EVALUATION OF IRON SUPPLEMENTS IN PREVENTION OF IRON-DEFICIENCY ANÆMIA

175 tissue almost to zero whilst that through normal liver was only slightly reduced. In our series necrosis of tumour deposits was demonstrated on liver biopsy in four patients up to 11 months after operation. The presence of viable tumour tissue in the subcapsular region in two cases shows that collateral circulation through the capsule may provide an important blood-supply to such metastases. The sharp rise in serum-aspartate-transaminase after hepatic-artery ligation indicates that some necrosis of normal hepatic parenchyma did occur, and this was demonstrated in the early postoperative liver biopsies from cases 3 and 9. Furthermore serial liver scans showed that the area of normal liver fell in tumour

patients. ten patients who returned home were considerably improved symptomatically and had clinical remissions lasting up to 10 months. The most striking changes were the loss of abdominal pain and the gain in weight. The three patients with the carcinoid syndrome were relieved of their distressing symptoms and the immediate postoperative rise in urinary

with hepatic metastases is very poor, with a median survival time of 75 days in one series 16 although occasional patients survive for long periods. A controlled trial is needed to establish that life expectancy is prolonged, but it is clear that worthwhile symptomatic improvement can be achieved by hepatic-artery ligation. Furthermore, this is relatively easy to carry out, rarely upsets the patients for more than a few days, requires no special apparatus, and is attended by few

complications. We thank Mr. N. H. Porter for permission to include details case 11 and to Dr. Merton Sandler for his help with the patients with the carcinoid syndrome.

of

Requests

for

reprints should

some

The

5-H.I.A.A. output was a clear biochemical marker of the extent of the tumour necrosis. The subsequent drop in output towards normal levels suggests that a major part of the tumour mass had been destroyed. The main indication for this form of therapy is pain due to hepatic tumour deposits in patients who do not have clinical evidence of widespread metastatic disease. The presence of small peritoneal seedlings in several of our cases did not seem to detract from the benefits of the treatment. It is clearly not possible to assess the independent effect of the cytotoxic therapy and the hepatic-artery ligation in many of these patients. Five cases, however, did not have 5-fluorouracil at first and yet showed good symptomatic and biochemical improvement. After clinical relapse further local or systemic 5-fluorouracil seemed to have little effect though more benefit would be expected from portal-vein

infusion immediately following hepatic-artery ligation when the surviving tumour tissue is receiving its

blood-supply largely from the portal vein. Several technical problems were encountered in the portalvein infusion, including displacement of the catheters from thin-walled venous tributaries. The umbilical vein is thicker walled, but, usually, only the left lobe of the liver can be infused by this route. Nylon catheters tend to harden after some weeks and kink at the site of ligatures, and we are now trying catheters made of siliconised rubber. It is arterial

probably impossible completely to cut off the blood-supply to the liver. Michels 14 described twenty-six routes by which arterial blood can reach the liver and the development of a collateral circulation has been demonstrated in man by arteriography as soon as one week after hepatic-artery ligation.15 Repeat angiography in our cases showed that the arterial supply was considerably reduced even months after ligation. The enlargement of the phrenic artery seen in case 1 has also been observed in dogs after hepatic-artery ligation. Nilsson et all reported a doubling in survival-times of rats with secondary malignant tumours after ligation of the hepatic artery. In man the prognosis of patients

be addressed

to

R. W.

REFERENCES G. Am.

Breedis, C., Young, J. Path. 1954, 30, 969. Markowitz, J. Surgery Gynec. Obstet. 1952, 95, 644. Mori, W., Masuda, M., Miyanaga, T. Surgery, St. Louis, 1966, 59, 359. 4. Plengvanit, U., Limwonges, K., Viranuvatti, V., Hitanant, S., Chearanai, O. 3rd int. Symp. int. Ass. Study Liver; p. 490. Antwerp, 1967. 5. Nilsson, L. A. V. Rev. Surg. 1966, 23, 374. 6. Bengmark, S. Schweiz. med. Wschr. 1969, 99, 571. 7. Moertel, C. G. in Year Book of Drug Therapy (edited by H. Beckman); p. 129. Chicago, 1969. 8. Sullivan, R. D., Zurek, W. Z. J. Am. med. Ass. 1965, 194, 481. 9. Graham, R. R., Cannell, D. Br. J. Surg. 1933, 20, 566. 10. Brittain, R. S., Marchioro, T. L., Hermann, G., Waddell, W. R., Starzl, T. E. Am. J. Surg. 1964, 107, 822. 11. Almersjö, O., Bengmark, S., Engevik, L., Hafstrom, L. O., Loughbridge, B. P., Nilsson, L. A. V. Ann. Surg. 1968, 167, 9. 12. Markowitz, J., Rappaport, A., Scott, A. C. Proc. Soc. exp. Biol. Med. 1949, 70, 305. 13. Gelin, L.-E., Lewis, D. H., Nilsson, L. Acta hepato-splenolo. 1968, 15, 21. 14. Michels, N. A. J. Am. med. Ass. 1960, 172, 125. 15. Loughbridge, B. P., Almersj&oacgr;, O., Bengmark, S., Hafström, L. O. J. Okla. St. med. Ass. 1968, 61, 207. 16. Jaffe, B. M., Donegan, W. L., Watson, F., Spratt, J. S. Surgery Gynec. Obstet. 1968, 127, 1. 17. Nilsson, L. A. V., Rudenstam, C-M., Zettergren, L. Bibl. anat. 1967, 9, 425. 1. 2. 3.

EVALUATION OF IRON SUPPLEMENTS IN PREVENTION OF IRON-DEFICIENCY ANÆMIA P. C. ELWOOD

W. E. WATERS

W. J. W. GREENE Medical Research Council

Epidemiology Cardiff CF2 3AS

Unit

(South Wales),

In many countries an attempt is made a national level to prevent iron deficiency by enriching food with iron. The amount by which iron intake should be increased is unknown, and decisions seem to be based on very inadequate evidence. Trials of iron supplements in two at-risk groups revealed an effect on hæmoglobin level of a supplement of 10 mg. iron per day, but gave no clear evidence of an effect of a smaller supplement.

Summary

at

Introduction

By how much should the daily iron intake be increased to prevent iron deficiency in the community ? The Committee on Iron Deficiency of the Council on Foods and Nutritionhas recommended a mean dietary intake of 20 mg. per day in women in the U.S.A., even though they recognise that this could at

176 the

time lead to an intake of up to 50 mg. per in males in the same community. White and day White2 recommended an increase of " three to four fold " in the present food-enrichment practices in the U.S.A. to achieve an increase of 10 mg. on average in the daily iron intake. Finch3 stated that iron intakes in the U.S.A. were inadequate, and that the addition of 10-15 mg. iron to food was " highly desirable ". None of these estimates seem to be based on experimental evidence. We describe here two experimental models for the evaluation of iron supplements, and present some results. same

Method all based on subgroups of a general population, a high proportion of whom, we assumed, would not be absorbing enough iron. These were adolescent girls at an age when growth was rapid, and adult women who had lately been iron deficient and whose deficiency had been corrected, but in whom the basic cause of the deficiency had not been identified or treated. All the iron supplements used were ferrous fumarate.

The studies

TABLE I-SUMMARY OF RESULTS OF THE TRIAL IN ADOLESCENT GIRLS

OF SMALL IRON SUPPLEMENTS

*Differs

were

Adolescent Girls A 1-in-3 random sample of all the 14-year-old girls attending schools in the City of Cardiff, was chosen. These girls, and their parents, were asked to cooperate in a longterm study in which daily iron tablets were to be supplied for 3 years and a yearly blood-test performed. Packets of tablets were sent by post every month and these contained either 0, 10, or 30 mg. iron, allocation being random. The tablets also contained a trace of riboflavine, and this enabled spot tests to be made in which a sample of urine was checked for fluorescence under an ultraviolet lamp (Woods light). Preliminary tests showed that this test was strongly positive for about 4-6 hours after a tablet had been taken. Adult Women Two trials have been done in adult women following surveys of total communities in which over 90% of women (20-64 years) were seen. Those found to have hmmoglobin levels below 12-0 g. per 100 ml. were given sufficient iron to raise this above 12-0 g. per 100 ml. They were then allocated at random to groups, one of which, in each trial, received tablets which contained no iron. The others received 30, 10, or 5 mg. iron per day for 6 months. The effect of the iron supplement was assessed by the degree to which it prevented the fall which usually happens in

from corresponding change in the significantly at p<0-05 given no extra iron during the same year.

group

TABLE II-SUMMARY OF RESULTS OF TRIALS OF THE PROPHYLACTIC EFFECTS OF SMALL IRON SUPPLEMENTS GIVEN TO IRON-DEFICIENT WOMEN WHOSE ANEMIA HAD BEEN TREATED

’

Differs significantly at p
supplements

in at-risk

women.

change in the

group

given

0 mg.

haemoglobin level and packed-cell volume after conventional treatment of anaemia. The design of these trials and the results are indicated in the figure. All these women were questioned carefully at the beginning and at the end of the trials about symptoms which might indicate a serious underlying condition. All those who had such symptoms, together with those whose response to the preliminary course of iron treatment was judged to be unsatisfactory were referred to hospital for further investigation. Results

Table i summarises the results of the trial in the adolescent girls. Within the results for each year there is consistent evidence of a haematinic effect of iron, and this is almost always greater for the 30 mg. than for the 10 mg. iron. The greatest changes were in the first year, but most of the differences between the groups had increased slightly by the end of the trial. The data for the first year were reanalysed using only the results for those girls who had had a positive spot urine test. These girls cannot be assumed to have taken a tablet on every day during that year, but they are likely to have taken the tablets more regularly than those who had a negative spot urine test. Again, the results in these girls indicate a hæmatinic effect of the iron supplements. Table 11 summarises the results of the trials in the adult women. In both trials the group given no iron showed a fall. The 10 mg. supplement clearly prevented a fall in mean hsemoglobin level, but although the smaller supplement may have had some effect, the difference from that of the placebo tablets is not statistically significant at conventional levels of

probability.

Evaluation of

from

Discussion

There have been several trials of iron supplements, but none has been wholly satisfactory. Natvig et al.4 studied the effect of 30 mg. iron daily in adult men and

177 in schoolchildren 10-13 years of age. They detected effect on haemoglobin level, and concluded that the supply of iron in the regular diet was adequate for these individuals. Scott and Hellergave a daily supplement of 6-5 mg. iron to a small number of adult Eskimos. This led to a significant rise in hxmoglobin level in thirteen women who had initial levels below 11-7 g. per 100 ml., but there was no evidence of an effect in the other women or in males. These workers concluded that, in these Eskimos, the normal dietary iron intake (estimated to be 10-15 mg. per day) was inadequate where the haemoglobin level was below 11-7 g. per 100 ml. and this represented 25% of the women studied. Bradfield et al.6 gave 5 mg. iron per day to small groups of prepubertal schoolchildren in Peru, a third of whom had haemoglobin levels below 10-0 g. per 100 ml. The results suggested that the iron had a haematinic effect, though the change in haemoglobin level was not significant at the 5% level. All these workers looked for a therapeutic effect of a small dose of iron. This would not seem to be an entirely satisfactory way of evaluating prophylactic doses of iron. It seems pointless to look for any effect in adult males or in prepubertal children. Although a high proportion of the children in the study of Bradfield et al.6 seem to have been in negative iron balance, such a state is very unusual in children in economically advanced countries, and results from such trials are relevant only to the population from which they were drawn. The groups we have investigated represent individuals who are most at risk of iron deficiency. Nevertheless there are certain limitations in our trials. There was some selection, and a few omissions when the preliminary course of iron did not cause a sufficient rise in haemoglobin. Such non-responders are likely to have a lower than average absorption of iron than normal, and hence will require a larger prophylactic supplement than the women who were admitted to the trials; their omission will, therefore, tend to overestimate the effects of iron supplements. On the other hand, the tablets were certainly not taken regularly by everyone, and this will have led to an underestimate of their effect. The spot urine tests indicated that in the trial in adolescent girls, about 70% took a tablet each day during the first year. Unfortunately, we could not continue these tests during the rest of the trial but, from close questioning of the girls and some of their parents, we estimated that the proportion who took the tablets regularly subsequently fell to around 40%. The trials in adult women are probably more satisfactory in this respect, and we think it likely that a very high proportion took the tablets regularly. Women who have been found to be iron deficient and had been given a course of treatment are likely to cooperate well in a preventive scheme, particularly if this lasts only six months or so. Taken together these trials suggest that a supplement of 10 mg. per day has an effect on the mean hxmoglobin levels of adolescent girls and women. The evidence relating to the supplement of 5 mg. iron is equivocal, but our data are few. Our experience in these trials has convinced us that the long-term administration of tablets is im-

no

If iron intake is to be supplemented iron should be added to a foodstuff. However, in large-scale community-based feeding trials7 we found that the addition of an iron salt to flour raises considerable problems within the food industry, and it appeared that about 2-7 mg. additional iron per 100 g. flour is close to the maximum acceptable in normal commercial practice in Great Britain. This level would

practicable.

each person about 2-3 mg. extra iron per day. The results reported here and other studies of ours7.88 suggest that an increase of this magnitude is unlikely to lead to a detectable effect on haemoglobin level. We thank Dr. Powell Phillips and Dr. C. W. Anderson, formerly of the Cardiff School Medical Service, and Dr. R. Morley-Davies, Rhondda Borough Council. Glaxo Laboratories Ltd. kindly supplied the iron and placebo tablets. Requests for reprints should be addressed to P. C. E.

give

REFERENCES 1. Council on Foods and Nutrition. J. Am. med. Ass. 1968, 203, 119. 2. White, H. S., White, P. L. Food Nutr. News, 1968, 39, no. 7, p. 1. 3. Finch, C. A. Nutr. Rev. 1965, 23, 129. 4. Natvig, H., Bjerkedal, T., Jonassen, O. Acta med. scand. 1963, 174, 341. 5. Scott, E. M., Heller, C. A. Am. J. clin. Nutr. 1964, 15, 282. 6. Bradfield, R. B., Jensen, M. V., Gonzales, L., Garrayar, C. ibid.

1968, 21, 57. Elwood, P. C., Waters, W. E. Unpublished. 8. Elwood, P. C. Lancet, 1968, ii, 516.

7.

MENTAL SYMPTOMS IN PARKINSONIAN PATIENTS TREATED WITH L-DOPA RAMON B.

JENKINS

ROBERT H. GROH

Departments of Neurology and Psychiatry, Washington Hospital Center, Washington, D.C. 20010, U.S.A. Summary

Eighteen of ninety consecutive patients

with Parkinson’s disease had mental disturbances attributable to therapy with L-dopa. Seven of them became moderately to severely depressed, four became suicidal, five became psychotic, and one became psychotic and later depressed. One patient developed delusions and hallucinations when L-dopa was temporarily withdrawn. The abrupt appearance and rapid worsening of mental side-effects in five patients, three of whom became suicidal and two psychotic, underlines the need for awareness of mental complications of therapy with L-dopa in order to avoid delay in diagnosis and treatment. Introduction THE ability of L-dopa to reverse many of the clinical features of Parkinson’s disease is now well established.1 However, the drug produces a large number of physical side-effects, many of which are mediated through the central nervous system. These include nausea and vomiting, involuntary dyskinetic movements, and disturbance of sleep. Although mental disturbances have often been reported they have received little specific consideration as major sidementioned include effects-those depression2

agitation,I-6 confusion,5 delirium,l.3 paranoia,l.4-7 hallucinations,I-3 delusions,4 and psychosis.l.3-5 A report on aggravation of the mental status of patients with chronic schizophrenia,8 the high inci-