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WHEN DO GALLSTONES MATTER?
1186 reduces the incidence of strokes. Will better control of plasmapotassium levels further reduce the incidence? Department of Medicine, University of Benin Teaching Hospital, Benin City, Nigeria
C. O. ANAH
WHEN DO GALLSTONES MATTER?
SIR,-In your editorial (May 15, p. 1061) you suggest that the demonstration of gallstones in patients with flatulent dyspepsia serves no purpose. This somewhat surprising statement seems to be based on the evidence that such symptoms are nonspecific and may occur in the absence of gallstones; and you conclude that more careful selection of patients for cholecystectomy is required. One can understand the need for caution in advising cholecystectomy in patients whose symptoms include those of gastro-cesophageal reflux, for the symptomatic response to surgery is frequently unsatisfactory in such cases,’ but it is certainly debatable whether such caution is justified in patients with flatulent dyspepsia. In a prospective study of patients undergoing cholecystectomy for gallstones it has been shown that flatulent dyspepsia is relieved or cured in 80% of cases.2 Any improvement on these figures by better case selection requires the facility to demonstrate an alternative pathological process or cause of dyspeptic symptoms. It is alleged that duodenogastric reflux and bile gastritis may cause non-specific dyspeptic symptoms3 but these are very common findings in patients with gallstonesand the demonstration of abnormal pyloric function does not seem to be helpful in the case selection for
cholecystectomy. I do not share your view that the search for gallstones in patients with flatulent dyspepsia is without purpose. Indeed, there is a sense of relief when gallstones are found in such cases, for very high incidence of symptomatic relief or improvement which occurs after cholecystectomy is much more than one can achieve with any form of therapy in patients who have X-ray-negative dyspepsia. University Surgical Unit, Royal Infirmary,
THOMAS T. IRVIN
Sheffield S6 3DA
the patient will be a victim of dual vascular complicationsthose of diabetes and hypertension? This important facet (deterioration of glucose tolerance on prolonged diuretic therapy for hypertension) needs to be further investigated to see whether or not these patients develop complications similar to those of diabetes mellitus. Department of Medicine, Rhode Island Hospital, Providence, Rhode Island 02902, U.S.A.
C. V. S. RAM
BONE RESORPTION BY BREAST-CANCER TISSUE
SIR,-Dr Powles and his colleagues (March 20, p. 608) that the incidence of hypercalcxmia and bone metascorrelated with the ability of the tumour to release 4’Ca from bone in vitro. Prostaglandins can produce bone resorption in vitro,’ and tissues which release prostaglandin-like substances can cause bone resorption both in vivo and in vitro.2 A raised concentration of the metabolite of prostaglandin E has been found in the urine of patients with hypercalcxmia and malignant tumours, both the hypercalcaemia and the excretion of the metabolite being reduced by indomethacin treatment. The release of prostaglandin may explain the hypercalcaemia seen in some cancers. If the tumour is small and localised there may be no hypercalcxmia since any prostaglandins released into the circulation would be rapidly metabolised. However, the tumour should be capable of causing bone resorption in vitro where no mechanism exists for the rapid destruction of prostaglandins if prostaglandin production is an inherent property of the tumours. The following experiments were done to investigate this hypothesis. Non-necrotic tumour obtained by breast biopsy was cut into 1 mm cubes (15-25 mg) and cultured for 2 days in 3 H of medium. This spent medium was then diluted with an equal volume of fresh medium, and 1 - 5 ml of mixture was added to half calvaria from 6-day-old albino mice which had previously been incubated for 48 h. The control half calvaria contained 1 -5 ml of fresh medium. The resorption was estimated by measuring the difference between the calcium concentration of the medium of the experimental half and that of the control bone. The initial 48 h incubation was used to correct the results for any difference between the half calvaria. The medium and method used for calculating the results have already been de-
reported tases
scribed.2 GLUCOSE INTOLERANCE AND DIURETICS
SIR,-Dr Kohner and her colleagues (March 13, p. 564) have reported that prolonged treatment of hypertension with oral thiazide diuretics is associated with deterioration in glucose tolerance. This report is of great concern to the physician who deals with hypertensive patients, mostly on oral diuretics. Of particular interest is the fact that the same group of patients, when tested after only one year of oral thiazide therapy had not shown glucose intolerance.5 Now these workers report glucose intolerance in the same group of patients after they had been on oral diuretics for 6 years. The results have to be accepted though the later sample was much smaller than the one tested 6 years earlier. These findings suggest a time-dependent glucose intolerance. We need to know whether the patients with thiazide-associated glucose intolerance are subject to the same course and complications as those of classical diabetes mellitus. If this is so, it would mean a setback to the fairly effective diuretic therapy of hypertension. Indeed, if patients with thiazide-induced glucose intolerance do develop the vascular complications of classical diabetes mellitus then would it not mean that 1. 2. 3. 4.
Barber, J. R., Alexander-Williams, J. Br. J. Surg. 1974, 61, 346. Kingston, R. D., Windsor, C. W. O. ibid. 1975, 62, 231. Johnson, A. G. Postgrad. med. J. 1971, 47, 767. Capper, W. M., Butler, T. J., Kilby, J. O., Gibson, M. J. Lancet, 1967, i, 413.
5. Kohner, E. M.,
Dollery, C. T., Lowy, C., Schumer,
B.
Lancet, 1971, i, 986.
For each tumour between four and seven cultures were done, and results were expressed as the difference in calcium concentration of the medium between experimental and control bones. Only a small fraction of the tumours studied released a substance or substances into the medium capable of causing bone resorption when cultured with 4-day-old mouse calvaria. The difference between experimental and control bones was significant for only 3 out of 8 samples of carcinoma and for only 2 out of 11samples of benign lesions. This is in striking contrast with the intraosseous dental cyst where spent incubation media from cyst cultures was capable of producing bone resorption even when diluted 100 fold with fresh medium.2 Although a higher proportion of malignant tumours were active only one malignant tumour was extremely active in producing bone resorption, the experimental-control difference being 0.93±0.23 mg/dl (mean ±s,E.m. for seven cultures). The lack of efficacy of the spent tumour medium to cause bone resorption could be due either to a lack of bone-resorbing substances or to the presence of inhibitors of bone resorption. If inhibitors were not present the release of significant amounts of prostaglandins into the medium by the tumours is unlikely since small quantities of prostaglandins E1 1. 2.
Klein, D. C., Raisz, L. G. Endocrinology, 1970, 86, 1436. Harris, M., Jenkins, M. V., Bennett, A., Wills, M. R. Nature, 1973, 245,
3.
Seyberth, H. W., Segre, G. V., Morgan, J. L., Sweeyman, B. J., Potts, J. T., Oats, J. A. New Engl. J. Med. 1975, 293, 1278.
213.
C. O. ANAH
WHEN DO GALLSTONES MATTER?
SIR,-In your editorial (May 15, p. 1061) you suggest that the demonstration of gallstones in patients with flatulent dyspepsia serves no purpose. This somewhat surprising statement seems to be based on the evidence that such symptoms are nonspecific and may occur in the absence of gallstones; and you conclude that more careful selection of patients for cholecystectomy is required. One can understand the need for caution in advising cholecystectomy in patients whose symptoms include those of gastro-cesophageal reflux, for the symptomatic response to surgery is frequently unsatisfactory in such cases,’ but it is certainly debatable whether such caution is justified in patients with flatulent dyspepsia. In a prospective study of patients undergoing cholecystectomy for gallstones it has been shown that flatulent dyspepsia is relieved or cured in 80% of cases.2 Any improvement on these figures by better case selection requires the facility to demonstrate an alternative pathological process or cause of dyspeptic symptoms. It is alleged that duodenogastric reflux and bile gastritis may cause non-specific dyspeptic symptoms3 but these are very common findings in patients with gallstonesand the demonstration of abnormal pyloric function does not seem to be helpful in the case selection for
cholecystectomy. I do not share your view that the search for gallstones in patients with flatulent dyspepsia is without purpose. Indeed, there is a sense of relief when gallstones are found in such cases, for very high incidence of symptomatic relief or improvement which occurs after cholecystectomy is much more than one can achieve with any form of therapy in patients who have X-ray-negative dyspepsia. University Surgical Unit, Royal Infirmary,
THOMAS T. IRVIN
Sheffield S6 3DA
the patient will be a victim of dual vascular complicationsthose of diabetes and hypertension? This important facet (deterioration of glucose tolerance on prolonged diuretic therapy for hypertension) needs to be further investigated to see whether or not these patients develop complications similar to those of diabetes mellitus. Department of Medicine, Rhode Island Hospital, Providence, Rhode Island 02902, U.S.A.
C. V. S. RAM
BONE RESORPTION BY BREAST-CANCER TISSUE
SIR,-Dr Powles and his colleagues (March 20, p. 608) that the incidence of hypercalcxmia and bone metascorrelated with the ability of the tumour to release 4’Ca from bone in vitro. Prostaglandins can produce bone resorption in vitro,’ and tissues which release prostaglandin-like substances can cause bone resorption both in vivo and in vitro.2 A raised concentration of the metabolite of prostaglandin E has been found in the urine of patients with hypercalcxmia and malignant tumours, both the hypercalcaemia and the excretion of the metabolite being reduced by indomethacin treatment. The release of prostaglandin may explain the hypercalcaemia seen in some cancers. If the tumour is small and localised there may be no hypercalcxmia since any prostaglandins released into the circulation would be rapidly metabolised. However, the tumour should be capable of causing bone resorption in vitro where no mechanism exists for the rapid destruction of prostaglandins if prostaglandin production is an inherent property of the tumours. The following experiments were done to investigate this hypothesis. Non-necrotic tumour obtained by breast biopsy was cut into 1 mm cubes (15-25 mg) and cultured for 2 days in 3 H of medium. This spent medium was then diluted with an equal volume of fresh medium, and 1 - 5 ml of mixture was added to half calvaria from 6-day-old albino mice which had previously been incubated for 48 h. The control half calvaria contained 1 -5 ml of fresh medium. The resorption was estimated by measuring the difference between the calcium concentration of the medium of the experimental half and that of the control bone. The initial 48 h incubation was used to correct the results for any difference between the half calvaria. The medium and method used for calculating the results have already been de-
reported tases
scribed.2 GLUCOSE INTOLERANCE AND DIURETICS
SIR,-Dr Kohner and her colleagues (March 13, p. 564) have reported that prolonged treatment of hypertension with oral thiazide diuretics is associated with deterioration in glucose tolerance. This report is of great concern to the physician who deals with hypertensive patients, mostly on oral diuretics. Of particular interest is the fact that the same group of patients, when tested after only one year of oral thiazide therapy had not shown glucose intolerance.5 Now these workers report glucose intolerance in the same group of patients after they had been on oral diuretics for 6 years. The results have to be accepted though the later sample was much smaller than the one tested 6 years earlier. These findings suggest a time-dependent glucose intolerance. We need to know whether the patients with thiazide-associated glucose intolerance are subject to the same course and complications as those of classical diabetes mellitus. If this is so, it would mean a setback to the fairly effective diuretic therapy of hypertension. Indeed, if patients with thiazide-induced glucose intolerance do develop the vascular complications of classical diabetes mellitus then would it not mean that 1. 2. 3. 4.
Barber, J. R., Alexander-Williams, J. Br. J. Surg. 1974, 61, 346. Kingston, R. D., Windsor, C. W. O. ibid. 1975, 62, 231. Johnson, A. G. Postgrad. med. J. 1971, 47, 767. Capper, W. M., Butler, T. J., Kilby, J. O., Gibson, M. J. Lancet, 1967, i, 413.
5. Kohner, E. M.,
Dollery, C. T., Lowy, C., Schumer,
B.
Lancet, 1971, i, 986.
For each tumour between four and seven cultures were done, and results were expressed as the difference in calcium concentration of the medium between experimental and control bones. Only a small fraction of the tumours studied released a substance or substances into the medium capable of causing bone resorption when cultured with 4-day-old mouse calvaria. The difference between experimental and control bones was significant for only 3 out of 8 samples of carcinoma and for only 2 out of 11samples of benign lesions. This is in striking contrast with the intraosseous dental cyst where spent incubation media from cyst cultures was capable of producing bone resorption even when diluted 100 fold with fresh medium.2 Although a higher proportion of malignant tumours were active only one malignant tumour was extremely active in producing bone resorption, the experimental-control difference being 0.93±0.23 mg/dl (mean ±s,E.m. for seven cultures). The lack of efficacy of the spent tumour medium to cause bone resorption could be due either to a lack of bone-resorbing substances or to the presence of inhibitors of bone resorption. If inhibitors were not present the release of significant amounts of prostaglandins into the medium by the tumours is unlikely since small quantities of prostaglandins E1 1. 2.
Klein, D. C., Raisz, L. G. Endocrinology, 1970, 86, 1436. Harris, M., Jenkins, M. V., Bennett, A., Wills, M. R. Nature, 1973, 245,
3.
Seyberth, H. W., Segre, G. V., Morgan, J. L., Sweeyman, B. J., Potts, J. T., Oats, J. A. New Engl. J. Med. 1975, 293, 1278.
213.