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Megaloblastic anaemia in Africans at the Coast Province General Hospital during 1960
34 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. VO1. 57. No. 1. January, 1963.
M E G A L O B L A S T I C ANAEMIA IN AFRICANS AT T H E COAST PROVINCE GENERAL H O S P I T A L D U R I N G 1960 BY
PETER P. TURNER, M.D., M.R.C.P.,D.P.H., D.I.H.
Dept. of Medicine, Mulago Hospital, Kampala Anaemias are very common at the Kenya Coast. If haemoglobin levels under 50 per cent. (7.4 g. per cent.) are regarded as indicating anaemia, then during 1960 they were the cause of admission to the medical wards of the Coast Province General Hospital, Mombasa, of 12.5 per cent. of the adults and of 13.5 per cent. of the children (TURNER, 1962). Amongst adults the anaemias were much more common in females, being the cause of admission of 21 per cent. of the total female medical admissions and of only 6.5 per cent. of the total male medical admissions. In children the sex distribution was more equal. In females the anaemias were much the most common cause of admission to hospital, in males bacillary dysentery was a little more common and in children the pneumonias were much more common (TURNER, 1962). Most of our anaemias are of the iron-deficient type and are usually associated with hookworm infestation. However, megaloblastic anaemias accounted for more than onequarter of the female adult anaemias and, more interestingly, they accounted for about one-sixth of the male adult anaemias. In children megaloblastic anaemias formed a much smaller fraction of the whole--a little over 4 per cent. (TURNER, 1962). Taking anaemias in the medical wards as a whole during 1960, some 15 per cent. were megaloblastic, but if only the adult wards are considered then the figure would be 22 per cent., rather greater that that given by FoY and KONDI (1960) after a short sojourn at the Coast and in great contrast to their very high figure of 45 per cent. for the King George VI Hospital in Nairobi. Within East Africa the geographical distribution of megaloblastic anaemias seems to vary greatly. They are well known, as already indicated, on the Kenya plateau (FoY and KONDI, 1958) and in this paper are shown to be common, although less common, at the Kenya Coast. However, at Mulago Hospital in Kampala they are very rare indeed. On]y one case in an adult male was seen in 1957 (SHAPER and SHAPER, 1958). Most of the megaloblastic anaemias seen in the tropics are in females and are associated with the child-bearing years of life. They are often seen during or soon after pregnancy. They are well recognized in various tropical countries such as India, Malaya and in various parts of Africa. Addisonian megaloblastic anaemia is rare ; however, examples have been recorded from Nairobi (FoY and KONDI, 1958) and from Uganda (TROWELL, 1951 ; MONEY, 1960). The purpose of this paper is to describe those cases of megaloblastic anaemia seen in women in the African hospital in Mombasa during 1960 and, more important, to draw attention to non-Addisonian megaloblastic anaemia occurring not infrequently in men and occasionally in children in this hospital.
PETER P. TURNER
35
METHODS Haemoglobin was estimated by the cyanmethaemoglobin method using the E E L colorimeter. Stemal marrow was aspirated and films made, stained and examined in all cases. Progress was followed in many cases by reticulocyte counts. Gastric acidity was determined in a proportion of cases after the administration of histamine. In 12 cases liver function tests were performed. Serum proteins were estimated quantitatively. Electrophoresis was not then available so that only total albumin and globulin is known. Serum bilirubin was estimated by the method of KING and COXON (1950), alkaline phosphatase in KIYG-ARMSTRONGunits (1934) and thymol turbidity as described by MACLACAN(1944). MATERIAL
Female Adults During 1960 at this hospital 31 female adults were admitted and found to have a megaloblastic anaemia. Nineteen (61 per cent.) of them were of Coastal origin, rather higher than would be expected (TURNER, 1962). Of the others, eight were Mkamba, two Kikuyu and two were from Nyasaland. Mombasa is a port and attracts labour from far and wide. The age range was from 14-45 years, the latter being rather unusual, for most were young women. Eight (26 per cent.) were pregnant and nine (29 per cent.) had delivered within the preceding three months so that 17 (55 per cent.) could clearly be associated with pregnancy. The true figure may have been higher, for in six no obstetric history was given in the notes. However, there are a few cases which are definitely not related to pregnancy. The symptoms were those usually associated with anaemia; anginal pain was described by three. The stated duration of the symptoms varied from 1 day to 18 months with a mean of only 5 weeks for the group associated with pregnancy, and 18 weeks for those not associated with pregnancy. Pyrexia occurred in 29 of the 31 patients and varied from 99.0 ° to 102.5°F. This is a common feature of megaloblastic anaemias and disappears with treatment. It is of some value in clinical diagnosis. The physical findings were unexceptional. Haemic ejection systolic murmurs were usual and a raised jugular venous pressure and enlarged tender liver were occasionally seen. Frank congestive cardiac failure was seen on only one occasion. Associated parasitic infestation was common. Hookworm was found in 29 per cent., Ascaris in 13 per cent., Trichuris in 6 per cent., Taenia saginata in 3 per cent., Schistosoma haematobium in 3 per cent. and Plasmodium falciparum in 6 per cent. of the patients. The incidence of hookworm was about twice that in the general female medical population of the hospital (T~Jm,~ER, 1962), but then so was that of ascaris infestation. The probable explanation is that in most patients a single routine stool is examined, whereas in anaemic patients a special search for hookworm is made and many stools are examined, and concentration methods are used. The haemoglobin on admission varied from 7 per cent. (1.0 g. per cent.) to 46 per cent. (6.8 g. per cent.) with a mean figure of 22 per cent. (3.2 g. per cent.)--a severe degree of anaemia. Most of the patients had an associated iron deficiency however, macrocytosis in the peripheral blood was seen in 14 (45 per cent.). Megaloblasts were seen in the peripheral blood several times. Marrow aspirated from the sternum showed frank megaloblastic erythropoiesis in 27 patients ; in the other three a mixed megaloblastic and normoblastic pattern was seen. In only three patients was a fractional test meal done and in only one of these was a histamine-fast achlorhydria found. Treatment was with folic acid 15 mg. daily for 7 days or occasionally longer. One patient with a haemoglobin of 7 per cent. (1.0 g. per cent.) had to be transfused initially because she was in such distress. All who survived responded satisfactorily. Because of
36
MEGALOBLASTIC
ANAEMIA
IN AFRICANS
the demand for beds most patients were discharged when their haemoglobin had reached 50 per cent. (7.4 g. per cent.), so that the mean haemoglobin on discharge was only 55 per cent. (8.1 g. per cent). In half the patients daily reticulocyte counts were done and the response varied from 15 per cent. to 48 per cent. depending on the initial severity. In two patients marrow puncture was repeated before discharge and in both had become normoblastic. Four patients (13 per cent.) died. T h e y all died of their anaemia. T h e y had initial haemoglobin values of 10 per cent. (1.5 g. per cent.), 16 per cent. (2.3 g. per cent.), 14 per cent. (2.0 g. per cent.) and 15 per cent. (2.2 g. per cent.), respectively. One was pregnant and the other three had delivered but a few days earlier, giving an alarming mortality for the group associated with pregnancy of 24 per cent. Liver function tests were done in six of these patients, two in the pregnant and four in the non-pregnant groups (Table) T h e numbers are too small for definite conclusions to be drawn. However, it is of interest that the only one within a reasonable range of the normal limits was in the pregnant group. On discharge the patients were given iron, since all had some degree of associated iron deficiency. TABLE. Liver function tests in megaloblastic anaemia. Serum bilirubin
Alkaline phosphatase
Thymol turbidity
Serum albumin
Serum globulin
mg.% 1.1 1.6 0.2 0.2 0.5 3.3
K.A. units 8.8 6.3 4.3 2.4 4.8 5.3
units 9 6 4 7 3 8
g.% 2.5 3.7 3.7 2.8 2.5 3.5
g.% 3.5 2.5 1.5 2.8 2.7 4.0
5.6 14.8 7.2 24.0 9.1 17.0
9 2 4 8 10 10
3.2 3.5 2.7 4.7 3.5 3.8
2.8 2.2 5.0 2.0 2.8 3.5
Females 1
2 (P) 3 (P) 4 5 6 Males 1
2 3 4 5 6 P--Pregnant.
0.2 0.5 0.4 0.2 0.2 2.2
A--Abnormal.
N--Normal.
I
Normal or abnormal A A N A A A A N Ax
I i!
a a
A
x--Liver biopsy normal.
Male Adults
During 1960 at the Coast Province General Hospital 14 male adults were admitted with megaloblastic anaemias. However, two of these were discarded from this analysis ; one because the anaemia was associated with a hepatoma and multiple secondary deposits from which he rapidly died, and the other because it was associated with hypoplasia of the white series in the bone marrow and a white blood count of only 750 with 36 per cent. of polymorphonuclear leucocytes. H e also died in a very short time. This leaves 12 patients to be considered. Only five (42 per cent.) were of Coastal o r i g i n ; the other seven were all Wakamba. This is far more than the general figure for Wakamba who constituted 20 per cent. of all medical admissions to this hospital in 1960 (TuRN~R, 1962). T h e age range was
PETER P. TURNER
37
from 16 to 65 years. Most were men in their 30's or 40's, rather older than the women with megaloblastie anaemia. T h e history was of the usual symptoms associated with anaemia and was of short duration, except in one otherwise typical patient who gave a 3-year history. The mean in the other 11 was 4 . 6 weeks. Pyrexia occurred in all but one and varied from 99.0 ° to 102.0°F. There were no particularly unusual physical findings. Ejection systolic murmurs were usual and a raised jugular venous pressure was seen occasionally. Congestive cardiac failure was not seen. Hookworm was found in three (25 per cent.), rather more than would be expected (TURNER, 1962), but this has already been discussed. Ascaris was found in one patient and P. falciparum in another. The haemoglobin on admission varied from 15 per cent. (2.2 g. per cent.) to 46 per cent. (6.8 g. per cent.) with a mean of 29 per cent. (4.3 g. per cent.). Macroeytosis in the peripheral blood occurred in 10 (83 per cent.) of the patients and megaloblasts were seen on two occasions. The sternal marrow was frankly megaloblastic in 11 of the patients, and mixed megaloblastic and normoblastic in one. In six, half of the patients, a fractional test meal was done and showed the presence of free hydrochloric acid in all of them. Treatment was with folic acid 15 mg. daily for a week or longer. All but two responded rapidly and satisfactorily. One patient showed no response at all and died somewhat unexpectedly after 3 weeks, and the other absconded before any reassessment after treatment. The reticulocyte response showed a peak varying from 10 per cent. to 78 per cent. (Fig.) in the eight patients in whom it was followed. High peak figures were common. In three patients marrow puncture was repeated before discharge, and in all had become normoblastic.
Hoemoqlobin
78
80.
....... t~
¢~ ,,I,-
j
\
I
u
o
Rel'iculocytes
7o, e
60
',60
56
u re-
50
¢.-
o
40
'~",\.
c-
O
30
0
E~
20
/
o -r-
,'~
16/
1
\~17
.......
i i |
io.
l
i
.Dayof
I
2
3
4
5
6
7
treatment
8
9
I0
II
12
i3
14 15
16
17 18 19 20
15mcj. folic acid daily FIGURE
38
MEGALOBLASTICANAEMIAIN AFRICANS
The mean haemoglobin on discharge of the 10 satisfactory patients was 63 per cent. (9.3 g. per cent.). Several were given iron on discharge, particularly if they also had hookworm infestation. One patient died as mentioned above. Liver function tests were done in six of the 10 patients (Table). It is of interest to note that only one of these can be regarded as normal. One had a liver biopsy ; this was reported as showing normal histological structure.
Children During 1960 six children were admitted and found to have megaloblastic anaemias. All but a Mkamba child were of Coastal origin, which is a different distribution from the general intake in 1960 (TURNER, 1962) ; however, the number is few. Four were female and two male. The ages ranged from two to nine years. The history in most was indefinite but usually of only a few weeks' duration. Pyrexia from 99.0 ° to 101.0°F. occurred in all and ejection systolic murmurs were usual. Hookworm was found in four (67 per cent.) which was much higher than would be expected (TURNER, 1962). However, the total number is few and the argument previously used is valid. T. saginata, Asearis, Trichuris and S. haematobium were each found on one occasion. The haemoglobin on admission ranged from 12 per cent. (1.7 g. per cent.) to 25 per cent. (3.7 g. per cent.) ~ith a mean of 18 per cent. (2.6 g. per cent.), a severe degree of anaemia. Macrocytosis in the peripheral blood was found in three (50 per cent.) but in none were megaloblasts seen. T h e sternal marrow was frankly megaloblastic in all the cases. Fractional test meals were not done. Treatment was with folic acid 5 mg. daily for 7 days. All responded satisfactorily. Unfortunately the reticulocyte response was not followed in any, nor were any marrows examined after treatment. The demand for paediatric beds is even greater than that for adult beds, so the children were discharged as soon as possible. The mean haemoglobin on discharge was therefore only 49 per cent. (7.2 g. per cent.), but this had been achieved in remarkably short time. All were given iron on discharge, since all were also iron deficient. None of the children died No liver function tests were done on any of the children. DISCUSSION F o r and KONDI (1955) have classified the tropical megaloblastic anaemias into three types as follows: i. Pernicious anaemia, which they have encountered but which is very rare (FoY and KONDI, 1958). ii. Megaloblastic anaemia, which responds to either the administration of penicillin or to oral vitamin Blz. The serum vitamin B12 level is low. iii. Megaloblastic anaemia, which responds to folic acid but not to penicillin or to vitamin BI~. This anaemia has normal serum levels of vitamin B12. Foy and Kondi have stressed the multi-factorial aetiology of anaemia in the tropics and this is brought out in their classification. F o v et al. (1955) found both kinds of non-Addisonian anaemia in both males and females, and some pregnant female patients who responded to penicillin or to oral vitamin Blz and who were not folic acid deficient. M y female cases all responded to folic acid and were presumably of the folic acid deficient kind. However, at the Lady Grigg Maternity Hospital, Mombasa, where megaloblastic anaemia is also a common problem, they have seen occasional
PETER P. T U R N E R
39
cases that did not respond to folic acid. All but one of my male cases responded to folic acid and all the childhood cases responded. It would seem that at the Coast the folic acid deficient type is much the most common. This is rather like Malaya where most are folic acid deficient, and vitamin B12 deficiency is only an occasional secondary deficiency (TAsKER, 1960). It is tempting to conclude that the aetiology of these anaemias is a nutritional one, whether or not the effect is a direct one or indirect due to the encouragement of an intestinal bacterial population that competes for essential haematinic substances such as vitamin B12 and folic acid (FoY and KONDI, 1958). Presumably, pregnancy places even greater demands on the available supply and accounts for the greater number of cases in pregnant and lactating women, or it could be that some factors associated with pregnancy may affect the intestinal bacteria. However, FoY and KONDI (1958) in view of the high incidence of these anaemias in males at the King George VI Hospital in Nairobi (39 per cent. male and 61 per cent. female) wonder whether pregnancy is really as important as previously thought. That it may well be is suggested by their own figures (FoY and KONOI, 1958), for, of their megaloblastic anaemias in women, 95 per cent. were pregnant or lactating, but of their iron-deficient anaemias in women only 56 per cent. were so engaged. In this series megaloblastic anaemia in females was five times as common a cause for admission than that for males, and many other cases are known to have been admitted to the adjoining Lady Grigg Maternity Hospital. Foy and Kondi have often observed a seasonal incidence of megaloblastic anaemias in Nairobi. Our numbers are small, yet it is of interest that the greatest incidence of these anaemias was in the months of May and June when likewise the rainfall was the heaviest of the year. These are also the months of the largest total medical admissions in 1960 (TURNER, 1962) however, the difference is still greater than would be expected statistically. That it is necessary to investigate megaloblastic anaemias in females carefully is underlined by M~TZ et al. (1961) who found three cases of typical pernicious anaemia in young African females. These cases were most thoroughly investigated and the diagnosis cannot be in doubt. The four cases seen by FoY and KONDI (1958) were all in women. The presence of free acid after stimulation with histamine should therefore always be sought in spite of the temptation just to give folic acid. Whether or not liver damage plays any part in these anaemias is doubtful. FoY and KONm (1958) found that serum proteins were of low to normal values. The y-globulins were often raised but this is also common in healthy Africans. FoY and KONDI (1958) also did liver biopsies in a small number of their cases. Many of these showed rather non-specific changes. They felt that further research was needed. FORBESand GELFAND (1961) found evidence of cirrhosis of the liver in 50 per cent. of their eight patients with " macrocytic " anaemia compared with only 12 per cent. of the iron-deficiency anaemias. However, marrows were only examined in six of these and only four were megaloblastic. In this series liver function tests were done in 12 patients (Table). Most of these were performed just before the patient's discharge so that raised serum bilirubin levels were not as common as would be expected in this type of anaemia. Only two of the 12 were regarded as being within reasonably normal limits. Even if abnormal protein patterns are ignored, the thymol turbidity is raised in eight of the 10 regarded as abnormal. It would seem that abnormal liver function is a possible factor to be considered, although whether as cause or effect it is difficult to say.
40
MEGALOBLASTIC ANAEMIA IN AFRICANS SUMMARY AND CONCLUSIONS
T h e cases of megaloblastic anaemia admitted to the Coast Province General Hospital in 1960 are presented. T h e y n u m b e r more than might be expected in a Coastal area. All were non-Addisonian. Most were in women and many of these occurred during or within 3 months of pregnancy. However, the incidence in males is shown to be appreciable and even in children occasional cases were seen. Nearly all seemed to be due to folic acid deficiency. T h e mortality rate in the group associated with pregnancy was very high. It is considered that the aetiology must be nutritional, whether or not this has a direct or a secondary effect via the intestinal bacteria. T h e possibility of abnormal liver function as a factor is considered. I should like to thank Mr. J. R. Gilmour for his interest in these anaemias and for carrying out most of the haematological work. REFERENCES FORBES, J. & GELVAND, M. (1961). Trans. R. Soc. trop. Med. Hyg., 55, 161. FoY, H. & KONDI, A. (1956). Cent. Aft. J. Med., 2, 254. - &- (1958), Trans. R. Soe. trop. Med. Hyg., 52, 46. - &- (1960). Ibid., 54, 419. & MANSON-BAHR,P. E. C. (1955). Lancet, 2, 693. KINC, E. J. & ARMSTRONG,A. R. (1934). Canad. med. Ass. J., 31, 376. & COXON, V. J. (1950). J. Clin. Path., 3, 248. MACLACAN, N. F. (1944). Brit. J. exp. Path., 25, 234. METZ, J., RANDALL,T. W. & KNIEP, C. H. (1961). Brit. med. J., 1, 178. MONEY, G. L. (1960). E. Aft. med. J., 37, 535. SHAVER,A. G. & SHAPER, L. (1958). Ibid., 35, 647. TASKER, P. W. G. (1960). Trans. R. Soc. trop. Med. Hyg., 54, 578. TROWELL, H. C. (1951). Lancet, 2, 761. TtmNER, P. P. (1962). E..4ft. reed. J., 39, 121. -
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M E G A L O B L A S T I C ANAEMIA IN AFRICANS AT T H E COAST PROVINCE GENERAL H O S P I T A L D U R I N G 1960 BY
PETER P. TURNER, M.D., M.R.C.P.,D.P.H., D.I.H.
Dept. of Medicine, Mulago Hospital, Kampala Anaemias are very common at the Kenya Coast. If haemoglobin levels under 50 per cent. (7.4 g. per cent.) are regarded as indicating anaemia, then during 1960 they were the cause of admission to the medical wards of the Coast Province General Hospital, Mombasa, of 12.5 per cent. of the adults and of 13.5 per cent. of the children (TURNER, 1962). Amongst adults the anaemias were much more common in females, being the cause of admission of 21 per cent. of the total female medical admissions and of only 6.5 per cent. of the total male medical admissions. In children the sex distribution was more equal. In females the anaemias were much the most common cause of admission to hospital, in males bacillary dysentery was a little more common and in children the pneumonias were much more common (TURNER, 1962). Most of our anaemias are of the iron-deficient type and are usually associated with hookworm infestation. However, megaloblastic anaemias accounted for more than onequarter of the female adult anaemias and, more interestingly, they accounted for about one-sixth of the male adult anaemias. In children megaloblastic anaemias formed a much smaller fraction of the whole--a little over 4 per cent. (TURNER, 1962). Taking anaemias in the medical wards as a whole during 1960, some 15 per cent. were megaloblastic, but if only the adult wards are considered then the figure would be 22 per cent., rather greater that that given by FoY and KONDI (1960) after a short sojourn at the Coast and in great contrast to their very high figure of 45 per cent. for the King George VI Hospital in Nairobi. Within East Africa the geographical distribution of megaloblastic anaemias seems to vary greatly. They are well known, as already indicated, on the Kenya plateau (FoY and KONDI, 1958) and in this paper are shown to be common, although less common, at the Kenya Coast. However, at Mulago Hospital in Kampala they are very rare indeed. On]y one case in an adult male was seen in 1957 (SHAPER and SHAPER, 1958). Most of the megaloblastic anaemias seen in the tropics are in females and are associated with the child-bearing years of life. They are often seen during or soon after pregnancy. They are well recognized in various tropical countries such as India, Malaya and in various parts of Africa. Addisonian megaloblastic anaemia is rare ; however, examples have been recorded from Nairobi (FoY and KONDI, 1958) and from Uganda (TROWELL, 1951 ; MONEY, 1960). The purpose of this paper is to describe those cases of megaloblastic anaemia seen in women in the African hospital in Mombasa during 1960 and, more important, to draw attention to non-Addisonian megaloblastic anaemia occurring not infrequently in men and occasionally in children in this hospital.
PETER P. TURNER
35
METHODS Haemoglobin was estimated by the cyanmethaemoglobin method using the E E L colorimeter. Stemal marrow was aspirated and films made, stained and examined in all cases. Progress was followed in many cases by reticulocyte counts. Gastric acidity was determined in a proportion of cases after the administration of histamine. In 12 cases liver function tests were performed. Serum proteins were estimated quantitatively. Electrophoresis was not then available so that only total albumin and globulin is known. Serum bilirubin was estimated by the method of KING and COXON (1950), alkaline phosphatase in KIYG-ARMSTRONGunits (1934) and thymol turbidity as described by MACLACAN(1944). MATERIAL
Female Adults During 1960 at this hospital 31 female adults were admitted and found to have a megaloblastic anaemia. Nineteen (61 per cent.) of them were of Coastal origin, rather higher than would be expected (TURNER, 1962). Of the others, eight were Mkamba, two Kikuyu and two were from Nyasaland. Mombasa is a port and attracts labour from far and wide. The age range was from 14-45 years, the latter being rather unusual, for most were young women. Eight (26 per cent.) were pregnant and nine (29 per cent.) had delivered within the preceding three months so that 17 (55 per cent.) could clearly be associated with pregnancy. The true figure may have been higher, for in six no obstetric history was given in the notes. However, there are a few cases which are definitely not related to pregnancy. The symptoms were those usually associated with anaemia; anginal pain was described by three. The stated duration of the symptoms varied from 1 day to 18 months with a mean of only 5 weeks for the group associated with pregnancy, and 18 weeks for those not associated with pregnancy. Pyrexia occurred in 29 of the 31 patients and varied from 99.0 ° to 102.5°F. This is a common feature of megaloblastic anaemias and disappears with treatment. It is of some value in clinical diagnosis. The physical findings were unexceptional. Haemic ejection systolic murmurs were usual and a raised jugular venous pressure and enlarged tender liver were occasionally seen. Frank congestive cardiac failure was seen on only one occasion. Associated parasitic infestation was common. Hookworm was found in 29 per cent., Ascaris in 13 per cent., Trichuris in 6 per cent., Taenia saginata in 3 per cent., Schistosoma haematobium in 3 per cent. and Plasmodium falciparum in 6 per cent. of the patients. The incidence of hookworm was about twice that in the general female medical population of the hospital (T~Jm,~ER, 1962), but then so was that of ascaris infestation. The probable explanation is that in most patients a single routine stool is examined, whereas in anaemic patients a special search for hookworm is made and many stools are examined, and concentration methods are used. The haemoglobin on admission varied from 7 per cent. (1.0 g. per cent.) to 46 per cent. (6.8 g. per cent.) with a mean figure of 22 per cent. (3.2 g. per cent.)--a severe degree of anaemia. Most of the patients had an associated iron deficiency however, macrocytosis in the peripheral blood was seen in 14 (45 per cent.). Megaloblasts were seen in the peripheral blood several times. Marrow aspirated from the sternum showed frank megaloblastic erythropoiesis in 27 patients ; in the other three a mixed megaloblastic and normoblastic pattern was seen. In only three patients was a fractional test meal done and in only one of these was a histamine-fast achlorhydria found. Treatment was with folic acid 15 mg. daily for 7 days or occasionally longer. One patient with a haemoglobin of 7 per cent. (1.0 g. per cent.) had to be transfused initially because she was in such distress. All who survived responded satisfactorily. Because of
36
MEGALOBLASTIC
ANAEMIA
IN AFRICANS
the demand for beds most patients were discharged when their haemoglobin had reached 50 per cent. (7.4 g. per cent.), so that the mean haemoglobin on discharge was only 55 per cent. (8.1 g. per cent). In half the patients daily reticulocyte counts were done and the response varied from 15 per cent. to 48 per cent. depending on the initial severity. In two patients marrow puncture was repeated before discharge and in both had become normoblastic. Four patients (13 per cent.) died. T h e y all died of their anaemia. T h e y had initial haemoglobin values of 10 per cent. (1.5 g. per cent.), 16 per cent. (2.3 g. per cent.), 14 per cent. (2.0 g. per cent.) and 15 per cent. (2.2 g. per cent.), respectively. One was pregnant and the other three had delivered but a few days earlier, giving an alarming mortality for the group associated with pregnancy of 24 per cent. Liver function tests were done in six of these patients, two in the pregnant and four in the non-pregnant groups (Table) T h e numbers are too small for definite conclusions to be drawn. However, it is of interest that the only one within a reasonable range of the normal limits was in the pregnant group. On discharge the patients were given iron, since all had some degree of associated iron deficiency. TABLE. Liver function tests in megaloblastic anaemia. Serum bilirubin
Alkaline phosphatase
Thymol turbidity
Serum albumin
Serum globulin
mg.% 1.1 1.6 0.2 0.2 0.5 3.3
K.A. units 8.8 6.3 4.3 2.4 4.8 5.3
units 9 6 4 7 3 8
g.% 2.5 3.7 3.7 2.8 2.5 3.5
g.% 3.5 2.5 1.5 2.8 2.7 4.0
5.6 14.8 7.2 24.0 9.1 17.0
9 2 4 8 10 10
3.2 3.5 2.7 4.7 3.5 3.8
2.8 2.2 5.0 2.0 2.8 3.5
Females 1
2 (P) 3 (P) 4 5 6 Males 1
2 3 4 5 6 P--Pregnant.
0.2 0.5 0.4 0.2 0.2 2.2
A--Abnormal.
N--Normal.
I
Normal or abnormal A A N A A A A N Ax
I i!
a a
A
x--Liver biopsy normal.
Male Adults
During 1960 at the Coast Province General Hospital 14 male adults were admitted with megaloblastic anaemias. However, two of these were discarded from this analysis ; one because the anaemia was associated with a hepatoma and multiple secondary deposits from which he rapidly died, and the other because it was associated with hypoplasia of the white series in the bone marrow and a white blood count of only 750 with 36 per cent. of polymorphonuclear leucocytes. H e also died in a very short time. This leaves 12 patients to be considered. Only five (42 per cent.) were of Coastal o r i g i n ; the other seven were all Wakamba. This is far more than the general figure for Wakamba who constituted 20 per cent. of all medical admissions to this hospital in 1960 (TuRN~R, 1962). T h e age range was
PETER P. TURNER
37
from 16 to 65 years. Most were men in their 30's or 40's, rather older than the women with megaloblastie anaemia. T h e history was of the usual symptoms associated with anaemia and was of short duration, except in one otherwise typical patient who gave a 3-year history. The mean in the other 11 was 4 . 6 weeks. Pyrexia occurred in all but one and varied from 99.0 ° to 102.0°F. There were no particularly unusual physical findings. Ejection systolic murmurs were usual and a raised jugular venous pressure was seen occasionally. Congestive cardiac failure was not seen. Hookworm was found in three (25 per cent.), rather more than would be expected (TURNER, 1962), but this has already been discussed. Ascaris was found in one patient and P. falciparum in another. The haemoglobin on admission varied from 15 per cent. (2.2 g. per cent.) to 46 per cent. (6.8 g. per cent.) with a mean of 29 per cent. (4.3 g. per cent.). Macroeytosis in the peripheral blood occurred in 10 (83 per cent.) of the patients and megaloblasts were seen on two occasions. The sternal marrow was frankly megaloblastic in 11 of the patients, and mixed megaloblastic and normoblastic in one. In six, half of the patients, a fractional test meal was done and showed the presence of free hydrochloric acid in all of them. Treatment was with folic acid 15 mg. daily for a week or longer. All but two responded rapidly and satisfactorily. One patient showed no response at all and died somewhat unexpectedly after 3 weeks, and the other absconded before any reassessment after treatment. The reticulocyte response showed a peak varying from 10 per cent. to 78 per cent. (Fig.) in the eight patients in whom it was followed. High peak figures were common. In three patients marrow puncture was repeated before discharge, and in all had become normoblastic.
Hoemoqlobin
78
80.
....... t~
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8
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15mcj. folic acid daily FIGURE
38
MEGALOBLASTICANAEMIAIN AFRICANS
The mean haemoglobin on discharge of the 10 satisfactory patients was 63 per cent. (9.3 g. per cent.). Several were given iron on discharge, particularly if they also had hookworm infestation. One patient died as mentioned above. Liver function tests were done in six of the 10 patients (Table). It is of interest to note that only one of these can be regarded as normal. One had a liver biopsy ; this was reported as showing normal histological structure.
Children During 1960 six children were admitted and found to have megaloblastic anaemias. All but a Mkamba child were of Coastal origin, which is a different distribution from the general intake in 1960 (TURNER, 1962) ; however, the number is few. Four were female and two male. The ages ranged from two to nine years. The history in most was indefinite but usually of only a few weeks' duration. Pyrexia from 99.0 ° to 101.0°F. occurred in all and ejection systolic murmurs were usual. Hookworm was found in four (67 per cent.) which was much higher than would be expected (TURNER, 1962). However, the total number is few and the argument previously used is valid. T. saginata, Asearis, Trichuris and S. haematobium were each found on one occasion. The haemoglobin on admission ranged from 12 per cent. (1.7 g. per cent.) to 25 per cent. (3.7 g. per cent.) ~ith a mean of 18 per cent. (2.6 g. per cent.), a severe degree of anaemia. Macrocytosis in the peripheral blood was found in three (50 per cent.) but in none were megaloblasts seen. T h e sternal marrow was frankly megaloblastic in all the cases. Fractional test meals were not done. Treatment was with folic acid 5 mg. daily for 7 days. All responded satisfactorily. Unfortunately the reticulocyte response was not followed in any, nor were any marrows examined after treatment. The demand for paediatric beds is even greater than that for adult beds, so the children were discharged as soon as possible. The mean haemoglobin on discharge was therefore only 49 per cent. (7.2 g. per cent.), but this had been achieved in remarkably short time. All were given iron on discharge, since all were also iron deficient. None of the children died No liver function tests were done on any of the children. DISCUSSION F o r and KONDI (1955) have classified the tropical megaloblastic anaemias into three types as follows: i. Pernicious anaemia, which they have encountered but which is very rare (FoY and KONDI, 1958). ii. Megaloblastic anaemia, which responds to either the administration of penicillin or to oral vitamin Blz. The serum vitamin B12 level is low. iii. Megaloblastic anaemia, which responds to folic acid but not to penicillin or to vitamin BI~. This anaemia has normal serum levels of vitamin B12. Foy and Kondi have stressed the multi-factorial aetiology of anaemia in the tropics and this is brought out in their classification. F o v et al. (1955) found both kinds of non-Addisonian anaemia in both males and females, and some pregnant female patients who responded to penicillin or to oral vitamin Blz and who were not folic acid deficient. M y female cases all responded to folic acid and were presumably of the folic acid deficient kind. However, at the Lady Grigg Maternity Hospital, Mombasa, where megaloblastic anaemia is also a common problem, they have seen occasional
PETER P. T U R N E R
39
cases that did not respond to folic acid. All but one of my male cases responded to folic acid and all the childhood cases responded. It would seem that at the Coast the folic acid deficient type is much the most common. This is rather like Malaya where most are folic acid deficient, and vitamin B12 deficiency is only an occasional secondary deficiency (TAsKER, 1960). It is tempting to conclude that the aetiology of these anaemias is a nutritional one, whether or not the effect is a direct one or indirect due to the encouragement of an intestinal bacterial population that competes for essential haematinic substances such as vitamin B12 and folic acid (FoY and KONDI, 1958). Presumably, pregnancy places even greater demands on the available supply and accounts for the greater number of cases in pregnant and lactating women, or it could be that some factors associated with pregnancy may affect the intestinal bacteria. However, FoY and KONDI (1958) in view of the high incidence of these anaemias in males at the King George VI Hospital in Nairobi (39 per cent. male and 61 per cent. female) wonder whether pregnancy is really as important as previously thought. That it may well be is suggested by their own figures (FoY and KONOI, 1958), for, of their megaloblastic anaemias in women, 95 per cent. were pregnant or lactating, but of their iron-deficient anaemias in women only 56 per cent. were so engaged. In this series megaloblastic anaemia in females was five times as common a cause for admission than that for males, and many other cases are known to have been admitted to the adjoining Lady Grigg Maternity Hospital. Foy and Kondi have often observed a seasonal incidence of megaloblastic anaemias in Nairobi. Our numbers are small, yet it is of interest that the greatest incidence of these anaemias was in the months of May and June when likewise the rainfall was the heaviest of the year. These are also the months of the largest total medical admissions in 1960 (TURNER, 1962) however, the difference is still greater than would be expected statistically. That it is necessary to investigate megaloblastic anaemias in females carefully is underlined by M~TZ et al. (1961) who found three cases of typical pernicious anaemia in young African females. These cases were most thoroughly investigated and the diagnosis cannot be in doubt. The four cases seen by FoY and KONDI (1958) were all in women. The presence of free acid after stimulation with histamine should therefore always be sought in spite of the temptation just to give folic acid. Whether or not liver damage plays any part in these anaemias is doubtful. FoY and KONm (1958) found that serum proteins were of low to normal values. The y-globulins were often raised but this is also common in healthy Africans. FoY and KONDI (1958) also did liver biopsies in a small number of their cases. Many of these showed rather non-specific changes. They felt that further research was needed. FORBESand GELFAND (1961) found evidence of cirrhosis of the liver in 50 per cent. of their eight patients with " macrocytic " anaemia compared with only 12 per cent. of the iron-deficiency anaemias. However, marrows were only examined in six of these and only four were megaloblastic. In this series liver function tests were done in 12 patients (Table). Most of these were performed just before the patient's discharge so that raised serum bilirubin levels were not as common as would be expected in this type of anaemia. Only two of the 12 were regarded as being within reasonably normal limits. Even if abnormal protein patterns are ignored, the thymol turbidity is raised in eight of the 10 regarded as abnormal. It would seem that abnormal liver function is a possible factor to be considered, although whether as cause or effect it is difficult to say.
40
MEGALOBLASTIC ANAEMIA IN AFRICANS SUMMARY AND CONCLUSIONS
T h e cases of megaloblastic anaemia admitted to the Coast Province General Hospital in 1960 are presented. T h e y n u m b e r more than might be expected in a Coastal area. All were non-Addisonian. Most were in women and many of these occurred during or within 3 months of pregnancy. However, the incidence in males is shown to be appreciable and even in children occasional cases were seen. Nearly all seemed to be due to folic acid deficiency. T h e mortality rate in the group associated with pregnancy was very high. It is considered that the aetiology must be nutritional, whether or not this has a direct or a secondary effect via the intestinal bacteria. T h e possibility of abnormal liver function as a factor is considered. I should like to thank Mr. J. R. Gilmour for his interest in these anaemias and for carrying out most of the haematological work. REFERENCES FORBES, J. & GELVAND, M. (1961). Trans. R. Soc. trop. Med. Hyg., 55, 161. FoY, H. & KONDI, A. (1956). Cent. Aft. J. Med., 2, 254. - &- (1958), Trans. R. Soe. trop. Med. Hyg., 52, 46. - &- (1960). Ibid., 54, 419. & MANSON-BAHR,P. E. C. (1955). Lancet, 2, 693. KINC, E. J. & ARMSTRONG,A. R. (1934). Canad. med. Ass. J., 31, 376. & COXON, V. J. (1950). J. Clin. Path., 3, 248. MACLACAN, N. F. (1944). Brit. J. exp. Path., 25, 234. METZ, J., RANDALL,T. W. & KNIEP, C. H. (1961). Brit. med. J., 1, 178. MONEY, G. L. (1960). E. Aft. med. J., 37, 535. SHAVER,A. G. & SHAPER, L. (1958). Ibid., 35, 647. TASKER, P. W. G. (1960). Trans. R. Soc. trop. Med. Hyg., 54, 578. TROWELL, H. C. (1951). Lancet, 2, 761. TtmNER, P. P. (1962). E..4ft. reed. J., 39, 121. -
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