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Management of Chronic Gout
381
LEADING ARTICLES
cid by themselves and others. The most important of these were gastro-intestinal symptoms (in 3-1%), rashes (1-3%), and reactions of hypersensitivity (0-3%). One group of incidents during treatment was an inevitable result of uric-acid diuresis rather than a toxic effect. Such incidents included costovertebral pain, renal colic, and hæmaturia—all attributable to the precipitation of urate crystals in the urinary tract. BoGER and STRICKLAND advise scrupulous care in making sure that the urine is alkaline during the early weeks of treatment. No deaths have been attributed to treatment with probenecid and there has been no reason to suspect any chronic toxicity. It has been common to get more acute attacks during the initial stages of treatment with
THE LANCET LONDON :
SATURDAY, AUGUST 20, 1955
Gout years a more hopeful attitude the management of chronic
Management of Chronic
DURING the past five has emerged towards gout, and this is reflected in the title of the article by Dr. MARSON which we publish this week-Complete1 Relief of Gout-and in a recent paper by BARTELS (Gout-Now Amenable to Control). It is clear that the continuous administration of uricosuric agents can, in most cases, reduce the size of tophi, reverse the radiographic abnormalities, and eventually control acute attacks. Apart from the choice of uricosuric drug, the clinician must decide at what point in the course of the disease this treatment should be started and how long it should be continued. Sodium sali-
probenecid ; colchicine (or, perhaps, phenylbutazone) can be given to relieve or prevent these. The common toxic effects of salicylate are conspicuous with the large doses required, but MARSON is apparently able to induce most of his patients to accept these, and he finds that the symptoms become less troublesome in time. On the score of cost salicylate wins handsomely : a
week’s treatment of a
cid
(2-0
90 1s. 9d.
(gr.
hospital patient with probenedaily) costs 13s. ; for sodium salicylate daily, in a flavoured mixture) the figure is g.
cylate and probenecid (’ Benemid ’) are at present A sound theoretical case could be made for starting the main alternatives, and the choice between them a uricosuric drug as soon as the diagnosis of gout must rest on their relative efficiency, the frequency is established and for continuing it for the firmly with which they produce undesirable effects, and their remainder of the patient’s life. It is impossible to be cost. SOUGIN-MIBASHAN and HORWITZ2 have lately certain of the point at which deposits of urate first added ethyl biscoumacetate (’ Tromexan ’) to the list in the tissues and initiate the irreversible of uricosuric agents-an observation of considerable appear which changes may lead in the end to permanently theoretical interest but hardly likely to influence and perhaps kidneys. On the other joints damaged practical therapeutics. BARTELSi dismissessalicylate hand, many will know of patients who have had summarily (and, it seems, unjustifiably) as not active years of freedom after a single acute attack of goutenough to restore the serum uric-acid level to normal it was as many as 62 years in a case described by except in early or mild gout, or when the uric-acid BA-UEP..8 To start lifelong treatment (especially with level is only slightly raised. MARSON, on the other high doses of salicylate) after a single attack of gout hand, by giving salicylate, in daily doses of about would demand a singularly firm physician and a gr. 90, has been able to maintain the serum uric-acid particularly amenable patient. But there can be little at a lower level than was possible with 2-0 g. daily of doubt that frequently recurring attacks of gout, probenecid 3 ; and he has produced impressive evi- incomplete resolution of arthropathy between attacks, dence that salicylate treatment favourably influences radiographic changes in bones, and tophi in the soft the course of the disease.4 With both methods the tissues are firm indications for starting treatment with lowest serum uric-acid levels were reached during the It is or rational that treatment probenecid salicylate. first few days of treatment, and subsequent values should be continuous but almost certainly unnecestended to be higher. Reports56 of antagonism between close it with to restriction of any sary supplement the two drugs when given together were not condiet. And it is important to bear in mind that treatfirmed, but there was nothing to be gained from using ment must be continued for many months before them in combination.3 In one of MARSON’s cases benefit can be expected. acetylsalicylic acid seemed as effective as sodium This notable advance in treatment has thrown littlesalicylate, and the former certainly merits considera- fresh light on the mechanism whereby a chronic tion as a more convenient preparation. familial defect of metabolism is punctuated by In the matter of toxic effects MARSON’S impression episodes of acute gout. Certainly such of probenecid seems to have been less favourable than explosive attacks can continue after the uric-acid level in the that of other workers : of 15 patients treated 2 had serum has been lowered by treatment to well within severe hypersensitivity reactions, 6 had gastro-intesthe normal range. This strengthens the evidence that tinal symptoms (but not bad enough to stop treat- uric acid itself is not responsible for acute attacks, ment), and 1 had unexplained pain in the loin.3 and it has suggested to MASON9 that a precursor of BOGER and STRICKLANDhave studied the incidence uric acid may be involved, the formation of which of toxic effects in 2502 patients treated with probenebe blocked may by colchicine. He points out that 1. 2. 3. 4.
Bartels, E. C. Ann. intern. Med. 1955, 42, 1. Sougin-Mibashan, R., Horwitz, M. Lancet, 1955, i, 1191. Marson, F. G. W. Ann. rheum. Dis. 1954, 13, 233. Marson, F. G. W. Quart. J. Med. 1953, 22, 331. 5. Pascale, L. R., Dubin, A., Hoffman, W. S. J. Amer. med. Ass. 1952, 149, 1188. 6. Gutman, A. B., Yü, T. F. Amer. J. med. 1952, 13, 744. 7. Boger, W. P., Strickland, S. C. Arch. intern. Med. 1955, 95, 83.
,
such a precursor must be abnormal, for colchicine has no effect on the concentration of uric acid in the From experiments with isotopic glycine blood. 8. Bauer, W. New Engl. J. Med. 1943, 229, 583. 9. Mason, R. W. Ann. rheum. Dis. 1954, 13, 120.
382
LEADING ARTICLES
BENEDICT et al.10 concluded that in gouty subjects there may be a more rapid mechanism for transforming glycine into uric acid than is normally the case, and they suggested that this transformation may be accomplished by a different metabolic route.
Research on Human Nutrition IN the 19th century, nutritional research was concentrated on energy requirements and the interrelations of the three basic foodstuffs-proteins, fats, and carbohydrates. In the first half of the 20th century the predominant interest was in the vitamins. After their discovery by HopKiNs and FuNK, knowledge of their properties accumulated rapidly, and consequently we now know enough to prevent the five major vitamin-deficiency diseases-beriberi, pellagra, scurvy, rickets, and keratomalacia. That these five diseases can still be seen here on occasion, and remain prevalent in some other parts of the world, is due to the great difficulty of applying new nutritional knowledge and in particular the need for more instruction on the subject. Today, in the second half, of the 20th century, the principal problems in human nutrition about which the general public, the clinician, and the research-worker would all like more information include : (1) the relation of dietary habits to degenerative processes of ageing, and particularly to atheroma and the growth-rates of tumours ; (2) the effects on health of the manifold chemical and physical treatments involved in the processing of all the common foods, which is inevitable in an industrial community ; (3) the effects of various foods and dietary habits on the efficiency and working capacity of the industrial population ; (4) the effects of diet on resistance to infectious disease, especially the common respiratory infections ; and (5) the constitution of the diets most favourable to human growth and development at all stages from prenatal life to adolescence. The importance of this last problem was emphasised in the latest annual report of the Medical Research Council," in which a section on the investigation of human nutrition is almost wholly devoted to kwashiorkor and the supply of suitable proteins for the young. In most of Africa, and in some other countries, probably nothing else is so important for the improvement of health. A research nutritionist, if asked to tackle any of these problems, might well reply that this would be easy provided he had a suitable supply of volunteers, prepared to live on controlled diets for months or years. He might.add that if he was expected to rely on the excellent equipment for housing and feeding small rodents, which he had inherited from his predecessors of the vitamin era," he would have little hope of doing much towards their solution. In fact he can contribute new knowledge only by careful field observations, when circumstances permit, and by "
rare opportunity that may arise for a experiment. Nevertheless, valuable contributions have been made in the last decade, including
seizing
the
controlled
the field studies of SMITH and WOODRUFF 12 in a Japanese prisoner-of-war camp, of the Cambridge Benedict, J. D., Roche, M., Yü, T. F., Bien, E. J., Gutman, A. B., Stetten, DeW. jun. Metabolism, 1952, 1, 3. 11. Report of the Medical Research Council for the year 1953-54. H.M. Stationery Office. 12. Smith, D. A., Woodruff, M. F. A. Spec. Rep. Ser. med. Res. Coun., Land. no. 274, 1951. 10.
school of experimental medicine in Western Germany,13 and of BROCK and AUTRET 14 and others in Africa. A good example of a careful attempt to correlate diet with morbidity and mortality is the study by KEY& and his colleagues 15 of the association between the incidence of coronary-artery disease and a high national consumption of fats in many countries. Controlled experiments, however, have been few and far between. The most comprehensive has been the Minnesota experiment 16 on human starvation, but chances of tests on such a scale rarely arise, though groups of volunteers have been collected among conscientious objectors in war-time. WIDDOWSON and MCCANCE’s 17 controlled trial of the nutritive value of breads made from various flours, carried out in orphanages in post-war Germany, were excellent attempts to elucidate a most difficult problem ; but, as we pointed out the other day,18 their results are none too easy to interpret and certainly give no clear-cut guidance to those responsible for the regulation of milling processes. This week we publish a paper, by Professor BROCK and his colleagues from three centres in South Africa, on the treatment of kwashiorkor. For the last five there has been doubt that no years dry skimmed-milk is effective for an but kwashiorkor; remedy powder skimmed milk is a complex chemical mixture, and the nature of the active therapeutic agent has been uncertain. In this latest work a good series of controlled trials have shown. that casein is the factor that initiates the cure, and in this respect its action has proved to be independent of the addition of a general vitamin mixture. A few further trials have indicated that an amino-acid mixture alone can be equally effective in causing immediate improvement in children with kwashiorkor. These findings will be valuable to physicians responsible for the treatment of the many cases of kwashiorkor in Africa, but they should be still- more useful in planning preventive measures. Milk is certainly an excellent prophylactic against the disease ; but in Africa, as in many other places, it is impracticable to wait and hope for the development of dairy-herds capable of supplying the needs of the children, especially in their critical second year. When we can define accurately in chemical terms the property of the substance or substances in the milk that is so critical for child development, then it should become possible to find alternative sources, perhapsfrom vegetable products, and to plan agriculture so as to enable prophylaxis to be carried out on the scale required. The investigations of BROCK and his colleagues are a promising start in the task of finding out what the critical chemical agents are. Their trials have been on a large scale in three separate cities. Good central organisation and a sufficiency of skilled staff-chemists, doctors, and nurses-have been the factors responsible for the success already achieved. Opportunity to elucidate the nutritional problems of our day is not easily found ;; and we must hope 13. Members of the Department of Experimental Medicine, Cambridge. Spec. Rep. Ser. med. Res. Coun., Lond. no. 275, 1951. See Lancet, 1951, ii, 390. 14. Brock, J. F., Autret, M. F.A.O. Nutritional Studies no. 8. Rome, 1952. See Lancet, 1952, ii, 1070. 15. Keys, A. Circulation, 1952, 5, 115. 16. Keys, A., Brozek, J., Henschel, A., Michelsen, O., Taylor, H. L. Biology of Human Starvation. Minneapolis, 1950. See Lancet, 1951, i, 95. 17. Widdowson, E. M., McCance, R. A. Spec. Rep. Ser. med. Res. Coun., Lond. no. 287, 1954. See Lancet, 1954, ii, 1006. 18. See Lancet, July 30, 1955, p. 235.
LEADING ARTICLES
cid by themselves and others. The most important of these were gastro-intestinal symptoms (in 3-1%), rashes (1-3%), and reactions of hypersensitivity (0-3%). One group of incidents during treatment was an inevitable result of uric-acid diuresis rather than a toxic effect. Such incidents included costovertebral pain, renal colic, and hæmaturia—all attributable to the precipitation of urate crystals in the urinary tract. BoGER and STRICKLAND advise scrupulous care in making sure that the urine is alkaline during the early weeks of treatment. No deaths have been attributed to treatment with probenecid and there has been no reason to suspect any chronic toxicity. It has been common to get more acute attacks during the initial stages of treatment with
THE LANCET LONDON :
SATURDAY, AUGUST 20, 1955
Gout years a more hopeful attitude the management of chronic
Management of Chronic
DURING the past five has emerged towards gout, and this is reflected in the title of the article by Dr. MARSON which we publish this week-Complete1 Relief of Gout-and in a recent paper by BARTELS (Gout-Now Amenable to Control). It is clear that the continuous administration of uricosuric agents can, in most cases, reduce the size of tophi, reverse the radiographic abnormalities, and eventually control acute attacks. Apart from the choice of uricosuric drug, the clinician must decide at what point in the course of the disease this treatment should be started and how long it should be continued. Sodium sali-
probenecid ; colchicine (or, perhaps, phenylbutazone) can be given to relieve or prevent these. The common toxic effects of salicylate are conspicuous with the large doses required, but MARSON is apparently able to induce most of his patients to accept these, and he finds that the symptoms become less troublesome in time. On the score of cost salicylate wins handsomely : a
week’s treatment of a
cid
(2-0
90 1s. 9d.
(gr.
hospital patient with probenedaily) costs 13s. ; for sodium salicylate daily, in a flavoured mixture) the figure is g.
cylate and probenecid (’ Benemid ’) are at present A sound theoretical case could be made for starting the main alternatives, and the choice between them a uricosuric drug as soon as the diagnosis of gout must rest on their relative efficiency, the frequency is established and for continuing it for the firmly with which they produce undesirable effects, and their remainder of the patient’s life. It is impossible to be cost. SOUGIN-MIBASHAN and HORWITZ2 have lately certain of the point at which deposits of urate first added ethyl biscoumacetate (’ Tromexan ’) to the list in the tissues and initiate the irreversible of uricosuric agents-an observation of considerable appear which changes may lead in the end to permanently theoretical interest but hardly likely to influence and perhaps kidneys. On the other joints damaged practical therapeutics. BARTELSi dismissessalicylate hand, many will know of patients who have had summarily (and, it seems, unjustifiably) as not active years of freedom after a single acute attack of goutenough to restore the serum uric-acid level to normal it was as many as 62 years in a case described by except in early or mild gout, or when the uric-acid BA-UEP..8 To start lifelong treatment (especially with level is only slightly raised. MARSON, on the other high doses of salicylate) after a single attack of gout hand, by giving salicylate, in daily doses of about would demand a singularly firm physician and a gr. 90, has been able to maintain the serum uric-acid particularly amenable patient. But there can be little at a lower level than was possible with 2-0 g. daily of doubt that frequently recurring attacks of gout, probenecid 3 ; and he has produced impressive evi- incomplete resolution of arthropathy between attacks, dence that salicylate treatment favourably influences radiographic changes in bones, and tophi in the soft the course of the disease.4 With both methods the tissues are firm indications for starting treatment with lowest serum uric-acid levels were reached during the It is or rational that treatment probenecid salicylate. first few days of treatment, and subsequent values should be continuous but almost certainly unnecestended to be higher. Reports56 of antagonism between close it with to restriction of any sary supplement the two drugs when given together were not condiet. And it is important to bear in mind that treatfirmed, but there was nothing to be gained from using ment must be continued for many months before them in combination.3 In one of MARSON’s cases benefit can be expected. acetylsalicylic acid seemed as effective as sodium This notable advance in treatment has thrown littlesalicylate, and the former certainly merits considera- fresh light on the mechanism whereby a chronic tion as a more convenient preparation. familial defect of metabolism is punctuated by In the matter of toxic effects MARSON’S impression episodes of acute gout. Certainly such of probenecid seems to have been less favourable than explosive attacks can continue after the uric-acid level in the that of other workers : of 15 patients treated 2 had serum has been lowered by treatment to well within severe hypersensitivity reactions, 6 had gastro-intesthe normal range. This strengthens the evidence that tinal symptoms (but not bad enough to stop treat- uric acid itself is not responsible for acute attacks, ment), and 1 had unexplained pain in the loin.3 and it has suggested to MASON9 that a precursor of BOGER and STRICKLANDhave studied the incidence uric acid may be involved, the formation of which of toxic effects in 2502 patients treated with probenebe blocked may by colchicine. He points out that 1. 2. 3. 4.
Bartels, E. C. Ann. intern. Med. 1955, 42, 1. Sougin-Mibashan, R., Horwitz, M. Lancet, 1955, i, 1191. Marson, F. G. W. Ann. rheum. Dis. 1954, 13, 233. Marson, F. G. W. Quart. J. Med. 1953, 22, 331. 5. Pascale, L. R., Dubin, A., Hoffman, W. S. J. Amer. med. Ass. 1952, 149, 1188. 6. Gutman, A. B., Yü, T. F. Amer. J. med. 1952, 13, 744. 7. Boger, W. P., Strickland, S. C. Arch. intern. Med. 1955, 95, 83.
,
such a precursor must be abnormal, for colchicine has no effect on the concentration of uric acid in the From experiments with isotopic glycine blood. 8. Bauer, W. New Engl. J. Med. 1943, 229, 583. 9. Mason, R. W. Ann. rheum. Dis. 1954, 13, 120.
382
LEADING ARTICLES
BENEDICT et al.10 concluded that in gouty subjects there may be a more rapid mechanism for transforming glycine into uric acid than is normally the case, and they suggested that this transformation may be accomplished by a different metabolic route.
Research on Human Nutrition IN the 19th century, nutritional research was concentrated on energy requirements and the interrelations of the three basic foodstuffs-proteins, fats, and carbohydrates. In the first half of the 20th century the predominant interest was in the vitamins. After their discovery by HopKiNs and FuNK, knowledge of their properties accumulated rapidly, and consequently we now know enough to prevent the five major vitamin-deficiency diseases-beriberi, pellagra, scurvy, rickets, and keratomalacia. That these five diseases can still be seen here on occasion, and remain prevalent in some other parts of the world, is due to the great difficulty of applying new nutritional knowledge and in particular the need for more instruction on the subject. Today, in the second half, of the 20th century, the principal problems in human nutrition about which the general public, the clinician, and the research-worker would all like more information include : (1) the relation of dietary habits to degenerative processes of ageing, and particularly to atheroma and the growth-rates of tumours ; (2) the effects on health of the manifold chemical and physical treatments involved in the processing of all the common foods, which is inevitable in an industrial community ; (3) the effects of various foods and dietary habits on the efficiency and working capacity of the industrial population ; (4) the effects of diet on resistance to infectious disease, especially the common respiratory infections ; and (5) the constitution of the diets most favourable to human growth and development at all stages from prenatal life to adolescence. The importance of this last problem was emphasised in the latest annual report of the Medical Research Council," in which a section on the investigation of human nutrition is almost wholly devoted to kwashiorkor and the supply of suitable proteins for the young. In most of Africa, and in some other countries, probably nothing else is so important for the improvement of health. A research nutritionist, if asked to tackle any of these problems, might well reply that this would be easy provided he had a suitable supply of volunteers, prepared to live on controlled diets for months or years. He might.add that if he was expected to rely on the excellent equipment for housing and feeding small rodents, which he had inherited from his predecessors of the vitamin era," he would have little hope of doing much towards their solution. In fact he can contribute new knowledge only by careful field observations, when circumstances permit, and by "
rare opportunity that may arise for a experiment. Nevertheless, valuable contributions have been made in the last decade, including
seizing
the
controlled
the field studies of SMITH and WOODRUFF 12 in a Japanese prisoner-of-war camp, of the Cambridge Benedict, J. D., Roche, M., Yü, T. F., Bien, E. J., Gutman, A. B., Stetten, DeW. jun. Metabolism, 1952, 1, 3. 11. Report of the Medical Research Council for the year 1953-54. H.M. Stationery Office. 12. Smith, D. A., Woodruff, M. F. A. Spec. Rep. Ser. med. Res. Coun., Land. no. 274, 1951. 10.
school of experimental medicine in Western Germany,13 and of BROCK and AUTRET 14 and others in Africa. A good example of a careful attempt to correlate diet with morbidity and mortality is the study by KEY& and his colleagues 15 of the association between the incidence of coronary-artery disease and a high national consumption of fats in many countries. Controlled experiments, however, have been few and far between. The most comprehensive has been the Minnesota experiment 16 on human starvation, but chances of tests on such a scale rarely arise, though groups of volunteers have been collected among conscientious objectors in war-time. WIDDOWSON and MCCANCE’s 17 controlled trial of the nutritive value of breads made from various flours, carried out in orphanages in post-war Germany, were excellent attempts to elucidate a most difficult problem ; but, as we pointed out the other day,18 their results are none too easy to interpret and certainly give no clear-cut guidance to those responsible for the regulation of milling processes. This week we publish a paper, by Professor BROCK and his colleagues from three centres in South Africa, on the treatment of kwashiorkor. For the last five there has been doubt that no years dry skimmed-milk is effective for an but kwashiorkor; remedy powder skimmed milk is a complex chemical mixture, and the nature of the active therapeutic agent has been uncertain. In this latest work a good series of controlled trials have shown. that casein is the factor that initiates the cure, and in this respect its action has proved to be independent of the addition of a general vitamin mixture. A few further trials have indicated that an amino-acid mixture alone can be equally effective in causing immediate improvement in children with kwashiorkor. These findings will be valuable to physicians responsible for the treatment of the many cases of kwashiorkor in Africa, but they should be still- more useful in planning preventive measures. Milk is certainly an excellent prophylactic against the disease ; but in Africa, as in many other places, it is impracticable to wait and hope for the development of dairy-herds capable of supplying the needs of the children, especially in their critical second year. When we can define accurately in chemical terms the property of the substance or substances in the milk that is so critical for child development, then it should become possible to find alternative sources, perhapsfrom vegetable products, and to plan agriculture so as to enable prophylaxis to be carried out on the scale required. The investigations of BROCK and his colleagues are a promising start in the task of finding out what the critical chemical agents are. Their trials have been on a large scale in three separate cities. Good central organisation and a sufficiency of skilled staff-chemists, doctors, and nurses-have been the factors responsible for the success already achieved. Opportunity to elucidate the nutritional problems of our day is not easily found ;; and we must hope 13. Members of the Department of Experimental Medicine, Cambridge. Spec. Rep. Ser. med. Res. Coun., Lond. no. 275, 1951. See Lancet, 1951, ii, 390. 14. Brock, J. F., Autret, M. F.A.O. Nutritional Studies no. 8. Rome, 1952. See Lancet, 1952, ii, 1070. 15. Keys, A. Circulation, 1952, 5, 115. 16. Keys, A., Brozek, J., Henschel, A., Michelsen, O., Taylor, H. L. Biology of Human Starvation. Minneapolis, 1950. See Lancet, 1951, i, 95. 17. Widdowson, E. M., McCance, R. A. Spec. Rep. Ser. med. Res. Coun., Lond. no. 287, 1954. See Lancet, 1954, ii, 1006. 18. See Lancet, July 30, 1955, p. 235.