Pure Megaloblastic Anemia and Megaloblastic Anemia - Blood

18 Pages·2005·1.59 MB·English

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Megaloblastic Anemia of Pregnancy : Characteristics of
Pure Megaloblastic Anemia and Megaloblastic
Anemia Associated with Iron Deficiency
By MIGuEL LAYRISSE, OSCAR ACUERO, NORMA BLUMENFELD,
HENRY \V(cid:1)i.LIS, IRIS DUGARTE AND ADELINA OJEDA
LTHOUGH megaboblastic anemia of pregnancy is considered mainly as
a folic acid deficiency anemia, since this vitamin induces remission in
most cases, its mechanism of production is still obscure. Dietary deficiency
has been claimed to be the principal cause. However, this anemia has been
observed in well-to-do women whose diet was satisfactory.
Some other factors such as gastrointestinal upset, repeated pregnancies,
hemorrhages, infections and toxemia have been reported as contributing
to the development of vitamin deficiency.
In Venezuela, Laynisse and Aguero have found 38 cases of megaloblastic
anemia of pregnancy out of 1000 cases of anemic pregnant women, which,
with the incidence published by Lilbie et al.’ in Dublin, represents the highest
frequency of this disorder yet found in the available literature. The clinical
and hematoiogic data of the first 20 cases have already been published.2
Seventeen of the last 18 cases were studied in more detail with special refer-
ence to the metabolism of iron, vitamin B12 and fobic acid, as well as studies
of hemolysis and treatment. The results provide information on the patho-
physiology of this anemia in Venezuela and perhaps in other countries with
similar geographic or social conditions.
MATERIAL AND METHODS
The clinical nlateriai is represented by 17 cases of illegaloblastic anemia seen at the
Maternidad Concepcion Palacios, Caracas, during the last two years.
The following laboratory tests were performed.
A. Morphologic study of the peripheral blood including red cell count, hemoglobin
determination by the cyanonlethemoglobin method,i packed red cell volume, reticulocyte
count by tile methylene blue technic,4 platelet count, white cell and differential counts.
B. Morphology of the sternal bone marrow and estimation of the amount of ilemosiderin
according to Rath and Finch’s method.5
C. Serum vitamin B1, concentration according to Rosenthal and Saret’s method.6
D. Plasma iron concentration by the metllod of Peters et al.7
E. Folic acid tissue storage and intestinal absorption by Girdwood’s method.8
From Centro de Investigaciones c/el Bunco Municipal c/c Sangre, Caracas, Venezuela,
and Maternidad Concepcion Palacios and In5titut() c/c Investigaciones Meclicas (Fundacion
Luie Roche).
This work was supported in part by a grant from time “Fundacion Creole,” Caracas. We
are greatly indebted to Drs. Rafael Dmninguez Siueo, Manuel Sanchez Carvajal and Viso
Pitaluga for permi,usion to study some cases hospitalized in their wards. Time folic acid used
in this work was supplied by Laboratorios Biogen, time local representative of Led erl(cid:1)
Laboratories.
Presented in part at the VII International Congress of Hematology, Rrnne.
724
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MEGALOBLASTIC ANEMIA OF PREGNANCY 725
F. Serum bilinmbin by Malloy and Evelyn technic.#{176}
G. Fecal urobilinogen using Watson’s nlethod.10 Tile feces were collected for four days,
homogenized, and an aliquot of 1 Gm. taken for chemical analysis.
H. Survival time of the red cells was performed by tagging the patient’s own erythro-
cytes with Cr51. Blood was taken every two or three days for about 30 days, and the radio-
activity of all samples was counted simultaneously. The percentage of radioactivity in each
sample was plotted on semi-log paper and the erythrocyte half-life was determined graphi-
cally. The survival studies in patients 9, 10 and 12 were started 10 days after the injection
of Fe59, and radioactivity was counted through a pulse height analyzer (Nuclear Chicago-
Model 1910).
I. The studies with F&9 were carried out by injecting into the cubital veins ap-
proximately 8 of 10 ml. of citrate buffer containing about 5 p.c. of Fe59 with a specific activity
of about 2.0 to 2.8 me/mg. iron in the form of anhilionium iron citrate. Blood was with-
drawn 10, 40, 70, 120, 190 and 250 minutes after injection and every two or three days
dunng the following 15 days. The plasma Fe59 half-life was determined by counting the
radioactivity of the i)lood samples taken tile first clay and plotting on semi-log paper,
extrapolating back to zero time the 100 per cent radioactivity. The iron turnover was
calculated by the method of Huff et (cid:1)(cid:1) expressed in milligrams per day, and by the
method of Bothwcll et al.’2 expressed in milligrams per day per 100 ml. of whole blood.
J. The total plasma volume was estimated by both the Evans blue techni&3 and Fe59.14
An average of the results obtained with these methods was taken as the final value of the
total plasma volume. For estimation of the total red cell volume, the values of the venous
hematocrit were transformed into whole blood hematocrit by multiplication : venous hemato-
crit observed X0.96 X0.91.
K. Erythrocyte production was calculated in three ways: the marrow erythroid-myeloid
ratio according to the method of Giblett and associates,15 the reticulocyte index and the
plasma iron turnover index according to the method of Bothweli and associates.12 The
fecai urobilmnogen index15 and red cell survival index” were utilized for estimating the
destruction of circulating red cells. The normal values used in the expression of erythro-
kinetics in our laboratory were as follows:
Four normal women
Men and non- during last month
pregnant normal women of pregnancy
Erytllroicl-nlyeloid ratio 410: 1000 558:1000
Reticulocytes per comm.
whole blood 51,000 48,000
Plasma iron turnover
(mg/day’ 100 ml. whole blood) 0.60 0.68
Fecal urobuinogen
(mg/clay/Gm. Hb. ) 0.20
T #{18C9}r5’ red cell survival 26
According to Lowenstein, the erythroid-myeioid ratio in women during the third tn-
muester of pregnancy and a few days after delivery are very similar’7; so we are using our
features in normal pregnant women to compare witll antepartum and postpartum megalo-
blastic anemia. Since the reticulocyte counts in both normal groups are so close, we will use
51,000 for our normal conlparative data, as it represents the average of 200 samples.
CLINICAL FINDINGS
Four cases were studied during tileir pregnancy; the others, although complaining of
weakness and sometimes of diarrhea and fever during the end of their pregnancy, did not
attend the prenatal public clinics; the hcmatologic tests were performed a few days after
delivery. Tllree cases were having their second pregnancy, 5 cases their third, 1 case her
fourth, and the other eight cases had had more than 6 pregnancies. The ages of the pa-
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726 MIGUEL LAYRISSE AND CO-WORKERS
tients were between 20 and 30 years, excepting patients 3 and 7, who were 39 and 37
years old, respectively.
As in our previous report,2 fever, diarrhea and edema were the principal clinical findings.
Fever ranging from 99.5 to 101 F. was observed in 9 cases, edema limited to tile ankles
and the inferior part of the legs in 11 cases. The diarrhea observed in 11 patients consisted
of about 5 to 10 yellow or brown stools in 24 hours, witilout any special characteristics.
The diarrhea was accompanied only by sporadic intestinal colic; and gastric symptoms were
almost absent.
Smooth and sore tongue was seen in 5 cases. Hepatomegaly was present in only 3 cases,
and splenornegaly in one. No nervous system disturbance was noticed.
It was difficult to obtain appropriate data about tile hematologic status of the patients
during previous pregnancies. Four patients said they had had anemia in their last preg-
nancy which improved after delivery; the type of anemiiia was not established. These pa-
tients did not give a past history of gastrointestinal symptoms suggestive of some type of
intestinal malabsorption. The diarrilea reported in 11 cases started only during the last
month of the pragnancy. In addition, the stools did not show parasites Wllich were likely
to produce diarrhea.
The megaloblastic anemia of pregnancy does not seem to interfere with the normal
development of the fetus, even in severe cases. Of the 38 cases studied by Layrisse and
Ag#{252}ero, 30 mothers delivered apparently normal babies; 4 had premature babies and 4
had stillborns as a consequence of pre-eclampsia, uterina rupture, anaencephalia and
ahruptio placenta.
MORPHOLOGY OF THE PERIPHERAL BLOOD AND THE BONE MARROw
There was a wide variation in the values of the hematocnit from one case
to another, as compared with the variation in values of hemoglobin and red
cell count (table 1) This variation is reflected in the MCV and MCHC,
.
showing macrocytosis with hyperchromia in some instances, macrocytosis
with normochromia or hypochnomia in others and normocytosis or micro-
cytosis with hypochromia in still others.
The stained blood film was in agreement with the blood values, exhibiting
macrocytic as well as microcytic red cells; the predominance of one popula-
tion over the other varied almost in every case. Microcytic hypochromic red
cells in variable numbers were seen in all cases. The term “dimorphic” sug-
gested for this type of anemia is certainly descriptive of what is seen in the
peripheral blood. In the review of the films, ortho- or polychromatophilic
megaloblasts were seen in 5 cases.
The leukocyte counts showed extreme variations. In only 4 cases was the
count below 5000 cu.mm., but the polysegmented neutrophils were not mark-
edly reduced. Multisegmented neutrophils in variable proportion were seen in
all blood films. There was not a marked diminution of the number of platelets.
All the bone marrows were hypencellular. Megaboblastic proliferation as
seen in pernicious anemia was observed in only 9 cases; the other 8 showed
intermediate megaboblastic series, and in 5 the erythroblastic series was also
observed. Giant metamyelocytes were present in all cases.
The ratio between the number of nucleated red cells and myeboid cells
did not show hyperplasia of the megaloblastic series in all instances. Marked
hyperplasia (4 times above normal values ) was seen on two occasions;
moderate hyperplasia (2 to 3 times above normal values ) in 8 cases, slight
hyperplasia in 1, and a normal ratio in 5 cases. In these latter 5 cases, the
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MEGALOBLASTIC ANEMIA OF PREGNANCY 727
marrows were hypercellular, but the granulocytic series was so abundant
that the ratio appeared normal or reduced in number.
IRON METABOLISM
Imi table 2, values for plasma iron and bone marrow hemosidenin are
shown. Studies with Fe59 were done only in the last 9 cases. The patients
were divided into 2 groups : those exhibiting megaloblastic series and those
exhibiting intermediate megaboblastic series.
The tissue iron storage and plasma iron concentration were strikingly
different in the two groups. The cases with intermediate megaloblastic prolif-
eration in the bone marrow also had iron deficiency. On the other hand,
cases with megaloblastic series had a normal tissue iron storage and normal
plasma iron level. There was one case in each group which showed different
patterns. Case 4, which will be described in detail later, exhibited megabo-
blastic series with traces of hemosidenin in the marrow and low plasma iron,
developing hypochromic anemia in the course of treatment with folic acid.
Case 6, belonging to the second group, showed low plasma iron but abundant
granules of hemosiderin in the marrow. This patient had chronic nephritis
with blood urea levels over 100 mg./100 ml. of blood. This complication
may explain the discrepancy bet(cid:1)veen the plasma and marrow findings.
In the 7 patients with iron deficiency, postpartum hemorrhage had been
excessive in 4. Case 12, examined during the eighth month of pregnancy,
was in poor nutritional condition because of severe vomiting since the
beginning of pregnancy. Case 6 had chronic nephnitis, and in 2 cases there
was nothing abnormal to explain the deficiency.
The radioactive iron studies were quite in agreement with tile chemical
results. In cases of the first group the T #{189p}lasma iron clearance was slow,
the plasma iron turnover slightly increased and the Fe59 was incorporated
into the red cells at a relatively slow rate. In the second group, the levels of
T #{189p}lasma iron clearance showed values close to those found in iron
deficiency anemia; the plasma iron turnover was increased to twice the normal
and the red cells rapidly incorporated Fe5”. Although the average plasma
iron turnover in the two groups appears to have a distinct pattern, there
was not a significant difference between them.
The data on iron metabolism in case 15 are markedly different from those
obtained in the other cases. This patient was in the eighth month of
pregnancy. She stated she had been taking iron before she came to the
hospital, but no further iron treatment was given during the eight days
prior to the blood tests. Her serum iron bevel and the amount of hemosidenin
in the bone marrow indicated a full iron tissue storage, which may explain
the results obtained with Fe59.
Comparing our results with those obtained by other authors, we can see
that the data on iron metabolism of the first group are in agreement with
the ferrokinetics of pernicious 1,1218,19 However, the plasma iron
turnover was not as high as it usually is found to be in pernicious anemia.
The plasma iron disappearance and iron turnover values of the second
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728 MIGUEL LAYRISSE AND CO-WORKERS
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MEGALOBLASTIC ANEMIA OF PREGNANCY 729
Table 2.- Iron Metab olism Data
Plasma iron Red cell Fe’s
turnover uptake
Plasma Bone .
iron marrow mg./day days
((cid:1)g./iOO hemo- T % 100 ml. after
Cases ml.) siderin (mm.) mg/day whole blood % inject.
1.188
- - - - - -
2.176 - - - - - -
Exhibiting 3. 100 4 - - - - -
megaloblastic 4. 70 traces - - - - -
series in the 7. 98 2 - - - - -
bone marrow 10. 128 2 110 31.05 0.89 68 15
11. 102 3 100 - 0.89 - -
15. 372 5 360 55.41 0.77 90 14
17. 115 3 107 69.76 0.84 87 11
Mean 149.88 169.25 52.07 0.84 82 13
S.D. ±90.98 ±132.20 ±0.05
5. 58 traces - - - - -
Exhibiting 6. 70 3 - - - - -
intermediate 8. 64 0 - - - - -
niegaloblastic 9. 76 traces 44 80.08 1.42 103 4
series in the 12. 42 0 50 34.00 0.66 100 5
bone marrow 13. 30 0 22 49.39 1.02 99 6
14. 50 0 26 67.86 1.46 96 6
16. 49 0 26 99.40 1.64 90 5
Mean 54.87 33.60 66.15 1.24 97 5
S.D. ±15.17 ±12.5 ±0.39
Pt <0.01 <0.01 >0.01
14 normal 123.4
subjects ±34.4 900 0.63#{176}
4 normal women
during last month 79 traces 72 44 0.68
of pregnancy
#{176}Fivecases studied.
fp was calculated by comparing the two groups of Megaloblastic anemia of pregnancy.
group apparently appear as an intermediate stage between the pattern of
iron deficiency anemia and pernicious anemia.
METABOLISM OF F0LIc Acm
The subcutaneous folic acid test was always performed prior to the oral
test. Twelve of 14 cases showed impairment of PGA absorption. Six of
them had a diminution of both subcutaneous and oral test values, but
after appropriate saturation with the vitamin, only malabsorption was
present. Only a few patients could be followed for a significant period of
time after treatment. It was observed that, in spite of complete recovery
from the anemia, in only one case was the malabsorption corrected.
METABOLISM OF THE VITAMIN B12
The serum level of vitamin B12 in patients with megabobbastic anemia of
pregnancy showed a wide range. In 9 of 15 cases the values were below
100 (cid:1)t,sg./ml. However, the mean was not significantly different from those
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730 MIGUEL LAYRISSE AND CO-WORKERS
Table 3.-Intestinal Absorption and Tissue Storage of Folic Acid
24 hour folic acid urinary activity
Before treatment After starting treatment
After 5 mg. After After
folic acid 5 mg. folic 5 mg. folic
subcutaneous acid orally acid orally
Cases (pg.) (ag.) (pg.)
1. A. L. 800 300 531 (6 lilOntilS)
2. H. R. 650 400
3. C. P. 500 230
4. S. P. 2638 835 1000 (64 days)
5. M. M. 1800 1967
6. T. C. 500 585 653 (3 months)
7. C. C. 2142 500 424 (62 days)
8. Ca. R. 2100 1025 1534 (57 days)
9. Ca. M. 2700 1069
10. C.Med. 3400 1261 633 (6months)
11. C. Mart. 837 948
12. (cid:1)uI. Mont. 500 948 764 (4 months)
13. 2494 1061
14. 164() 1440
15. 935
Mean 1575.7 8(cid:1)7.7
±967.3 ±476.9
9 nOrillal subjects
2318.8 2138.7
±393.8 ±430.9
of normal women of a similar economic status or those of well-to-do women
during the last month of pregnancy or few days after delivery. The Schilling
test performed in 10 cases was within normal limits.
ERYTHROKINETICS
The cases of megaboblastic anemia of pregnancy were divided into 2
groups for the study of erythrokinetics: cases exhibiting megaboblastic pro-
liferation in tile marrow, and cases exhibiting intermediate megaloblastic
proliferation.
Production
The erythroid marrow activity and the plasma iron turnover in pregnant
women showed a slight increase compared with the mean in normal men
and nonpregnant women (table 5 ) The estimation of the red cell produc-
.
tion in megaboblastic anemia of pregnancy compared with normal pregnant
women was approximately twice normal according to the M/E ratio average.
However, since the granulocytic series was also increased, it seems probable
that the absolute increase of the erythroid series was 5 or more times normal.
The plasma iron turnover was twice normal. As has been observed by
several students’5’18 in other types of megaloblastic anemias, the circulating
reticulocytes were markedly diminished. This reduction was not similar in
both groups; while slightly reduced in the second group, the reduction in
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MEGALOBLASTIC ANEMIA OF PREGNANCY 731
Table 4.-Serum Vitamin B1) Concentration and Urinary Excretion of B,2Co6#{176} in
Megaloblastic Anemisi Patients and Normal Pregnant Women
Urinary excretion
BI2Co’#{176}
% Adminis-
Serum B12 tered Doses
Cases ((cid:1)jtg./ml.) (Schilling)
1. AL. 99 18.0
2. H. R. 73 18.5
3. C. P. 99 16.5
4. S. P. 187 23.0
5. M. NI. 71 22.0
6. T.G. 182 14.0
Patients with 7. C. C. 50 20.0
megaloblastic anemia 8. C. R. 76 15.0
of pregnancy 9. C. Mat. 116 13.0
10. C. Med. 248
-
11. CM. 69 -
12. M. Mont. 337 17.0
13. V. R. 282 -
14. MV. 84 -
15. M. I). 57
-
Mean 135.3 17.7
±90.5 ±3.5
Pregnant women during the
eighth month (attending 13 137.9
plil)liC hospitals ) ±45.0 -
Hb: 11.4 ± 1.2
Women a few days after
delivery (attending public 13 138.9
ilospitals ) ±46.8 -
Hh: 11.77 ± 0.9
(cid:1)Vell-to-do pregnant women 4 136.3
during tile eighth month
Normal nonpregnant 32 219.9
subjects ± 63.2
the first group was about 75 per cent below normal. It seems that the reticubo-
cyte count in all types of megaloblastic anemia does not provide a valid
measurement of erythropoiesis.
Destruction
Serum bilirubin was over 1 mg.,hlOO ml. of serum in only 5 cases; slightly
increased, between 0.7 and I mg., in 5 cases and below 0.7 mg. in the other
7 cases. These results are different from those in pernicious anemia, but are
in accordance with the findings in non-Addisonian megaboblastic anemia.2022
The fecal urobilinogen index according to Gibbett et al.15 (table 5) showed
an increase four times normal in cases with pure megaloblastic anemia, and
three times normal in cases with intermediate megalobbastic series.
The T 1/2 survival of the patients’ own Cr51-tagged red cells showed
marked reduction in the 7 cases studied. The destruction rate’6 was approxi-
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732 MIGUEL LAYRISSE AND CO-WORKERS
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From www.bloodjournal.org by guest on January 30, 2018. For personal use only.
MEGALOBLASTIC ANEMIA OF PREGNANCY 733
mately four times normal; there was no significant difference between the
2 groups. Diminution of the erythrocyte life span in pernicious anemia
has been reported by various authors,(cid:1)2(cid:1)24 using either differential agglu-
tination of red cells or tagged cells. The rate of red cell destruction in the
cases presented here corresponded to what has been reported for Addisonian
anemia.
In conclusion, the estimation of erythrokinetics in megaloblastic anemia
of pregnancy showed that although the iron turnover reflected the hyper-
activity of the erythroid marrow, the circulating reticulocytes did not show
an increase in effective erythropoiesis. This dysfunction was associated with
an increased rate of red cell destruction: about four times the normal.
TREATh [ENT
Treatment was started only with folic acid orally in all cases; however, it
was possible to follow only 13 (luring treatment. Of 8 cases in which the
marrow showed megalobbastic series, 6 had a complete remission, and 2
showed only partial remission, making it necessary to complement the folic
acid therapy with iron. One of the 5 with intermediate megaloblastic series
displayed full remission, 3 displayed partial remission, and one no response
at all during a week of treatment. It is important to notice that the diarrhea
and fever were relieved within 2 or 3 days. The patients exhibiting low
serum vitamin B,2 responded to PGA therapy as well as did those with
normal bevels. Also, cases 6, 7, 8 and 9, in which the Schilling test was
performed prior to the PGA treatment, did not respond during the following
5 days. Below, we will comment on 2 cases representative of pure PGA
deficiency and one of PGA plus iron deficiency.
Case C. 2(cid:1)Ie(/.-Twenty-seven years old, tllir(l prcgn:(cid:1)ncy, studied 5 days after delivery
(fig. 1). Physical (‘XallliflatiOll (li(1 not slu)W mm>’ abnorniality, with the exception of pallor
and miioderate eclenia of the ankles. The peripheral blOO(1 SlloWe(1: red cell count 1.6 fllilliofl;
Plasmo Hb
Iron Gm.
#{149}(cid:1)#{149}
(cid:1)oo(cid:1) 0 (cid:1)
loo(cid:1) 5(cid:1) Plasma Iron
, ,
I
Days-O (cid:1) 4 21 28
I
R(cid:1)
Folic Acid 15 mg. Doily
Fig. 1.-Case 10 (C. Med.) showing folic acid deficiency only.