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Gout
921
LEADING ARTICLES
THE LANCET LONDON::
SATURDAY, OCT. 31,
1953
Gout THE basic hereditary abnormality which forms the background to the clinical phenomena of gout remains beyond our therapeutic reach, and treatment is necessarily directed towards controlling acute attacks as they occur, reducing their frequency, and limiting the deposition of urate in the tissues. In acute gout colchicine remains the standard remedy, with corticotrophin (A.C.T.H.) as a useful alternative, or supplement, and phenylbutazone The mechanism of acute as a promising newcomer. attacks is obscure and the employment of colchicine empirical. Certainly it is difficult to relate these explosive inflammatory episodes to the slow accumulaof urate-a substance not of demonstrably capable inducing so sharp a reaction. In practice, however, measures which reduce the precipitation of urate do apparently lessen the frequency of attacks, and there is little reason to doubt that the crippling arthritis which may dominate the later picture can be attributed to a slow reaction to urate deposited in and around the joints. It has long been the aim of treatment in chronic gout to decrease uric-acid formation, notably by adjusting the diet, and to enhance its excretion by the kidneys, but the practical value of these measures has remained in considerable doubt. Not many years ago, in fact, BAUER and KLEMPERER1 expressed the view that interval treatment had been disappointing and that no pertinent evidence existed for the ability of diet or drugs, or a combination of both, to alter the clinical course of the disease or even to reduce the number of acute attacks. Recent experiences with old as well as new drugs have justified the happier conclusion that careful and long-continued treatment in the chronic stage can produce worthClinical observations of the effects while results. of treatment have been usefully supplemented by new methods of measuring the biochemical changes. In addition to measurements of the concentration of uric acid in the blood and urine, it is now possible, by injecting a small dose of uric acid labelled with a radioactive isotope, to calculate the size of the metabolic pool of uric acid in the body and the proportion replaced each day. In normal individuals this " miscible pool " of uric acid amounts to about a gramme and the daily rate of turnover to between 50 and 75%.2 In gout the pool may be flooded to as much as 30 g.,3 and there is reason to believe that it may include some urate already deposited in the superficial layers of tophi as well as that held in solution in the body water.2 If this is true, depletion of the expanded pool should bring some of the precipitated urate back into solution, tion
1.
in
the
tissues
Bauer, W., Klemperer, F. New Engl. J. Med. 1944, 231, 681. Benedict, J. D., Forsham, P. H., Stetten, DeW. jun. J. biol. Chem. 1949, 181, 183. 3. Benedict, J. D., Forsham, P. H., Roche, M., Soloway, S., Stetten, DeW. jun. J. clin. Invest. 1950, 29, 1104. 2.
and the indications are that potent uricosuric drugs can in fact accomplish this. It is generally believed that nearly all the plasmaurate is in filtrable form and that the amount filtered at the glomeruli is the product of filtration-rate and plasma-urate concentration.4 Normally over 90% of the urate is reabsorbed in the tubules, and the uricosuric drugs are believed to act by blocking this process. Among such drugs the choice for longterm use in gout lies at present between salicylate and probenecid (’ Benemid ’), which is p-(di-n-propylsulphamyl)-benzoic acid ; cincophen is less effective and rather toxic for lengthy treatment, and corticotrophin is more appropriately reserved for acute attacks. Phenylbutazone appears to lower the level of uric acid in the plasma, but reports on its effect on renal excretion are conflicting.56 Salicylate has been used in gout for a great many years, but a detailed study by MARSON7 has lately helped to establish it more firmly in its rightful place in the management of the disease. Sodium salicylate, with an equal amount of sodium bicarbonate, was given in a daily dosage of 60-140 g. ; 28 patients were treated, 14 for periods exceeding a year, and in all but 1 (the only patient with severe renal impairment) the plasma level of uric acid was reduced and maintained at normal throughout treatment. Relief from pain and stiffness in the joints became apparent after periods ranging from days to many months, and 20 patients eventually became entirely free from continuous joint symptoms. Tophi disappeared in 2 cases and tophaceous ulceration (present in 4 patients) healed in 3. No tophi increased in size during treatment and radiological abnormalities Acute either remained stationary or regressed. attacks seemed to diminish in frequency and severity. The correct use of salicylate is of prime importance and MARsoN’s good results were achieved by continuous treatment and by adjusting the dose so as to maintain a normal level of uric acid in the plasma without producing serious toxic reactions-an objective which others have found difficult to achieve. At lower dosage levels uric-acid excretion is unchanged or even reduced.8 In cases treated with acetylsalicylic acid BAUER and KLEMPERERfound that the control of the uric acid level was lost after about three months’ treatment, but MARSON did not encounter this difficulty. BENEDICT and her colleagues 23 were able to reduce the miscible pool in one of their patients from 31 to 2 g. with acetylsalicylic acid, but MARSON found this drug less effective than salicylate. Similar beneficial effects, with extensive, if slow, mobilisation of tophaceous deposits, have been reported in9-11cases treated for long periods with a substance originally introduced probenecid as a means of delaying the excretion of p-aminobenzoic acid or penicillin.12 As with salicylates, treatment is unsuccessful when renal function is impaired. 4. Berliner, R. W., Hilton, J. G., Yü, T. F.,
Kennedy,
T. J.
jun.
Ibid, p. 396. 5. Kidd, E. G., Boyce, K. C., Freyberg, R. H. Ann. rheum. Dis. 1953, 12, 20. 6. Yü, T. F., Gutman, A. B. Unpublished data quoted in reference 11. 7. Marson, F. G. W. Quart. J. Med. 1953, 22, 331. 8. Klemperer, F., Bauer, W. J. clin. Invest. 1944, 23, 950. 9. Gutman, A. B. Bull. N.Y. Acad. Med. 1951, 27, 194. 10. Pascale, L. R., Dubin, A., Hoffman, W. S. J. Amer. med. Ass. 1952, 149, 1188. 11. Gutman, A. B., Yü. T. F. Amer. J. Med. 1952, 13, 744. 12. Boger, W. P., Beatty, J. O., Pitts, F. W., Flippin, H. F. Ann. intern. Med. 1950, 33, 18.
922
salicylate and probenecid comparison of their toxicity. likely In MARsoN’s patients salicylism, as might be expected, was common in the early stages of treatment, but only occasional and mild after a month ; treatment had to be stopped on only 2 occasions. Probenecid rather commonly produces mild nausea and anorexia and appears to increase the frequency of acute attacks during the early weeks of treatment. The high content The final choice between
is
to rest
on
a
of urate in the urine may lead to the formation of crystals and to colic or hsematuria, but this difficulty should be avoided if a high fluid intake and an alkaline urine are maintained. GUTMAN and Yü 11
encountered allergic reactions calling for the withdrawal of treatment in 2 out of 40 patients treated with probenecid. In a report to the American Rheumatism Association last year TALBOTT and his colleagues 13 described a series of cases treated with probenecid for periods ranging up to two years in which the incidence of undesirable side-effects was " clinically unimportant " ; and MARSON may have been unfortunate in having 2 serious sensitivity reactions among 5 cases treated with the drug. Probenecid is, however, still a relatively unknown quantity in comparison with salicylate, and judgment should be reserved. No compromise is possible, for when salicylate and probenecid are given together their uricosuric activities are reciprocally inhibited. In contrast to an increased appreciation of the value of uricosuric drugs, less store is now set by dietetic adjustment. This is certainly true in the case of dietary purines, for theoretical considerations as well as direct experiments have cast serious doubts on the value of restricting their intake. Available knowledge about uric-acid metabolism in man, some of it contributed by recent experiments with radioactive tracers, has been summarised by SHEMmT.l4 Uric acid is derived normally from exogenous and endogenous sources in almost equal proportions ; glycine and ammonia contribute nitrogen to its formation and the carbon atoms are derived from formate, glycine, and carbon dioxide. In addition to purines, therefore, the dietary carbohydrates, fats, and protein are all potential precursors of uric acid. Endogenous uric acid is believed to be derived from the breakdown of cellular nucleoproteins, especially from the extruded nuclei of normoblasts,15 and it is unlikely that its formation could be reduced, at any rate for more than a short time. It is true that variations in purine intake can produce measurable biochemical effects, and MARSON confirmed that a change from a low to a high purine diet increased the concentrations of both plasma and urinary uric acid ; but the increases were small and it seemed unlikely that a purine-free diet could materially alter the clinical course of gout. Protein consumption may be more important. BIEN and his colleagues 16 have established that a high-protein diet accelerates uric-acid synthesis, and GUTMAN and Yü 17 found that this effect was sufficient to reverse the negative urate balance induced by probenecid. Imposition of irksome dietary restrictions in the 13.
14. 15. 16.
17.
Talbott, J. H., Lockic, L. M., Norcross, B. M., Bishop, C. Reported in Ann. rheum. Dis. 1952, 11, 294. Shemin, D. Amer. J. Med. 1950, 9, 802. Krafka, J. jun. J. biol. Chem. 1930, 86, 223. Bien, E. J., Yü, T. F., Benedict, J. D., Gutman, A. B., Stetten, DeW. jun. J. clin. Invest. 1953, 32, 778. Gutman, A. B., Yü, T. F. Trans. Ass. Amer. Phycns. 1951, 64, 279.
proof of their value is hard to justify evidence the best advice to the gouty present be to moderate his protein intake patient may simply and avoid gluttony. The basis for any advice about alcohol consumption must still be clinical experience, which favours some restriction, rather than controlled
absence of clear
and
on
experiments. Blood Formation and Vitamin C VITAMIN C (ascorbic acid) is commonly supposed to be important for proper blood formation, but unequivocal evidence has been lacking. In 1940 CRANDON et al.1 observed the effect on a normal adult of a diet devoid of vitamin C but adequate in all other respects ; after six months many features of scurvy had appeared, but anaemia was not one of these and even venesection totalling 6 litres failed to provoke it. Nevertheless anaemia is a recognised symptom of clinical scurvy, and it is often much more severe than can be accounted for by haemorrhage. In 1943 ISRAELS2 found in 3 cases of clinically severe scurvy that the bone-marrow showed diminished or normal cellularity, with depression of erythroblasts in 2; treatment with ascorbic acid alone caused a sharp increase in the normoblasts in the marrow and the anaemia disappeared. A year later McMiLLAN and INGLIS3 described a series of 53 cases of clinical scurvy admitted to an Edinburgh general hospital. Of these patients 22 had anaemia classed as moderate or severe; of the 6 in whom the bone-marrow was examined, erythropoiesis was normoblastic in 3, normoblastic with a few megaloblasts present in 2, and megaloblastic in 1. The patient with megaloblastic marrow had achlorhydria, but his anaemia responded to treatment with vitamin C alone. McMILLAN and INGLIS noted that patients could have severe clinical scurvy but no anaemia ; and that of patients kept on a diet deficient in vitamin C but otherwise adequate, some who were anaemic showed some regeneration of haemoglobin and red cells, whereas in others the anaemia could not be relieved until vitamin C was given. They concluded that vitamin C was only one of several factors responsible for the anaemia. VILTER et a1.4 in Cincinnati investigated the bone-marrow changes in 11scorbutic patients. The marrow was moderately hypercellular in 5, normal in 5, and moderately hypocellular in 1 ; erythropoiesis was normoblastic in all except I-a severely anaemic patient in whose marrow 11% of megaloblasts were found. The marrow seemed less cellular than would be expected if simple blood loss had produced anaemia of comparable degree. These patients had diets that were deficient in vitamin-B complex as well as in vitamin C: but some recovered when given vitamin C alone. VILTER et al. also noted that scorbutic patients were not necessarily anaemic, and suggested that patients with severe vitamin-C depletion might remain free of anaemia until additional strain was placed on the marrow by a deficiency of extrinsic factor, protein, iron, or other factors necessary for normal hæmopoiesis ; but such deficiency might not be serious enough to prevent remission when large amounts of 1. Crandon J. H., Lund, C. C., Dill, D. B. New Engl. J. Med. 1940. 223, 353. 2. Israëls, M. C. G. Lancet, 1943, i, 170. 3. McMillan, R. B., Inglis, V. C. Brit. med. J. 1944, ii, 233. 4. Vilter, R. W., Woolford, R. M., Spies, T. D. J. Lab. clin. Med. 1946, 31, 609.
LEADING ARTICLES
THE LANCET LONDON::
SATURDAY, OCT. 31,
1953
Gout THE basic hereditary abnormality which forms the background to the clinical phenomena of gout remains beyond our therapeutic reach, and treatment is necessarily directed towards controlling acute attacks as they occur, reducing their frequency, and limiting the deposition of urate in the tissues. In acute gout colchicine remains the standard remedy, with corticotrophin (A.C.T.H.) as a useful alternative, or supplement, and phenylbutazone The mechanism of acute as a promising newcomer. attacks is obscure and the employment of colchicine empirical. Certainly it is difficult to relate these explosive inflammatory episodes to the slow accumulaof urate-a substance not of demonstrably capable inducing so sharp a reaction. In practice, however, measures which reduce the precipitation of urate do apparently lessen the frequency of attacks, and there is little reason to doubt that the crippling arthritis which may dominate the later picture can be attributed to a slow reaction to urate deposited in and around the joints. It has long been the aim of treatment in chronic gout to decrease uric-acid formation, notably by adjusting the diet, and to enhance its excretion by the kidneys, but the practical value of these measures has remained in considerable doubt. Not many years ago, in fact, BAUER and KLEMPERER1 expressed the view that interval treatment had been disappointing and that no pertinent evidence existed for the ability of diet or drugs, or a combination of both, to alter the clinical course of the disease or even to reduce the number of acute attacks. Recent experiences with old as well as new drugs have justified the happier conclusion that careful and long-continued treatment in the chronic stage can produce worthClinical observations of the effects while results. of treatment have been usefully supplemented by new methods of measuring the biochemical changes. In addition to measurements of the concentration of uric acid in the blood and urine, it is now possible, by injecting a small dose of uric acid labelled with a radioactive isotope, to calculate the size of the metabolic pool of uric acid in the body and the proportion replaced each day. In normal individuals this " miscible pool " of uric acid amounts to about a gramme and the daily rate of turnover to between 50 and 75%.2 In gout the pool may be flooded to as much as 30 g.,3 and there is reason to believe that it may include some urate already deposited in the superficial layers of tophi as well as that held in solution in the body water.2 If this is true, depletion of the expanded pool should bring some of the precipitated urate back into solution, tion
1.
in
the
tissues
Bauer, W., Klemperer, F. New Engl. J. Med. 1944, 231, 681. Benedict, J. D., Forsham, P. H., Stetten, DeW. jun. J. biol. Chem. 1949, 181, 183. 3. Benedict, J. D., Forsham, P. H., Roche, M., Soloway, S., Stetten, DeW. jun. J. clin. Invest. 1950, 29, 1104. 2.
and the indications are that potent uricosuric drugs can in fact accomplish this. It is generally believed that nearly all the plasmaurate is in filtrable form and that the amount filtered at the glomeruli is the product of filtration-rate and plasma-urate concentration.4 Normally over 90% of the urate is reabsorbed in the tubules, and the uricosuric drugs are believed to act by blocking this process. Among such drugs the choice for longterm use in gout lies at present between salicylate and probenecid (’ Benemid ’), which is p-(di-n-propylsulphamyl)-benzoic acid ; cincophen is less effective and rather toxic for lengthy treatment, and corticotrophin is more appropriately reserved for acute attacks. Phenylbutazone appears to lower the level of uric acid in the plasma, but reports on its effect on renal excretion are conflicting.56 Salicylate has been used in gout for a great many years, but a detailed study by MARSON7 has lately helped to establish it more firmly in its rightful place in the management of the disease. Sodium salicylate, with an equal amount of sodium bicarbonate, was given in a daily dosage of 60-140 g. ; 28 patients were treated, 14 for periods exceeding a year, and in all but 1 (the only patient with severe renal impairment) the plasma level of uric acid was reduced and maintained at normal throughout treatment. Relief from pain and stiffness in the joints became apparent after periods ranging from days to many months, and 20 patients eventually became entirely free from continuous joint symptoms. Tophi disappeared in 2 cases and tophaceous ulceration (present in 4 patients) healed in 3. No tophi increased in size during treatment and radiological abnormalities Acute either remained stationary or regressed. attacks seemed to diminish in frequency and severity. The correct use of salicylate is of prime importance and MARsoN’s good results were achieved by continuous treatment and by adjusting the dose so as to maintain a normal level of uric acid in the plasma without producing serious toxic reactions-an objective which others have found difficult to achieve. At lower dosage levels uric-acid excretion is unchanged or even reduced.8 In cases treated with acetylsalicylic acid BAUER and KLEMPERERfound that the control of the uric acid level was lost after about three months’ treatment, but MARSON did not encounter this difficulty. BENEDICT and her colleagues 23 were able to reduce the miscible pool in one of their patients from 31 to 2 g. with acetylsalicylic acid, but MARSON found this drug less effective than salicylate. Similar beneficial effects, with extensive, if slow, mobilisation of tophaceous deposits, have been reported in9-11cases treated for long periods with a substance originally introduced probenecid as a means of delaying the excretion of p-aminobenzoic acid or penicillin.12 As with salicylates, treatment is unsuccessful when renal function is impaired. 4. Berliner, R. W., Hilton, J. G., Yü, T. F.,
Kennedy,
T. J.
jun.
Ibid, p. 396. 5. Kidd, E. G., Boyce, K. C., Freyberg, R. H. Ann. rheum. Dis. 1953, 12, 20. 6. Yü, T. F., Gutman, A. B. Unpublished data quoted in reference 11. 7. Marson, F. G. W. Quart. J. Med. 1953, 22, 331. 8. Klemperer, F., Bauer, W. J. clin. Invest. 1944, 23, 950. 9. Gutman, A. B. Bull. N.Y. Acad. Med. 1951, 27, 194. 10. Pascale, L. R., Dubin, A., Hoffman, W. S. J. Amer. med. Ass. 1952, 149, 1188. 11. Gutman, A. B., Yü. T. F. Amer. J. Med. 1952, 13, 744. 12. Boger, W. P., Beatty, J. O., Pitts, F. W., Flippin, H. F. Ann. intern. Med. 1950, 33, 18.
922
salicylate and probenecid comparison of their toxicity. likely In MARsoN’s patients salicylism, as might be expected, was common in the early stages of treatment, but only occasional and mild after a month ; treatment had to be stopped on only 2 occasions. Probenecid rather commonly produces mild nausea and anorexia and appears to increase the frequency of acute attacks during the early weeks of treatment. The high content The final choice between
is
to rest
on
a
of urate in the urine may lead to the formation of crystals and to colic or hsematuria, but this difficulty should be avoided if a high fluid intake and an alkaline urine are maintained. GUTMAN and Yü 11
encountered allergic reactions calling for the withdrawal of treatment in 2 out of 40 patients treated with probenecid. In a report to the American Rheumatism Association last year TALBOTT and his colleagues 13 described a series of cases treated with probenecid for periods ranging up to two years in which the incidence of undesirable side-effects was " clinically unimportant " ; and MARSON may have been unfortunate in having 2 serious sensitivity reactions among 5 cases treated with the drug. Probenecid is, however, still a relatively unknown quantity in comparison with salicylate, and judgment should be reserved. No compromise is possible, for when salicylate and probenecid are given together their uricosuric activities are reciprocally inhibited. In contrast to an increased appreciation of the value of uricosuric drugs, less store is now set by dietetic adjustment. This is certainly true in the case of dietary purines, for theoretical considerations as well as direct experiments have cast serious doubts on the value of restricting their intake. Available knowledge about uric-acid metabolism in man, some of it contributed by recent experiments with radioactive tracers, has been summarised by SHEMmT.l4 Uric acid is derived normally from exogenous and endogenous sources in almost equal proportions ; glycine and ammonia contribute nitrogen to its formation and the carbon atoms are derived from formate, glycine, and carbon dioxide. In addition to purines, therefore, the dietary carbohydrates, fats, and protein are all potential precursors of uric acid. Endogenous uric acid is believed to be derived from the breakdown of cellular nucleoproteins, especially from the extruded nuclei of normoblasts,15 and it is unlikely that its formation could be reduced, at any rate for more than a short time. It is true that variations in purine intake can produce measurable biochemical effects, and MARSON confirmed that a change from a low to a high purine diet increased the concentrations of both plasma and urinary uric acid ; but the increases were small and it seemed unlikely that a purine-free diet could materially alter the clinical course of gout. Protein consumption may be more important. BIEN and his colleagues 16 have established that a high-protein diet accelerates uric-acid synthesis, and GUTMAN and Yü 17 found that this effect was sufficient to reverse the negative urate balance induced by probenecid. Imposition of irksome dietary restrictions in the 13.
14. 15. 16.
17.
Talbott, J. H., Lockic, L. M., Norcross, B. M., Bishop, C. Reported in Ann. rheum. Dis. 1952, 11, 294. Shemin, D. Amer. J. Med. 1950, 9, 802. Krafka, J. jun. J. biol. Chem. 1930, 86, 223. Bien, E. J., Yü, T. F., Benedict, J. D., Gutman, A. B., Stetten, DeW. jun. J. clin. Invest. 1953, 32, 778. Gutman, A. B., Yü, T. F. Trans. Ass. Amer. Phycns. 1951, 64, 279.
proof of their value is hard to justify evidence the best advice to the gouty present be to moderate his protein intake patient may simply and avoid gluttony. The basis for any advice about alcohol consumption must still be clinical experience, which favours some restriction, rather than controlled
absence of clear
and
on
experiments. Blood Formation and Vitamin C VITAMIN C (ascorbic acid) is commonly supposed to be important for proper blood formation, but unequivocal evidence has been lacking. In 1940 CRANDON et al.1 observed the effect on a normal adult of a diet devoid of vitamin C but adequate in all other respects ; after six months many features of scurvy had appeared, but anaemia was not one of these and even venesection totalling 6 litres failed to provoke it. Nevertheless anaemia is a recognised symptom of clinical scurvy, and it is often much more severe than can be accounted for by haemorrhage. In 1943 ISRAELS2 found in 3 cases of clinically severe scurvy that the bone-marrow showed diminished or normal cellularity, with depression of erythroblasts in 2; treatment with ascorbic acid alone caused a sharp increase in the normoblasts in the marrow and the anaemia disappeared. A year later McMiLLAN and INGLIS3 described a series of 53 cases of clinical scurvy admitted to an Edinburgh general hospital. Of these patients 22 had anaemia classed as moderate or severe; of the 6 in whom the bone-marrow was examined, erythropoiesis was normoblastic in 3, normoblastic with a few megaloblasts present in 2, and megaloblastic in 1. The patient with megaloblastic marrow had achlorhydria, but his anaemia responded to treatment with vitamin C alone. McMILLAN and INGLIS noted that patients could have severe clinical scurvy but no anaemia ; and that of patients kept on a diet deficient in vitamin C but otherwise adequate, some who were anaemic showed some regeneration of haemoglobin and red cells, whereas in others the anaemia could not be relieved until vitamin C was given. They concluded that vitamin C was only one of several factors responsible for the anaemia. VILTER et a1.4 in Cincinnati investigated the bone-marrow changes in 11scorbutic patients. The marrow was moderately hypercellular in 5, normal in 5, and moderately hypocellular in 1 ; erythropoiesis was normoblastic in all except I-a severely anaemic patient in whose marrow 11% of megaloblasts were found. The marrow seemed less cellular than would be expected if simple blood loss had produced anaemia of comparable degree. These patients had diets that were deficient in vitamin-B complex as well as in vitamin C: but some recovered when given vitamin C alone. VILTER et al. also noted that scorbutic patients were not necessarily anaemic, and suggested that patients with severe vitamin-C depletion might remain free of anaemia until additional strain was placed on the marrow by a deficiency of extrinsic factor, protein, iron, or other factors necessary for normal hæmopoiesis ; but such deficiency might not be serious enough to prevent remission when large amounts of 1. Crandon J. H., Lund, C. C., Dill, D. B. New Engl. J. Med. 1940. 223, 353. 2. Israëls, M. C. G. Lancet, 1943, i, 170. 3. McMillan, R. B., Inglis, V. C. Brit. med. J. 1944, ii, 233. 4. Vilter, R. W., Woolford, R. M., Spies, T. D. J. Lab. clin. Med. 1946, 31, 609.