on other clinical features like neurocognitive
dysfunction, associated hyperhomocysteinemeia and occurrence of tremors and thrombocytosis during treatment are
highlighted. [Indian J Pediatr 2010; 77 (7) : 795-799] E-mail: [email protected]
Key words: Megaloblastic anemia; Pancytopenia; B12 deficiency; Folic acid deficiency
Megaloblastic anemia (MA) is a distinct type of anemia
characterized by macrocytic RBCs and typical
morphological changes in RBC precursors. The RBC
precursors are larger than the cells of same stage and
exhibit disparity in nuclear-cytoplasmic maturation. Basic
underlying pathogenetic mechanism in MA is deficiency
of folic acid (FA) and/or vitamin B12 at the cellular level
with resultant impairment of DNA synthesis. In
developing countries, most cases of MA result from
nutritional deficiency of these micronutrients.
Other than MA, deficiency of these hematopoeitic
micronutrients in children has been incriminated to cause
neuro-developmental dysfunction, abnormal movements
and failure to thrive. Neural tube defects result from
deficiency of folate in mothers during pregnancy. Because
of these ill effects, folate has since long been included in
the supplementation programmes to control anemia.
At community level most cases of nutritional anemia
result from deficiency of iron and can be prevented or
treated with iron administration. From public health
viewpoint, deficiency of folate and B12 has been regarded
to contribute little to nutritional anemia. Over the last two
decades, role of these micronutrients and their deficiency
has been brought to the forefront by various workers.
Presentation of patients with MA with pancytopenia,
vasculo-toxic effects of hyperhomocysteinemia resulting
Correspondence and Reprint requests : Dr. Jagdish Chandra, 5,
Lecturer Flats, Lady Hardinge Medical College Campus, Bangla
Sahib Road, New Delhi-110001, India.
[DOI-10.1007/s12098-010-0121-2]
[Received October 6, 2009; Accepted October 6, 2009]
Indian Journal of Pediatrics, Volume 77—July, 2010
from folate and/ or B12 deficiency and possible role of
their deficiency in causing bone loss leading to
osteopenia, osteoporosis and pathological fractures has
brought B12 and folate deficiency and MA back in focus.1,2
HISTORICAL BACKGROUND: INCREASING
PREVALENCE OF MA
Nutritional MA in adults is known for long. Jadhav et al
have been credited to report MA in six South Indian
infants for the first time in world literature in 1962. 3,4
However, stray reports of MA in Indian children can be
found in Indian literature even before that.
MA resulting from deficiency of folate and B12 appears
to be increasing over the last two decades, although
evidence for this may not be forthcoming easily as
varying criteria have been used in the literature to point
towards anemia resulting from deficiency of FA or vit B12.
Some studies have considered macrocytosis of red cells as
indicative of this type of anemia, while others have
defined MA by presence of megaloblastic changes in the
bone marrow. Still others have used subnormal
micronutrient levels to define this type of anemia. Table 1
shows the proportion of cases contributed by macrocytic
anemia or MA/FA- vit. B 12 deficiency as observed in
various series on nutritional anemia in children or during
survey of micronutrient deficiency. While proportion of
these cases seems to be increasing over the yrs, of
particular interest is the observation by Gera et al which
shows an almost four fold rise in proportion of macrocytic
anemia cases over less than a decade at one center-2 % in
1991 and 7.8% in 1999 (Table 1). A recent report shows
795
Jagdish Chandra
TABLE 1. Prevalence of MA, Macrocytic Anemia or B12/Folate
Deficiency
No and Series
Year
Proportion of cases (%)
1. Ghai et al5
2. Dalal et al6
3. Ghai et al7
4. Sharma et al8
5. Gomber et al9
6. Chaudhry et al10
7.Gera et al11
1956
1969
1977
1985
1998
2001
1991
1999
19.1
18.0
02.0
24.0
42.1
27.1
02.0
07.8
46.9% of non-anemic adult subjects having subnormal
levels of B12 or folate- B12 deficiency being five times more
common than that of folate.12
Further, the timing of the reports reveals a renewed
interest in the subject over last two decades. Observations
on adults and children from other developing countries
including Pakistan, Zimbabve, Mexico and Guatemala
during this period shows that the trend in India may be
reflecting a more generalized phenomenon. 13-16 The
increase in prevalence of MA is also supported by
observation that MA accounts for maximum/a large
number of cases of pancytopenia in many Indian series
(see details below.17-20
RELATIVE PREVALENCE OF B12/ FOLATE DEFICIENCY:
B12 DEFICIENCY BECOMING MORE COMMON
Deficiency of B12 or folate can not be differentiated easily
from one another as the clinical and hematological
features resulting from the deficiency of both
micronutrients are similar. Estimation of serum levels are
required to be certain of the deficient micronutrient.
Serum B 12 and folate assay used to be cumbersome
dependent upon biological methods, hence they were not
performed widely. Currently, most widely used methods
is radioimmunoassay which because of its high cost is not
routinely available in developing countries. HPLC based
assay have also become available. The problem is further
compounded by the wide range over which the levels are
obtained in normal individuals and normal values
obtained in patients with frank megaloblastic
morphology and severe anemia. Combined deficiency is
also seen in many cases.17, 18, 21-23
Table 2 shows the proportion of cases according to
micronutrient deficiency (the studies have not been
differentiated whether they are on cases with
megaloblastic anemia or population based studies as
under comparison are the proportions of deficiency of
folate and B12). The Indian series from 1965 shows that
isolated B12 or combined deficiency was present in nearly
7% and 5 % instances while folate deficiency accounted
for nearly 55%.24 However, Sarode et al from Chandigarh,
reported B 12 deficiency in nearly 85% cases with
megaloblastic anemia (adults included).17 The later studies
from other parts of the country have also highlighted that
B12 deficiency is far more common than folate deficiency.
A study from our hospital on cases with nutritional
anemia shows B12 deficiency in 19 % cases and folate
deficiency in 12 %. In addition nearly 35 % cases had
levels of B12 which could be classified as low.10
Higher prevalence of B12 deficiency among population
groups and cases with MA from India also reflects a more
widespread trend. A study from Mexico showed B12
deficiency in 19% - 41% of various population subgroups
while no cases with folate deficiency were observed.16
Another study on Guatemalan lactating mothers,
revealed B12 deficiency in 46% compared to 9%
prevalence of folate deficiency.15 Series on MA patients
from Pakistan and Zimbabve revealed B12 deficiency in
TABLE 2. Relative Prevalence of Vitamin B12 and Folate Deficiency
Indian Studies
Bhende et al24
Mittal et al25
Sarode et al17
Gomber et al26
Gomber et al9
Chaudhry MW 10
Chandra et al21
Khanduri et al12
Other countries
Mukibi et al14
Maddood-ul-Mannan et al13
Allen et al16
Casterline et al15
Garcia-Casal et al22
Year/ Country
1965
1969
1989
1998
1998
2001
2002
2005
1992, Zimbabwe
1995, Pakistan
1995, Mexico
1997, Guatemala
2005, Venezuala
Population/Study
group
Nutr. MA
MA, child
MA, all ages
MA, children
Preschool
Anemic child
MA, children
Gen. Population
MA, all ages
MA, all ages
Gen. population
Lactating mothers
Gen. PopulationPregnancy
Folate
Def. (%)
B12 def. (%)
Combined
deficiency (%)
54.9
57.1
6.8
10.0
2.2
12.0
20.0
6.8
7.0
22.4
76.4
50.0
36.6
19.0
32.0
33.0
5.3
10.2
8.8
20
2.2
14.0
30.0
8.3
17.0
8.0
9.0*
30.036.3
51.0
56.0
19-41
46.7*
11.461.3
32.0
20.0
–
–
–
*Includes deficient and low levels of folate and cobalamin
796
Indian Journal of Pediatrics, Volume 77—July, 2010
Megaloblastic Anemia: Back in Focus
over 50% cases while folate deficiency was seen in only
8% and 17% cases, respectively. 13, 14 These studies
including adults may have a direct relevance to pediatric
population as the most common cause of B12 deficiency in
young children is the maternal deficiency leading to
decreased stores at birth and its consequences. Stabler and
Allen, in a review have highlighted B12 deficiency as a
worldwide problem with breast-fed infants of B12 deficient
mothers being at highest risk. They also suggested that
possibility of intermittent B 12 supplementation for
combating nutritional anemia should be explored.27
Reasons for increasing B12 deficiency are also not very
clear. Indians of low socio-economic strata who eat
virtually no food of animal origin are regarded as most
vulnerable to have low B 12 levels. Baker and others in
studies from South India observed that in these areas, B12
levels in the blood were lower than observed in west but
surprisingly MA resulting from these low levels were
uncommon.28, 29 It was hypothesized that bulk of B12 is
derived from bacterial contamination of food and water.
Since free intrinsic factor is available in small intestine,
endogenously produced B12 may be absorbed and may
contribute to individual’s daily B12 requirement. Brit et al
on the other hand, observed higher prevalence of MA
among vegetarian Indian settlers in UK. They postulated
that this may be a “complication of migration to a more
sanitized environment” resulting in diminished bacterial
contamination of small intestine leading to reduced
endogenously available B 12.30 How much within the
country population migration from rural areas to urban
areas has contributed to increased prevalence of B 12
deficiency has not been explored.
Whatever may be the cause, B 12 deficiency now
appears to have displaced folate deficiency to second
place as far as causing nutritional anemia is concerned.
ETIOLOGY OF MA/B12-FOLATE DEFICIENCY
In India and other developing countries, most cases of
MA are caused by nutritional deficiency of folate, B12 or
both. Pernicious anemia due to intrinsic factor deficiency,
malabsorption resulting in folate deficiency (celiac
disease) and certain inborn errors of metabolism e.g.,
methylmalonic aciduria (B12 deficiency) and methylene
tetrahydrofolate reductase deficiency (folate) account for
minority of cases.
Nutritional deficiency is far more common in
vegetarian than in non-vegetarian families. 23, 31 B 12
deficiency seen in infants and young children has been
particularly related to maternal deficiency which results
in poor body stores at the time of birth. These
underprivileged infants who are exclusively/
predominantly breastfed for prolonged period (in some
instances as much as 3-5 years) tend to develop B 12
Indian Journal of Pediatrics, Volume 77—July, 2010
deficiency as the breast milk content of B12 in these
mothers is far below normal (poverty-vegetarianismexclusive prolonged breast feeding axis). Cobalamin
content of breast milk is lower in vegetarian mothers and
is positively correlated with their serum cobalamine
levels. 15, 32 We have documented a good co-relation
between serum levels of the mothers and their suckling
infants and young children. 21 From the developed
countries, cases of MA are being reported among infants
born to vegetarian mothers.31,33
Increasing B12 and folate deficiency may not be entirely
related to poverty and vegetarianism. Biochemical
evidence of recent B 12 malabsorption has been
documented in some populations. Giardia infection,
particularly acquired in Asian countries has been
demonstrated to cause folate malabsorption. H.pylori
infection has been incriminated to cause B12 malabsorption
among adults.16
CLINICAL PROFILE: ANEMIA AND BEYOND
Cases of MA are commonly from poor vegetarian
families. Most infants and young children with MA tend
to be moderately or severely malnourished as they are not
receiving adequate complementary feeding. Anemia,
anorexia, irritability, easy fatigability are clinical features
common to other causes of anemia.
Clinical features peculiar to MA include
hyperpigmentation of knuckles and terminal phalanges
(observed in Asian communities), enlargement of liver
and spleen (seen in upto30-40% cases). Petechial and other
hemorrhagic manifestations have been reported in upto
25% cases. Presence of bleeding with severe anemia
makes them clinically indistinguishable from aplastic
anemia. Cases with MA may mimic acute leukemia due
to presence of hepatosplenomegaly.24, 26, 34
Tremors have been described to occur as a distinct
entity in children of north and central India – The infantile
tremors syndrome.3, 35 Similar cases with tremors have
recently been described from other countries.36These cases
mostly have macrocytic anemia and developmental
regression in addition to tremors. Cases of MA not
presenting with tremors also exhibit developmental
retardation/ regression in association with severe anemia.
Recently, a group of infants have been described having
microcephaly and developmental retardation even before
anemia became clinically evident. Occurrence of
abnormal movements in association with hypotonia,
psychomotor retardation, apathy and failure to thrive is
being reported in western literature as well. These cases
have been shown to have diffuse frontotemporoparietal
cortical atrophy on MRI of brain. 31, 37, 38 Impairment of
cognitive function and persistence of neurological
consequences even after treatment are major areas of
797
Jagdish Chandra
concern.4, 39,
40
Laboratory investigations reveal macrocytic anemia. In
addition, neutropenia is seen in 17-49% cases in various
series. Similarly, platelet counts are decreased – observed
in as many as 44-80 % cases. It is thus not surprising that
the cases with MA manifest with pancytopenia and
mimic aplastic anemia. 17, 21, 26, 34 From India, in various
series of patients presenting with pancytopenia, MA has
been found to be more common cause compared to
aplastic anemia and acute leukemia. Sarode et al were
among the first to report this observation in patients of all
age groups from a referral hospital.17 In another series
from a referral hospital, MA accounted for 22.28% cases of
pancytopenia seen over 6 yrs. This was a common cause,
second only to aplastic anemia. 20 Khunger et al have
observed MA accounting for over 72% cases (all age
groups) with pancytopenia.19 In the present series of 109
patients of pediatric age group presenting with
pancytopenia, MA was the single most common cause
(28.4%). Aplastic anemia and acute leukemia accounted
for 20% and 21% cases, respectively.18 It is currently
recommended that MA should be carefully excluded in
cases presenting with pancytopenia.41
Serum or red cell levels of folate and B12 are required
to identify the deficient micronutrient. Serum levels of
homocystiene are increased in deficiency of folate and B12
but levels of methylmalonic acid (MMA) are increased in
B12 deficiency only ( even increased urinary levels of
MMA are considered diagnostic of B12 deficiency). Very
high specificity of methyl-malonicaciduria in B 12
deficiency has recently been confirmed. The authors also
observed high specificity of FIGLU test in folate
deficiency. The authors advocated for using these
relatively inexpensive tests for diagnosis of B12 and folate
deficiency.15, 42, 43 This assumes significance in light of the
fact that levels of B12 and folate are quite variable, difficult
to measure and influenced by even subclinical hepatic
dysfunction.
TREATMENT
Like any other deficiency state, replacement therapy is
required. Anemia and other cytopenias respond to
administration of very small doses of drugs. However,
since folate is available as a 5 mg tablet and its over dose
is not associated with adverse effects, 5 mg daily dose has
been used.
For B12 deficiency, parenteral administration of B12 is
usually recommended. Intramuscular 1mg dose has been
traditionally used but with this high dose cases have
developed tremors and other extrapyramidal symptoms.37
We observed development of tremors in 6 out of 51 cases
within few hrs of administration of 1 mg dose.44 However,
these tremors and other neurological signs have been self798
limiting but their appearance may influence the
compliance. Sudden increase in the levels of
neurotransmitters has been offered as the plausible
explanation for this neurological phenomenon. 37
Currently, we are using a dose of 250 µg in infants and
500 mg in older children.
The duration of treatment is not as standardized as in
case of iron deficiency anemia. Six to eight wk treatment
is usually described as sufficient. Decrease in MCV,
reticulocytosis, and improvement in platelet and
neutrophil counts are observed within few days. In the
follow up, some cases developed thrombocytosis which
resulted in stroke in one patient. 44 Hence careful
monitoring of blood counts is required during treatment.
CONCLUSIONS
It is very obvious that there is “resurgence” of articles on
folate-B12 deficiency/MA over the last two decades. This
clearly reflects renewed interest in the subject as more and
more cases are being seen in clinical practice. The
phenomenon appears to be widespread. Many
developing countries like India have anemia control/
prophylaxis programs and in addition there is overall
improvement in general standard of living. In light of
these facts, the causes for increased incidence of folate-B12
deficiency and /or MA needs to be elucidated. As pointed
out earlier, over the last few yrs, B12 deficiency has taken
over as more common micronutrient deficiency as
compared to folate. Even this shift needs to be explained.
Role of malabsorption and within country population
migration towards urban areas contributing to
diminished endogenous B 12 synthesis needs to be
elucidated.
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