Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Megaloblastic anemia

William B. Castle

To cite this article: William B. Castle (1978) Megaloblastic anemia, Postgraduate Medicine, 64:4,
117-122, DOI: 10.1080/00325481.1978.11714952

To link to this article: http://dx.doi.org/10.1080/00325481.1978.11714952

Published online: 07 Jul 2016.

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Download by: [Australian Catholic University] Date: 17 August 2017, At: 19:50
 Fourth of five
symposium articles
in this issue
Megaloblastic
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•
anem1a
Consider
What are the t_vpical hematologic.findings in
megaloblastic anemia due tofolic acid or vitam in
B12 de.ficiency?
How does the pathogenesis offolie acid de.ficiency
differfrom that ofvitamin Bu de.ficiency?
If serumfolate and vitam in B12/evels are
unavailable or available on/y in retrospect, how
should megaloblastic anemia be managed?
VOL 64/NO 4/0CTOBER 1978/POSTGRADUATE MEDICINE
William B. Castle, MD
In the majority of cases, megaloblastic anemia is
due to either folie acid or vitam in B12 deficiency.
Folie acid deficiency is usually caused by inade-
quate dietary intake, whereas vitamin B 12
deficiency is almost always related to a specifie ab-
sorption defect. Differentiation between the two
types of deficiency is important but is impossible
by blood and bone marrow morphology alone.
Megaloblastic anemia, usually due to vitamin 8 12
or folie acid deficiency, is marked by normo-
chromic macrocytes and smaller poikilocytes in
the blood and megaloblastic changes in erythroid
cells in the bane marrow.
Clinicat presentation
Anemia with pallor and slight icterus; sore
mouth and smooth tangue; and "indigestion,"
constipation, or diarrhea occur in bath vitamin B12
deficiency and folate deficiency. Persistent numb-
ness and tingling of the extremities, difficulty in
fine motions of the fingers, and unstable walking
are typical only of vitamin B12 deficiency; in-
deed, they can be precipitated by folie acid admin-
istration in that condition. Owing to graduai de-
velopment, even of considerable anemia, circula-
tory adjustments favoring oxygen transport may
allow comfort at rest.
Megaloblastic anemia due to folie acid
deficiency may develop in infants with a history of
prolonged breast or bottle feeding without supple-
mentation with ascorbic acid or solid food. Heat-
ing of formula or long cooking of food may !essen
folate content. Diarrhea may be either the cause or
the result of folate malabsorption. Alcoholism di-
minishes folate intake and inhibits assimilation or
metabolism. Long deprivation is not required, as
the half-life of folate in the body is only about a
month and may be shortened by the increased
metabolic demands of pregnancy, chronic hemo-
continued
117
 The clinical triad: Pallor, sore
mouth, and paresthesias, the last a
sign of probable vitamin 8 12
deficiency.

lytic anemia, intravenous hyperalimentation, or tory of gastric or small-bowel surgery or chronic

malignancy. pancreatitis also raises that possibility. Such
Megaloblastic anemia due to dietary deficiency precipitating causes may precede clinical onset of
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of vitamin B12 does not occur except in the most anemia by several years because the biologie half-
dedicated vegetarians (no meat or dairy products). life of vitamin B12 is about a year unless shortened
Rarely, inadequate maternai endowment or reces- by a protein-losing enteropathy (eg, acute tropical
sive hereditary defects of assimilation may cause sprue).
vitamin B12 malabsorption within the first year of
life. In an adult, a familial or persona} history of Diagnosis
"anemia," early graying of the hair, or vitiligo sug- Megaloblastic anemia will not be undetected if
gests absorption defect. Previous discontinuation a hemoglobin or hematocrit determination is
of liver extract or vitamin B12 injections or a his- made. Macroscopic methods demonstrate a mean
corpuscular volume of 100 to 140 cu J.L and mean
corpuscular hemog1obin concentration of 32% to
Table 1. Pathogenesls of folate deflciency 34%. The typical oval macrocytes are usually ap-
Fooddefect Utllizatlon defect
parent on microscopie <!xamination of a stained
Lack Ascorbic acid deficiency blood film, but the characteristic increase in the
Overcooking Liver disease number of lobes (five or more) of the nuclei of sev-
Antileukemic drugs
Assimilation defect (Jejunum era} large polymorphonuclear leukocytes is often
and ileum) lncreased requlrement more obvious. Mod•!rate leukopenia and
Celiac disease, sprue, etc Growth of fetus, tumors
Alcoholism, anticonvulsants (?) lncreased hematopoiesis thrombocytopenia are usual, and with severe ane-
mia an occasional nucl<!ated RBC or myelocyte
may be seen. Young basophilie ("shift") RBCs are
Table 2. Pathogenesis of vitamln 8 12 deflciency few, as is confirmed by the low reticulocyte count
( l% to 3%) obtained after supravital staining.
Fooddefect
Lack of animal protein As the important distinction between vitamin
Veganism B12 deficiency anemia and folie acid deficiency
Gastrlc defect: Lack of lntrlnsic factor (IF) anemia cannot be made from blood or bone mar-
Congenital: lsolated, recessive (HCI+) row morphology, the respective serum levels
Acquired: Gastritis, gastrectomy (HCI-)
should be determined at once. When such
ParasHic competition
Diphyllobothrium latum
Bacteria in diverticula
Stenoses Table 3. Phases of vltamin 8 12 assimilation
Blindloops
1. lntrinsic factor (IF) competitively binds vitamin 8 12
Pancreatic defect Acquired lack of trypsln released from food, especi 'illy at acid pH
Malabsorption: Distal ileal defects Il. IF-8 12 complex en routeto ileum is resistantto pepsin,
Congenital: lsolated, recessive (HCI+, IF+) chymotrypsin, and parasitEIS
Acquired
Regional: Resection or disease Ill. IF-8 12 complex adheres to microvilli of epithelial cells
Diffuse: Sprue or celiac disease in distal part of ileum. Ca+-t, trypsin, and pH >6.5 are
required
Transport defects (parenteral)
lntravascular: Recessive lack of transcobalamin Il IV. Species-related release of 11itamin 8 12 to interior of ileal
lntracellular: Congenitallack of vitam in 8 12 binder epithelial cells occui-s en rcute to blood

118 VOL 64/NO 4/0CTOBER 1978/POSTGRADUATE MEDICINE

 The dual causality: ln folate de-
ficiency, dietary lack is usual; in
vitamin B12 deficiency, a prolonged
specifie absorption defect is
al most always present.

information is available in retrospect, the diagno- megakaryocytes may display immature dispersion
sis of megaloblastic anemia can be confirmed by a of chromatin. A point to remember is that the
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rise in the reticulocyte count beginning by the
third day and becoming maximal by the tenth day
in response to a single injection of 100 J.lg of vita-
min 8 12 and the daily oral administration of 1 to 3
mg of folie acid. Ifvitamin 8 12 deficiency was pres-
ent initially, the serum leve! will be Jess than 100
pg/ ml; with folate deficiency, it will be Jess than 5
J.lg! ml. When such data are available in ad vance,
the diagnostic trial can be conducted with the ap-
propriate vitamin. A satisfactory clinical response
may make bone marrow biopsy or hospital admis-
sion unnecessary.
A Jack of the expected response to a diagnostic
trial suggests either the inhibitory effect of chronic
infection, uremia, or malignancy or an error in di-
agnosis. In the former instance, the complication
must if possible be eliminated. The possibility of
mistaken diagnosis necessitates further study
including bone marrow biopsy by needle and syr-
inge or trocar to distinguish aplastic anemia,
refractory anemia with cellular marrow,
preleukemia, aleukemia, and erythroleukemia.
Any of these may present with anemia, leukope-
nia, and thrombocytopenia, and recognition of
erythroleukemia is especially difficult because of
the "megaloblastoid" appearance of early red cell
precursors that may precede myeloblastic
proliferation.
In untreated nutritional megaloblastic anemia,
the bone marrow is hypercellular and the ratio of
myeloid precursors to erythroid precursors ap-
proaches unity (normal ratio, 4: 1) because of in-
creased production of megaloblastic red cell pre-
cursors. The hallmark of megaloblastosis is Jack of
condensation of nuclear chromatin relative to the
degree of hemoglobinization of the cytoplasm.
This is most apparent in the more mature mem-
bers of the erythroid series. ln addition, there are
many large metamyelocytes with C-shaped or dis-
torted nuclei, and the lobes of the nuclei of
megaloblastic character of the marrow morpho!.:.
ogy is greatly modified by a day or two of effective
therapy with the deficient vitamin or in vitamin 8 12
deficiency by a Schilling test. For this reason the
Schilling test should not be performed early.
Pathogenesis
Table 1 summarizes the mechanisms of folate
deficiency already touched on. Folate occurs in
foods mainly in the form of "conjugates,"
pteroylglutamic acid to which two to six addi-
tional glutamic acid molecules are gamma-linked.
Normally in passage across small-intestinal cells,
these glutamate molecules are enzymatically re-
moved and much of the resulting monoglutamate
is reduced and methylated to become the
metabolically active methyltetrahydrofolate of
the serum. Interference with this process may oc-
continued
William B. Cast le
Dr Castle is Francis W. Pcabody
Faculty Professor of Medicine.
Emeritus. Harvard Medical
School. Boston. He served as Dis-
tinguished Physician in the Vet-
erans Administration and isacon-
sultant in medicine at the Veterans
Administration Hospital. West
Roxbury. Massachusetts.

VOL 64/NO 4/0CTOBER 1978/POSTGRADUATE MEDICINE 119

 The laboratory diagnoses:
Macrocytic anemia, megaloblastic
changes on marrow biopsy, and low
serum folate or vitam in B12 level, in
increasing order of accuracy.
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Figure 1. Biochemistry of vitamin 8 12 folate interrelationships with
respect to DNA synthesis.
Adap!ed.from Waxman S. Melz J. Herber! V: Defeuiw DNA srmhesis
in human mega/oh/asiic bone marrow: E'ffeC!s o( lwmocysieine and
meihionine. J Clin lm•esl 48:284-289. /969.
cur with alcoholism or various intestinal disorders
detectable by x-ray films, depressed xylose or fat
absorption, or jejunal mucosal biopsy. Severe di-
etary deficiency of ascorbic acid may interfere
with folie acid reduction, as severa! antileukemic
drugs do even more effectively.
Vitamin 8 12 deficiency is almost always due to
sorne specifie type of malabsorption (table 2). Gas-
tric anacidity after betazole stimulation is invaria-
ble in pernicious anemia in association with Jack
of intrinsic factor, which occurs in the presence of
acid secretion only in a rare congenital disorder of
childhood. Table 3 defi nes the normal phases of vi-
120
tamin 8 12 assimilation, any one of which may be
interrupted. X-ray films may show evidence of to-
tal or partial gastrectomy or distal ileal disease or
resection. With jejunal diverticula, stenoses, or
blind loops, nutritional ,;ompetition by a luxuri-
ant bacterial flora may deprive the patient of vita-
min 8 12 • Diarrhea, abd,)minal pain, and trans-
verse irregular retroperitoneal calcification sug-
gest chronic pancreatitis and Jack of trypsin
secretion.
Part 1 of the Schilling test, performed with
radioisotope-labeled vitamin 8 12 given orally as a
tracer, shows poor assimilation with any kind of
absorption defect. Results of part 2, performed
with vitamin 8 12 and hog intrinsic factor, approxi-
mate normal only when the defect is solely Jack of
human intrinsic factor. Congenital defects of ileal
assimilation are uncommon, and parenteral trans-
port defects are very rare indeed.
In the body, folate and vitamin 8 12 are normally
involved in interdependent biochemical processes
leading to the eventual synthesis of nuclear DNA
(figure 1). Vitamin 8 12 functions as the coenzyme
methylcobalamin. With its help, methyltetra-
hydrofolate donates a methyl group to
homocysteine, and so as tetrahydrofolate is ready
to become the essenti.:.l molecule methylene
tetrahydrofolate. Methylene tetrahydrofolate is
the unique methyl-group donor to the enzyme
thymidylate synthetase (not shown), which causes
deoxyuridylate to becorne deoxymethyluridylate
(ie, thymidylate), an e:;sential component of
DNA. Thus, in effect, vitamin 8 12 deficiency con-
ditions a metabolic deficiency of methylene
tetrahydrofolate secondarily, while folie acid
deficiency does so more directly. Delayed synthe-
sis of DNA and consequent delayed nuclear divi-
sion and maturation due to deficiency of either vi-
tamin thus are express1!d morphologically as
megalo blastosis.
A second coenzyme of vitamin 8 12- adenosylco-
balamin, may be involved in synthesis of the mye-
VOL 64/NO 4/0CTOEIER 1978/POSTGRADUATE MEDICINE

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lin nerve sheath, and its deficiency may lead to
characteristic combined system disease. In vita-
min 8 12 deficiency, abnormal fatty acids with
odd numbers of carbon atoms have been found in
peripheral nerves on biopsy.
The megaloblastic anemias are the result not
only of delayed nuclear maturation but also of a
hemolytic process within the bone marrow. This
"ineffective erythropoiesis" causes release of much
hemoglobin from the red cell precursors,
including reticulocytes, that disintegrate in the
bone marrow. Catabolism of this hemoglobin by
the reticuloendothelial cells of the marrow and
liver accounts for the increased iron stores in those
organs and the bilirubinemia. Figure 2 illustrates
the ferrokinetics of the situation in megaloblastic
anemia: rapid decline in the plasma level of
radioiron as it enters the active early erythroid pre-
cursor cells of the marrow and, in contrast, its de-
layed and diminished reappearance as labeled he-
VOL 64/NO 4/0CTOBER 1978/POSTGRADUATE MEDICINE
Figure 2. Plasma clearance and
RBC utilization of radioiron
(S9 fe) in normal persons, patients
with erythroid hypoplasia, and
patients with ineffective erythro-
poiesis, as in vitam in 8 12 or folate
deficiency.
A dapted from Ers/el' A J,
Gabu=da TG: Pathophysiology
of 8/ood. Philadelphia, WB
Saunders Co, 1975.
moglobin in the circulating R8Cs. Similar mea-
surements in normal persons and in patients with
erythroid hypoplasia are shown for comparison.
Therapy
Clinical evidence of circulatory distress rather
than the "book values" for the anemia predicate
cautious transfusion of l or 2 units of packed
R8Cs. Otherwise, transfusion is undesirable if
specifie therapy is begun promptly. If serum levels
of folate and vitamin 8 12 are pending or unavaila-
ble, treatment should be begun at once: injections
of lOO p.g of vitamin 8 12 once a week and oral ad-
ministration of l to 3 mg of folie acid daily for a
month. Meanwhile, if serum vitamin levels were
not initially available, subsequent clinical analysis
must attempt to distinguish folate from vitamin
8 12 deficiency.
If vitamin 8 12 deficiency is possible, prolonged
therapy with folie acid alone is hazardous to the
continued
121
 The specifie treatment: Folie ac id,
1 to 3 mg daily by mouth, or vitam in
Bm 1 00 pg once a month by
injection.
nervous system and except in the presence of
diffuse intestinal disease, pregnancy, or chronic
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hemolytic anemia is unnecessary. On the other
hand, unless the cause of malabsorption of vita-
min 8 12 can be corrected by antibiotics or surgery,
the injection of 100 J.lg ofvitamin 8 12 once a month
should be continued throughout !ife.
Summary
Most, but not ali, megaloblastic anemia is pro-
duced by "ineffective erythropoiesis" in the bone
marrow due to either folie acid or vitamin B12
deficiency. In folie a cid deficiency the cause
frequently is inadequate dietary intake, whereas
vitamin B12 deficiency is almost always condi-
tioned by sorne specifie type of malabsorption.
Anemia with oval macrocytes, few reticulocytes,
moderate leukopenia, and thrombocytopenia is
typical of both. Aplastic anemia, refractory ane-
mias with cellular marrow, preleukemia,
aleukemia, and erythroleukemia may have some-
what similar blood findings but are usually recog-
nizable from bone marrow biopsy.
122
Decreased levels of folate or vitamin B12 are the
most reliable criteria of megaloblastic anemia.
With these available in advance, therapy with the
appropriate vitamin can be begun at once. If se-
rum levels are unavailable or available only in ret-
rospect, initial treatment, especially of severe ane-
mia, should be with both vitamins. Differentiation
between folate and vitarnin B12 deficiency is impor-
tant but impossible by blood and bone marrow
morphology alone. Thus, if serum levels are una-
vailable, the distinction must be made, sometimes
retrospectively, on the basis of other laboratory
examinations, such as gastric analysis, small-
bowel x-ray films, and the Schilling test.
Reprints will not be availablc.
CME Credit Quit bcgins on page LW.
Bibliography
Herbert V: Megaloblastic anem1as. ln Beeson PB. McDermott W
(Editors): Textbook of Medicine. Ed 14. Philadelphia. WB Saun-
ders Co. 1975. pp 1404-1413
Megaloblastic anaemia. Clin Haernatol. Oct 1976
Wintrobe MM. Lee .IR. Boggs DR. et al: Clinical Hematology: Ed 7.
Philadelphia. Lea & Febiger. 974. sec 2. chap 14and 15
VOL 64/NO 4/0CT03EA 1978/POSTGRADUATE MEDICINE