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KETOSIS AND BODY-WEIGHT
1189
’
This appeared to have been of constant severity except in six patients whose pain had been getting steadily worse over the preceding year. The patients had had a variety of treatments, including courses of radiotherapy, but in no case had the pain been significantly affected. Most of them had been taking aspirin, with varied relief. Four had moderate to severe osteoarthritic changes in joints next to the affected bones; these patients were able to distinguish between the constant dull ache in their bones and the more variable intermittent pain, particularly on weightbearing, from their joints. The joint pain was not affected by fluorides. All except two of the patients lost much of their bone pain about 4 to 6 weeks after they had started to take fluoride, and in four cases the relief was complete. There was no relation between the loss of pain and the duration of the disease. The most striking result was in a young man with a year’s history of increasing pain, deformity, and disability. Not only was he completely free of pain after 2 months, but he has remained so for a year and he has been able to resume his work and avocations. Another man, a former footballer with some 11 years’ pain and deformity of the legs, is pain-free and he has resumed football practice at the age of 52. Calcium Balance
In eight patients the calcium balance was measured before and after the administration of fluoride. On the first occasion five patients-all with extensive diseasewere found to be in negative balance (between 100 and 300 mg. calcium per day) whereas three others with restricted disease were in positive balance. After 2-3 months of fluoride, four of the five patients previously in negative balance were in positive balance, and two of those in positive balance were in more positive balance (fig. 1). In the other two patients the balance did not change. Further studies are being arranged in these and additional patients to see whether the balances are maintained on a lower dose of fluoride.
mality of the lesion in Paget’s disease remains unknown. Many of the effects of fluoride intoxication of bone mimic the histological appearances of Paget’s disease even to a type of mosaic formation (Weatherall and Weidmann 1959). How fluorides produce the effects reported here, the site of their action, and the toxic effects which may mitigate their benefit, are questions which remain to be clarified by further study.
Summary Sixteen patients with Paget’s disease have been given fluoride for periods up to a year, and the effects on bone pain, calcium balance, and external counting of calcium-47 are given. Fourteen of the patients gained sustained relief from their bone pain some 4-6 weeks after they had started taking fluoride, and this was sufficient to decrease the disability in many of them. In six out of eight patients fluorides changed negative calcium balances to positive ones, or made positive balances more positive. In two patients, there was no
significant change. The ratio of the counts of calcium-47 between normal and abnormal sides before treatment was between 2 and 6, and this ratio fell with fluoride administration. After 4-6 months six patients had ratios within normal limits. It is a pleasure to acknowledge the help of Prof. R. A. McCance, F.R.S., who first suggested this investigation; and of Dr. R. D. Montgomery, Sister P. F. Hennessy, and Nurse C. Alford. I am indebted to Mr. D. Southgate, who undertook the calcium determinations; to Mr. R. Pope and Miss T. M. Reynolds for their help in the external counting of calcium-47; and to Dr. W. A. Fell, Dr. R. R. P. Hayter, Dr. D. G. Bratherton, and Dr. P. T. Chopping, who referred patients to me. REFERENCES
Goldenberg, H., Sobel, A. E. (1951) Proc. Soc. exp. Biol., N.Y. 78, 719. Rich, C., Ensinck, J. (1961) Nature, Lond. 191, 184. Weatherall, J. A., Weidmann, S. M. (1959) J. Path. Bact. 67, 233. Weidmann, S. M., Weatherall, J. A. (1959) ibid. p. 243. Whitehead, R. G. (1959) ibid. p. 435. —
—
KETOSIS AND BODY-WEIGHT
External Counting with Calcium-47
M. E. CAREY
On their first test, all the patients had an external ratio of counts in normal and abnormal bones of between 2 and 6. On the second occasion, usually after 6-8 weeks of fluoride, the ratios were reduced in all cases. The results in two patients are given in fig. 2. In six patients in whom a third count was made the reduction in the ratio continued, and the ratio was normal within 4-6 months.
B.Sc. Lond. CHIEF DIETITIAN
T. R. E. PILKINGTON M.D. Lond., M.R.C.P. SENIOR LECTURER
E. TITTERINGTON B.Sc. N.Z. RESEARCH ASSISTANT
Discussion
,
Despite the reports on the skeletal changes in chronic fluorosis, and the experimental studies of Weidmann and Weatherall (1959) and others, the mechanism of the action of fluoride on bone still remains obscure. Weidmann et al. (1959) showed that fluoride partly replaces carbonate and hydroxyl ions in bone salt, and they suggested that the observed increase in magnesium might be due to the formation of MgF2. It is unlikely that the changes in the chemical composition of the bones by themselves explain the pathological changes found in chronic fluoride intoxication. Goldenberg and Sobel (1951) have shown that fluoride at the level of 10-4M (1-9 p.p.m.) blocks enolase activity, but that, in the absence of magnesium, 10-3 M of fluoride enhances rather than depresses the rate of in-vitro calcification. Preliminary studies in the present series show no histological evidence of reduced osteoclastic activity in bone after the administration of fluorides. The position is further complicated because the basic abnor-
MEDICAL
UNIT,
ST.
GEORGE’S HOSPITAL, LONDON, S.W.1
FROM time to time claims have been made that the metabolism of fat people differs qualitatively from that of people of normal build. McClellan et al. (1928) reported that, in 1 obese man, the threshold for the development of ketonuria was higher than in 5 normal subjects. No such difference between fat and thin was found by Lauter and Neuenschwander-Lemmer (1936): after two days on a similar diet the mean blood-ketones in 12 thin subjects was 8-2 mg. per 100 ml. (± 1-8) compared with 7-5 mg. (::1::: 0-95) in 17 fat subjects. In 1937 MacKay and Sherrill combined their own experience with that of Folin and Denis (1915) and Deuel and Gulick (1932) and showed that, after a fast of four or five days, the same degree of ketonuria developed in both obese and thin subjects. On the other hand, Kekwick et al. (1959) reported that obese subjects on low-calorie highfat diets became much less ketotic than normal subjects. z2
1190 DETAILS
OF THE
Discussion
11 SUBJECTS STUDIED
Our findings support those who have denied that there are metabolic differences between obese and non-obese people. Contrary results can perhaps best be explained by surreptitious eating-to which the obese are notoriously liable unless very carefully supervised.
Summary On low-calorie high-fat diets, fat and thin subjects developed the same levels of ketones in the blood. We wish to thank the board of governors of St. George’s Hospital for a generous grant; and we are also grateful to Sister M. Hall and the nursing staff, and the dietitians, Mrs. H. M. Adhihetty and Miss D. M. French, for their devoted service. REFERENCES
Their observations have been cited by Passmore (1961) evidence of the only known metabolic abnormality of the obese. We therefore decided to reinvestigate this problem. as
Deuel, H. J., Gulick, M. (1932) J. biol. Chem. 96, 25. Folin, O., Denis, W. (1915) ibid. 21, 183. Kekwick, A., Pawan, G. L. S., Chalmers, T. (1959) Lancet, ii, 1157. Lauter, S., Neuenschwander-Lemmer, N. (1936) Z. ges. exp. Med. 99, 745. McClellan, W. S., Spencer, H. J., Falk, E. A., Du Bois, E. F. (1928) J. biol. Chem. 80, 639. MacKay, E. M., Sherrill, J. W. (1937) Endocrinology, 21, 677. Passmore, R. (1961) Lancet, i, 839. Van Slyke, D. D. (1917) J. biol. Chem. 32, 455. Fitz, R. (1917) ibid. p. 495. (1919) ibid. 39, 23. —
Subjects and Methods Of 11 healthy subjects studied in the metabolic unit, 5 were obese and 6 of normal build (see table). The diet given supplied approximately 1000 calories and consisted of fat 102-0 g., carbohydrate 24-0 g., and protein
—
—
PREDNISOLONE PHOSPHATE IN RHEUMATOID ARTHRITIS
13 9 g. Blood was taken between 10 and 11 A.M., after breakfast at about 8 A.M. Total blood-ketones were estimated by the method of Van Slyke and Fitz (1917, 1919).
A NEW APPROACH TO STEROID-INDUCED DYSPEPSIA
B. A. LATHAM Cantab., M.R.C.P.
Results
M.B.
The accompanying figure shows that there is no difference between the blood-levels of " acetone " in the fat and the thin. We only once encountered failure of the diet to produce ketosis-in a thin man (not shown in the figure) who, when challenged, admitted to cheating
by eating
sweets.
. We therefore decided to test how little glucose was needed to reduce the ketosis produced by such a diet. For this we chose subject 4 (fat) and subject 10 (thin). Both were ketotic by the sixth day on the above diet. On the next three days we added to their breakfast 5 g., 10 g., and 15 g. of glucose. The ketosis was considerably reduced (see figure).
Blood-ketone levels, measured calorie ketogenic diet.
as
acetone, in 11 subjects
on a
1000-
REGISTRAR
R. M. MASON D.M. Oxon., F.R.C.P. PHYSICIAN
DEPARTMENT OF PHYSICAL MEDICINE AND REGIONAL RHEUMATISM CENTRE, THE LONDON HOSPITAL, LONDON, E.1
DYSPEPSIA, with
or without frank ulceration, has long recognised as a troublesome and often serious complication of steroid therapy in rheumatoid arthritis. Berntsen and Freyberg (1961) found that 19% of 183 patients with rheumatoid arthritis, treated with steroids for an average of ten years, had radiologically proven gastrointestinal ulceration, and 2 of 18 deaths in the series followed perforation of gastric ulcers. Morton (1958) reported 41 instances of peptic ulceration (including haemorrhage from an unknown source) in 1034 patients
been
with rheumatoid arthritis from’ ten British centres who had been treated with corticotrophin or steroids for an unspecified period-an incidence of 4%. Many of the patients in both series may be assumed to have been on salicylates also, which alone might have induced ulceration. But Baragar and Duthie (1960) found that only 3 out of 244 patients (1-2%) with rheumatoid arthritis followed for about six years, most of whom were on regular doses of aspirin, showed evidence of peptic ulceration whilst on this drug. Unless it is argued that rheumatoid arthritis protects patients from peptic ulceration, some patients with rheumatoid arthritis may be expected to have peptic ulceration as a result of whatever causes this condition in the general population. Dyspepsia and peptic ulceration have been assumed to be induced by the systemic activity of absorbed corticosteroid, but West (1959) suggested that steroid given by mouth might affect the stomach wall directly. He therefore treated 15 patients on prednisolone complaining of dyspepsia with an enteric-coated preparation and found
’
This appeared to have been of constant severity except in six patients whose pain had been getting steadily worse over the preceding year. The patients had had a variety of treatments, including courses of radiotherapy, but in no case had the pain been significantly affected. Most of them had been taking aspirin, with varied relief. Four had moderate to severe osteoarthritic changes in joints next to the affected bones; these patients were able to distinguish between the constant dull ache in their bones and the more variable intermittent pain, particularly on weightbearing, from their joints. The joint pain was not affected by fluorides. All except two of the patients lost much of their bone pain about 4 to 6 weeks after they had started to take fluoride, and in four cases the relief was complete. There was no relation between the loss of pain and the duration of the disease. The most striking result was in a young man with a year’s history of increasing pain, deformity, and disability. Not only was he completely free of pain after 2 months, but he has remained so for a year and he has been able to resume his work and avocations. Another man, a former footballer with some 11 years’ pain and deformity of the legs, is pain-free and he has resumed football practice at the age of 52. Calcium Balance
In eight patients the calcium balance was measured before and after the administration of fluoride. On the first occasion five patients-all with extensive diseasewere found to be in negative balance (between 100 and 300 mg. calcium per day) whereas three others with restricted disease were in positive balance. After 2-3 months of fluoride, four of the five patients previously in negative balance were in positive balance, and two of those in positive balance were in more positive balance (fig. 1). In the other two patients the balance did not change. Further studies are being arranged in these and additional patients to see whether the balances are maintained on a lower dose of fluoride.
mality of the lesion in Paget’s disease remains unknown. Many of the effects of fluoride intoxication of bone mimic the histological appearances of Paget’s disease even to a type of mosaic formation (Weatherall and Weidmann 1959). How fluorides produce the effects reported here, the site of their action, and the toxic effects which may mitigate their benefit, are questions which remain to be clarified by further study.
Summary Sixteen patients with Paget’s disease have been given fluoride for periods up to a year, and the effects on bone pain, calcium balance, and external counting of calcium-47 are given. Fourteen of the patients gained sustained relief from their bone pain some 4-6 weeks after they had started taking fluoride, and this was sufficient to decrease the disability in many of them. In six out of eight patients fluorides changed negative calcium balances to positive ones, or made positive balances more positive. In two patients, there was no
significant change. The ratio of the counts of calcium-47 between normal and abnormal sides before treatment was between 2 and 6, and this ratio fell with fluoride administration. After 4-6 months six patients had ratios within normal limits. It is a pleasure to acknowledge the help of Prof. R. A. McCance, F.R.S., who first suggested this investigation; and of Dr. R. D. Montgomery, Sister P. F. Hennessy, and Nurse C. Alford. I am indebted to Mr. D. Southgate, who undertook the calcium determinations; to Mr. R. Pope and Miss T. M. Reynolds for their help in the external counting of calcium-47; and to Dr. W. A. Fell, Dr. R. R. P. Hayter, Dr. D. G. Bratherton, and Dr. P. T. Chopping, who referred patients to me. REFERENCES
Goldenberg, H., Sobel, A. E. (1951) Proc. Soc. exp. Biol., N.Y. 78, 719. Rich, C., Ensinck, J. (1961) Nature, Lond. 191, 184. Weatherall, J. A., Weidmann, S. M. (1959) J. Path. Bact. 67, 233. Weidmann, S. M., Weatherall, J. A. (1959) ibid. p. 243. Whitehead, R. G. (1959) ibid. p. 435. —
—
KETOSIS AND BODY-WEIGHT
External Counting with Calcium-47
M. E. CAREY
On their first test, all the patients had an external ratio of counts in normal and abnormal bones of between 2 and 6. On the second occasion, usually after 6-8 weeks of fluoride, the ratios were reduced in all cases. The results in two patients are given in fig. 2. In six patients in whom a third count was made the reduction in the ratio continued, and the ratio was normal within 4-6 months.
B.Sc. Lond. CHIEF DIETITIAN
T. R. E. PILKINGTON M.D. Lond., M.R.C.P. SENIOR LECTURER
E. TITTERINGTON B.Sc. N.Z. RESEARCH ASSISTANT
Discussion
,
Despite the reports on the skeletal changes in chronic fluorosis, and the experimental studies of Weidmann and Weatherall (1959) and others, the mechanism of the action of fluoride on bone still remains obscure. Weidmann et al. (1959) showed that fluoride partly replaces carbonate and hydroxyl ions in bone salt, and they suggested that the observed increase in magnesium might be due to the formation of MgF2. It is unlikely that the changes in the chemical composition of the bones by themselves explain the pathological changes found in chronic fluoride intoxication. Goldenberg and Sobel (1951) have shown that fluoride at the level of 10-4M (1-9 p.p.m.) blocks enolase activity, but that, in the absence of magnesium, 10-3 M of fluoride enhances rather than depresses the rate of in-vitro calcification. Preliminary studies in the present series show no histological evidence of reduced osteoclastic activity in bone after the administration of fluorides. The position is further complicated because the basic abnor-
MEDICAL
UNIT,
ST.
GEORGE’S HOSPITAL, LONDON, S.W.1
FROM time to time claims have been made that the metabolism of fat people differs qualitatively from that of people of normal build. McClellan et al. (1928) reported that, in 1 obese man, the threshold for the development of ketonuria was higher than in 5 normal subjects. No such difference between fat and thin was found by Lauter and Neuenschwander-Lemmer (1936): after two days on a similar diet the mean blood-ketones in 12 thin subjects was 8-2 mg. per 100 ml. (± 1-8) compared with 7-5 mg. (::1::: 0-95) in 17 fat subjects. In 1937 MacKay and Sherrill combined their own experience with that of Folin and Denis (1915) and Deuel and Gulick (1932) and showed that, after a fast of four or five days, the same degree of ketonuria developed in both obese and thin subjects. On the other hand, Kekwick et al. (1959) reported that obese subjects on low-calorie highfat diets became much less ketotic than normal subjects. z2
1190 DETAILS
OF THE
Discussion
11 SUBJECTS STUDIED
Our findings support those who have denied that there are metabolic differences between obese and non-obese people. Contrary results can perhaps best be explained by surreptitious eating-to which the obese are notoriously liable unless very carefully supervised.
Summary On low-calorie high-fat diets, fat and thin subjects developed the same levels of ketones in the blood. We wish to thank the board of governors of St. George’s Hospital for a generous grant; and we are also grateful to Sister M. Hall and the nursing staff, and the dietitians, Mrs. H. M. Adhihetty and Miss D. M. French, for their devoted service. REFERENCES
Their observations have been cited by Passmore (1961) evidence of the only known metabolic abnormality of the obese. We therefore decided to reinvestigate this problem. as
Deuel, H. J., Gulick, M. (1932) J. biol. Chem. 96, 25. Folin, O., Denis, W. (1915) ibid. 21, 183. Kekwick, A., Pawan, G. L. S., Chalmers, T. (1959) Lancet, ii, 1157. Lauter, S., Neuenschwander-Lemmer, N. (1936) Z. ges. exp. Med. 99, 745. McClellan, W. S., Spencer, H. J., Falk, E. A., Du Bois, E. F. (1928) J. biol. Chem. 80, 639. MacKay, E. M., Sherrill, J. W. (1937) Endocrinology, 21, 677. Passmore, R. (1961) Lancet, i, 839. Van Slyke, D. D. (1917) J. biol. Chem. 32, 455. Fitz, R. (1917) ibid. p. 495. (1919) ibid. 39, 23. —
Subjects and Methods Of 11 healthy subjects studied in the metabolic unit, 5 were obese and 6 of normal build (see table). The diet given supplied approximately 1000 calories and consisted of fat 102-0 g., carbohydrate 24-0 g., and protein
—
—
PREDNISOLONE PHOSPHATE IN RHEUMATOID ARTHRITIS
13 9 g. Blood was taken between 10 and 11 A.M., after breakfast at about 8 A.M. Total blood-ketones were estimated by the method of Van Slyke and Fitz (1917, 1919).
A NEW APPROACH TO STEROID-INDUCED DYSPEPSIA
B. A. LATHAM Cantab., M.R.C.P.
Results
M.B.
The accompanying figure shows that there is no difference between the blood-levels of " acetone " in the fat and the thin. We only once encountered failure of the diet to produce ketosis-in a thin man (not shown in the figure) who, when challenged, admitted to cheating
by eating
sweets.
. We therefore decided to test how little glucose was needed to reduce the ketosis produced by such a diet. For this we chose subject 4 (fat) and subject 10 (thin). Both were ketotic by the sixth day on the above diet. On the next three days we added to their breakfast 5 g., 10 g., and 15 g. of glucose. The ketosis was considerably reduced (see figure).
Blood-ketone levels, measured calorie ketogenic diet.
as
acetone, in 11 subjects
on a
1000-
REGISTRAR
R. M. MASON D.M. Oxon., F.R.C.P. PHYSICIAN
DEPARTMENT OF PHYSICAL MEDICINE AND REGIONAL RHEUMATISM CENTRE, THE LONDON HOSPITAL, LONDON, E.1
DYSPEPSIA, with
or without frank ulceration, has long recognised as a troublesome and often serious complication of steroid therapy in rheumatoid arthritis. Berntsen and Freyberg (1961) found that 19% of 183 patients with rheumatoid arthritis, treated with steroids for an average of ten years, had radiologically proven gastrointestinal ulceration, and 2 of 18 deaths in the series followed perforation of gastric ulcers. Morton (1958) reported 41 instances of peptic ulceration (including haemorrhage from an unknown source) in 1034 patients
been
with rheumatoid arthritis from’ ten British centres who had been treated with corticotrophin or steroids for an unspecified period-an incidence of 4%. Many of the patients in both series may be assumed to have been on salicylates also, which alone might have induced ulceration. But Baragar and Duthie (1960) found that only 3 out of 244 patients (1-2%) with rheumatoid arthritis followed for about six years, most of whom were on regular doses of aspirin, showed evidence of peptic ulceration whilst on this drug. Unless it is argued that rheumatoid arthritis protects patients from peptic ulceration, some patients with rheumatoid arthritis may be expected to have peptic ulceration as a result of whatever causes this condition in the general population. Dyspepsia and peptic ulceration have been assumed to be induced by the systemic activity of absorbed corticosteroid, but West (1959) suggested that steroid given by mouth might affect the stomach wall directly. He therefore treated 15 patients on prednisolone complaining of dyspepsia with an enteric-coated preparation and found