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CALCIUM INFUSION IN PAINFUL PAGET'S DISEASE OF BONE
372 ANKLE REFLEX AND THYROID FUNCTION SIR,-Fowler et all pointed out for the first time that the relaxation phase of the ankle reflex is prolonged in over 90% of patients with anorexia nervosa. We were very interested because we recently saw a 14-year-old boy with classical anorexia nervosa who also had delay in the halfrelaxation-time of his ankle reflex (420 milliseconds). We would, however, like to take exception to the first " The measurement of the duration sentence of the article: of the ankle reflex is a valuable test of thyroid function." We realise that the literature on this test is somewhat confusing, but we have completed a study in which the thyroid status in a large group of patients was established unequivocally, clinically and by all the routinely used thyroid-function tests, and we found that the ankle-jerk was prolonged in only 53% of cases of hypothyroidism. A total of 153 patients had their ankle-reflex halfrelaxation-time measured by the photoelectric-cell technique (photomotogram). All the patients had been referred for a 1311 uptake and/or scan. In addition to the iodine studies, all were seen by three endocrinologists with experience in thyroid problems, and had blood taken for the following tests of thyroid function: protein-bound iodine,
thyroxine by column, thyroxine by binding displacement, free thyroxine, and thyroid antibodies. The final diagnosis in each
all the available data. The final diagnoses were: 83 euthyroid, 44 hyperthyroid, and 19 hypothyroid. In 7 cases no definite diagnosis could be made. Our normal range for the photomotogram, determined in 30 euthyroid hospital employees, was 260-380 milliseconds. 77 (93%) of the patients who were euthyroid had ankle-jerk relaxation-times within this range. However, 9 (47%) of the 19 hypothyroid patients also had ankle-jerk half-relaxation-times within that normal range. Therefore, the photomotogram was abnormal in only 53% of hypothyroid patients. The photomotogram was normal in 15 of the 44 hyperthyroid patients, being abnormally fast in the remaining 29 (66%). It seems, therefore, that the delay,in ankle-reflex relaxation-time is a better test of the presence of anorexia nervosa or of hyperthyroidism than it is of hypothyroidism. There are at least four techniques for measuring the half-relaxation-time of the ankle-jerk, but it is generally agreed that the photomotogram is the most sensitive method. Literature on the usefulness of measurement in diagnosing hypothyroidism in particular is quite controversial. In most papers the hypothyroid status of the patients was assessed clinically, with the aid of one or two laboratory tests. Our results, based on clinical evidence plus six tests of thyroid function, correlate well with those of Costin et al.,2 and Van Middlesworth,3 who also base their diagnosis of hypothyroidism on more than one test of thyroid function. IAN R. HART Department of Metabolism, KAMAL KUWAYTI Ottawa Civic Hospital, S. A. KHAN. Ottawa, Ontario K1Y 4E9. case was
based
on
* ** We showed this letter to Dr Fowler and his colleagues, whose reply follows.-ED. L. SiR,—Dr Hart kindly attributes to us the discovery of the prolonged ankle reflex in anorexia nervosa. We did point out in our paper4 that a prolonged ankle reflex was first noted in two patients with anorexia nervosa by Gooding5 in 1969. We are puzzled by Dr Hart’s observations on the value 1. Fowler, P. B. S., Banim, S. O., Ikram, H. Lancet, 1972, ii, 307. 2. Costin, G., Kaplan, S. A., Ling, S. M. J. Pediat. 1970, 76, 277. 3. Van Middlesworth, L. in Clinical Endocrinology II (edited by E. B. Astwood and C. E. Cassidy). New York, 1968. 4. Fowler, P. B. S., Banim, S. O., Ikram, H. Lancet, 1972, ii, 307. 5. Gooding, G. T. Br. J. clin. Pract. 1969, 23, 40.
of the ankle-reflex time (A.J.T.) in hypothyroidism. We have found that prolongation of the A.J.T. is a nearly constant finding in hypothyroidism when a satisfactory recording can be made. The A.J.T. in preclinical hypothyroidism is more interesting. Conventional tests of thyroid function in autoimmune thyroiditis are normal during the stage of preclinical hypothyroidism, but there is often a hyperlipidxmia, and thyrotrophin levels are raised, with a reduced thyroid reserve as judged by the effect of stimulation with thyrotrophin. The A.J.T. in preclinical hypothyroidism is often normal but may be 360-380 milliseconds to half relaxation. We therefore view with suspicion a recording of 360 milliseconds. Although it is now increasingly accepted that some patients with coronary-artery disease have preclinical hypothyroidism and that patients with preclinical hypothyroidism may be prevented from developing coronaryartery disease, the frequency of this condition in the general population is not known. Frank hypothyroidism, borderline hypothyroidism, and a proportion of patients with preclinical hypothyroidism could be detected by measurement of the A.J.T. in the general population. The A.J.T. could also be compared in patients with and without ischxmic heart-disease. Charing Cross Hospital, London WC2N 4DZ.
P. B. S. FOWLER S. O. BANIM H. IKRAM.
CALCIUM INFUSION IN PAINFUL PAGET’S DISEASE OF BONE
SiR,—Your columns have contained many reports of advances in the treatment of Paget’s disease-namely,
recent
thyrocalcitonin, diphosphonates, glucagon, and the cytotoxic antibiotics, mithramycin and actinomycin D. Each of these, although influencing Paget’s disease clinically and biochemically, have limitations for general use. It was thought that the intravenous infusion of high doses of calcium ions may also influence Paget’s disease, perhaps through a direct action on affected bone, or through the ability to increase endogenous thyrocalcitonin output. 9 patients with chronically painful Paget’s disease of at least one year’s standing, their pain unrelated to joint degeneration or bone infractions, were admitted to hospital and given infusions of calcium gluconate, following the regimen of Pak et al. They received daily for ten days 15 mg. of calcium per kg. body-weight, diluted to 1 litre with saline, over
four hours. Calcium output in the urine
was
measured.
Radioisotope scans and bone biopsies from areas of known Paget’s disease were performed before and after the infusions. Electrocardiograph monitoring was performed on the first day of infusion. An attempt was made to keep the patients’ physical activity as normal as possible. Early results have been encouraging. 8 of the patients stated they had striking relief from pain after the third day of infusion and relief had persisted sixteen weeks after the infusions ceased. They especially noticed they were able to sleep at night without awakening in pain. Their mobility was increased and walking became much less painful. 1 patient had no change in her symptoms. 8 patients had raised serum-alkaline-phosphatase, which fell by at least 30% during and after the infusions. No constant change in the histological appearances of bone or radioisotope scanning was observed in this group of patients. There were no serious complications of calcium infusion; 1 patient was mildly confused for several hours after the infusions, which left no after-effects. Thus, the infusion of calcium has been shown to 1.
cause a
Pak, C. Y., Evens, R., Jowsey, J., et al. Am. J. Med. 1969, 47, 7.
373 loss of symptoms in this group of patients. The fall in serumalkaline-phosphatase is also of interest in that calcium may affect bone turnover in Paget’s disease. This is a preliminary report and the patients are now being followed to assess the long-term results of calcium infusions. 9 Norwood New
Avenue, Lindfield, South Wales, Australia.
R. SEKEL.
SIGNIFICANCE OF VARIATION IN SELECTIVITY OF PROTEINURIA
SIR,-It is generally believed that the selectivity of proteinuria remains relatively constant in individual patients with the nephrotic syndrome. However, the few serial studies which provide the evidence for this spanned short periods only, never exceeding two years.I During the past six years our investigation of selectivity has included 22 children in each of whom at least 4 determinations have been made over periods of not less than three years. We wish to report, briefly, the findings in 7 children in whom the selectivity steadily declined. The method used was similar to that of Joachim et al.,2 the ratios of urine/plasma concentration (relative clearances) of 4 proteins-orosomucoid, albumin, transferrin, and IgG-being determined by double immunodiffusion. When present in the urine in sufficient concentration, Ct2-macroglobulin (Ct2M) was also measured. The selectivity was calculated as the angle 6 subtended by the regression of log protein clearance (expressed as a percentage transferrin clearance) on log protein molecular weight. The results were designated 64 when only the first 4 proteins were present, and 6 when all 5 were detected. A decline of 64 exceeding 15°, which is outside the limits of experimental error of the method, was observed in 7 children. Five had focal glomerulosclerosis (F.G.S.), 1 membranoproliferative glomerulonephritis (M.P.G.N.), and 1 Alport’s syndrome. Furthermore, where Ct2M was present and both 64 and 6could be calculated on the same urine specimens, these often differed. The results of serial studies show that this difference follows two distinct patterns. In F.G.S., 64 was usually lower than 65, the gap increasing with time, whereas in M.P.G.N., 64 usually exceeded 85and the difference remained relatively constant. This discrepancy could be due to an anomaly in the clearance of either IgG or C(2M. To investigate this the regression slopes based on five proteins (65) were recalculated with the IgG clearance omitted; the new angle of regression is designated 64M. Serial values of 64M and 85 in individual patients now showed close agreement, suggesting that in patients where 84 and 6differed significantly (see accompanying figure), it was the IgG clearance which was at fault. Discussion of these findings with Prof. J. Hardwicke led to the suggestion that some IgG in these patients may be present as fragments of smaller than normal molecular weight, which are preferentially filtered through the glomeruli. This is supported by the fact that, in one of our patients, the regression angle of relative clearances determined by ’Sephadex’ G200 column chromato’graphy,3 which separates according to molecular size, was almost identical with 65 and 64M determined immunochemically, and differed strikingly from 64. The correlation of declining selectivity with morphological findings is of great interest. In both F.G.S. and Alport’s syndrome, which account for 6 of our 7 cases, the lesions typically show a segmental distribution which Cameron, J. S. Proc. R. Soc. Med. 1966, 59, 4. Joachim, G. R., Cameron, J. S., Schwartz, M., Becker, J. clin. Invest. 1964, 43, 2332. 3. Hardwicke, J. Clinica chim. Acta, 1965, 12, 89.
1. 2.
E. L.
Results of serial determinations of 6,, 6, and 9M in a child with focal glomerulosclerosis, showing a progressive decline of 64 and separation from 65 and 6gl,q.
becomes diffuse as the disease advances. This is also true of quartan malarial nephropathy,4 in which high relative IgG clearances have also been observedthough not yet
investigated serially. One of the children whom we investigated continued to exhibit a discrepancy between 64 and 65/64M following cadaveric transplantation, when he developed a recurrence of the nephrotic syndrome. Recurrence of F.G.S. in transplanted kidneys was recently demonstrated by Hoyer et al., and their suggestion that this might be explained by a humoral factor would be strongly supported if the presence of IgG fragments in this disease is confirmed. The occurrence of this phenomenon in both F.G.S. and Alport’s syndrome, together with our finding that F.G.S. is the commonest glomerular lesion in the congenital familial nephrotic syndrome in Englandsuggests that the disease may be genetically determined. The Children’s Hospital,
Birmingham
B16 8ET.
R. J. MILLS D. N. RAINE R. H. R. WHITE.
IMMUNOLOGICAL REACTIVITY OF TRANSPLANT RECIPIENTS
SiR,—The papers on kidney-transplant analysis by the London and Leiden transplant groups (Dec. 30, pp. 1381, 1385) were read by us with great interest and some astonishment. Even after careful reading we could not find any evidence to justify the London group’s speculations about the presence of responsiveness genes for HL-A. Our own findings of unresponsiveness in certain transplant recipients were published in The Lancet several months ago7 and were extensively explored and reported in the December issue of Transplantation Proceedings. There is increasing evidence that this state of unresponsiveness is actively induced by blood-transfusions.8 Although the reason for development ofcytotoxins in some patients and induction of unresponsiveness in others may well be controlled by genes, as speculated by us earlier, the data presented by Dr Oliver and his colleagues do not support the postulate. Furthermore, we might point out that the immuno4. 5. 6.
7. 8. 9.
Hendrickse, R. G., Adeniyi, A., Edington, G. M., Glasgow, E. F., White, R. H. R., Houba, V. Lancet, 1972, i, 1143. Soothill, J. F., Hendrickse, R. G. ibid. 1967, ii, 629. Hoyer, J. R., Raij, L., Vernier, R. L., Simmons, R. L., Najarian, J. S., Michael, A. F. ibid. 1972, ii, 343. Moncrieff, M. W., White, R. H. R., Glasgow, E. F., Winterborn, M. H., Cameron, J. S., Ogg, C. S. Clin. Nephrol. (in the press). Opelz, G., Mickey, M. R., Terasaki, P. I. Lancet, 1972, i, 868. Opelz, G., Sengar, D. P. S., Mickey, M. R., Terasaki, P. I. 4th Congress of the Transplantation Society, San Francisco, September, 1972. Transpl. Proc. (in the press).
thyroxine by column, thyroxine by binding displacement, free thyroxine, and thyroid antibodies. The final diagnosis in each
all the available data. The final diagnoses were: 83 euthyroid, 44 hyperthyroid, and 19 hypothyroid. In 7 cases no definite diagnosis could be made. Our normal range for the photomotogram, determined in 30 euthyroid hospital employees, was 260-380 milliseconds. 77 (93%) of the patients who were euthyroid had ankle-jerk relaxation-times within this range. However, 9 (47%) of the 19 hypothyroid patients also had ankle-jerk half-relaxation-times within that normal range. Therefore, the photomotogram was abnormal in only 53% of hypothyroid patients. The photomotogram was normal in 15 of the 44 hyperthyroid patients, being abnormally fast in the remaining 29 (66%). It seems, therefore, that the delay,in ankle-reflex relaxation-time is a better test of the presence of anorexia nervosa or of hyperthyroidism than it is of hypothyroidism. There are at least four techniques for measuring the half-relaxation-time of the ankle-jerk, but it is generally agreed that the photomotogram is the most sensitive method. Literature on the usefulness of measurement in diagnosing hypothyroidism in particular is quite controversial. In most papers the hypothyroid status of the patients was assessed clinically, with the aid of one or two laboratory tests. Our results, based on clinical evidence plus six tests of thyroid function, correlate well with those of Costin et al.,2 and Van Middlesworth,3 who also base their diagnosis of hypothyroidism on more than one test of thyroid function. IAN R. HART Department of Metabolism, KAMAL KUWAYTI Ottawa Civic Hospital, S. A. KHAN. Ottawa, Ontario K1Y 4E9. case was
based
on
* ** We showed this letter to Dr Fowler and his colleagues, whose reply follows.-ED. L. SiR,—Dr Hart kindly attributes to us the discovery of the prolonged ankle reflex in anorexia nervosa. We did point out in our paper4 that a prolonged ankle reflex was first noted in two patients with anorexia nervosa by Gooding5 in 1969. We are puzzled by Dr Hart’s observations on the value 1. Fowler, P. B. S., Banim, S. O., Ikram, H. Lancet, 1972, ii, 307. 2. Costin, G., Kaplan, S. A., Ling, S. M. J. Pediat. 1970, 76, 277. 3. Van Middlesworth, L. in Clinical Endocrinology II (edited by E. B. Astwood and C. E. Cassidy). New York, 1968. 4. Fowler, P. B. S., Banim, S. O., Ikram, H. Lancet, 1972, ii, 307. 5. Gooding, G. T. Br. J. clin. Pract. 1969, 23, 40.
of the ankle-reflex time (A.J.T.) in hypothyroidism. We have found that prolongation of the A.J.T. is a nearly constant finding in hypothyroidism when a satisfactory recording can be made. The A.J.T. in preclinical hypothyroidism is more interesting. Conventional tests of thyroid function in autoimmune thyroiditis are normal during the stage of preclinical hypothyroidism, but there is often a hyperlipidxmia, and thyrotrophin levels are raised, with a reduced thyroid reserve as judged by the effect of stimulation with thyrotrophin. The A.J.T. in preclinical hypothyroidism is often normal but may be 360-380 milliseconds to half relaxation. We therefore view with suspicion a recording of 360 milliseconds. Although it is now increasingly accepted that some patients with coronary-artery disease have preclinical hypothyroidism and that patients with preclinical hypothyroidism may be prevented from developing coronaryartery disease, the frequency of this condition in the general population is not known. Frank hypothyroidism, borderline hypothyroidism, and a proportion of patients with preclinical hypothyroidism could be detected by measurement of the A.J.T. in the general population. The A.J.T. could also be compared in patients with and without ischxmic heart-disease. Charing Cross Hospital, London WC2N 4DZ.
P. B. S. FOWLER S. O. BANIM H. IKRAM.
CALCIUM INFUSION IN PAINFUL PAGET’S DISEASE OF BONE
SiR,—Your columns have contained many reports of advances in the treatment of Paget’s disease-namely,
recent
thyrocalcitonin, diphosphonates, glucagon, and the cytotoxic antibiotics, mithramycin and actinomycin D. Each of these, although influencing Paget’s disease clinically and biochemically, have limitations for general use. It was thought that the intravenous infusion of high doses of calcium ions may also influence Paget’s disease, perhaps through a direct action on affected bone, or through the ability to increase endogenous thyrocalcitonin output. 9 patients with chronically painful Paget’s disease of at least one year’s standing, their pain unrelated to joint degeneration or bone infractions, were admitted to hospital and given infusions of calcium gluconate, following the regimen of Pak et al. They received daily for ten days 15 mg. of calcium per kg. body-weight, diluted to 1 litre with saline, over
four hours. Calcium output in the urine
was
measured.
Radioisotope scans and bone biopsies from areas of known Paget’s disease were performed before and after the infusions. Electrocardiograph monitoring was performed on the first day of infusion. An attempt was made to keep the patients’ physical activity as normal as possible. Early results have been encouraging. 8 of the patients stated they had striking relief from pain after the third day of infusion and relief had persisted sixteen weeks after the infusions ceased. They especially noticed they were able to sleep at night without awakening in pain. Their mobility was increased and walking became much less painful. 1 patient had no change in her symptoms. 8 patients had raised serum-alkaline-phosphatase, which fell by at least 30% during and after the infusions. No constant change in the histological appearances of bone or radioisotope scanning was observed in this group of patients. There were no serious complications of calcium infusion; 1 patient was mildly confused for several hours after the infusions, which left no after-effects. Thus, the infusion of calcium has been shown to 1.
cause a
Pak, C. Y., Evens, R., Jowsey, J., et al. Am. J. Med. 1969, 47, 7.
373 loss of symptoms in this group of patients. The fall in serumalkaline-phosphatase is also of interest in that calcium may affect bone turnover in Paget’s disease. This is a preliminary report and the patients are now being followed to assess the long-term results of calcium infusions. 9 Norwood New
Avenue, Lindfield, South Wales, Australia.
R. SEKEL.
SIGNIFICANCE OF VARIATION IN SELECTIVITY OF PROTEINURIA
SIR,-It is generally believed that the selectivity of proteinuria remains relatively constant in individual patients with the nephrotic syndrome. However, the few serial studies which provide the evidence for this spanned short periods only, never exceeding two years.I During the past six years our investigation of selectivity has included 22 children in each of whom at least 4 determinations have been made over periods of not less than three years. We wish to report, briefly, the findings in 7 children in whom the selectivity steadily declined. The method used was similar to that of Joachim et al.,2 the ratios of urine/plasma concentration (relative clearances) of 4 proteins-orosomucoid, albumin, transferrin, and IgG-being determined by double immunodiffusion. When present in the urine in sufficient concentration, Ct2-macroglobulin (Ct2M) was also measured. The selectivity was calculated as the angle 6 subtended by the regression of log protein clearance (expressed as a percentage transferrin clearance) on log protein molecular weight. The results were designated 64 when only the first 4 proteins were present, and 6 when all 5 were detected. A decline of 64 exceeding 15°, which is outside the limits of experimental error of the method, was observed in 7 children. Five had focal glomerulosclerosis (F.G.S.), 1 membranoproliferative glomerulonephritis (M.P.G.N.), and 1 Alport’s syndrome. Furthermore, where Ct2M was present and both 64 and 6could be calculated on the same urine specimens, these often differed. The results of serial studies show that this difference follows two distinct patterns. In F.G.S., 64 was usually lower than 65, the gap increasing with time, whereas in M.P.G.N., 64 usually exceeded 85and the difference remained relatively constant. This discrepancy could be due to an anomaly in the clearance of either IgG or C(2M. To investigate this the regression slopes based on five proteins (65) were recalculated with the IgG clearance omitted; the new angle of regression is designated 64M. Serial values of 64M and 85 in individual patients now showed close agreement, suggesting that in patients where 84 and 6differed significantly (see accompanying figure), it was the IgG clearance which was at fault. Discussion of these findings with Prof. J. Hardwicke led to the suggestion that some IgG in these patients may be present as fragments of smaller than normal molecular weight, which are preferentially filtered through the glomeruli. This is supported by the fact that, in one of our patients, the regression angle of relative clearances determined by ’Sephadex’ G200 column chromato’graphy,3 which separates according to molecular size, was almost identical with 65 and 64M determined immunochemically, and differed strikingly from 64. The correlation of declining selectivity with morphological findings is of great interest. In both F.G.S. and Alport’s syndrome, which account for 6 of our 7 cases, the lesions typically show a segmental distribution which Cameron, J. S. Proc. R. Soc. Med. 1966, 59, 4. Joachim, G. R., Cameron, J. S., Schwartz, M., Becker, J. clin. Invest. 1964, 43, 2332. 3. Hardwicke, J. Clinica chim. Acta, 1965, 12, 89.
1. 2.
E. L.
Results of serial determinations of 6,, 6, and 9M in a child with focal glomerulosclerosis, showing a progressive decline of 64 and separation from 65 and 6gl,q.
becomes diffuse as the disease advances. This is also true of quartan malarial nephropathy,4 in which high relative IgG clearances have also been observedthough not yet
investigated serially. One of the children whom we investigated continued to exhibit a discrepancy between 64 and 65/64M following cadaveric transplantation, when he developed a recurrence of the nephrotic syndrome. Recurrence of F.G.S. in transplanted kidneys was recently demonstrated by Hoyer et al., and their suggestion that this might be explained by a humoral factor would be strongly supported if the presence of IgG fragments in this disease is confirmed. The occurrence of this phenomenon in both F.G.S. and Alport’s syndrome, together with our finding that F.G.S. is the commonest glomerular lesion in the congenital familial nephrotic syndrome in Englandsuggests that the disease may be genetically determined. The Children’s Hospital,
Birmingham
B16 8ET.
R. J. MILLS D. N. RAINE R. H. R. WHITE.
IMMUNOLOGICAL REACTIVITY OF TRANSPLANT RECIPIENTS
SiR,—The papers on kidney-transplant analysis by the London and Leiden transplant groups (Dec. 30, pp. 1381, 1385) were read by us with great interest and some astonishment. Even after careful reading we could not find any evidence to justify the London group’s speculations about the presence of responsiveness genes for HL-A. Our own findings of unresponsiveness in certain transplant recipients were published in The Lancet several months ago7 and were extensively explored and reported in the December issue of Transplantation Proceedings. There is increasing evidence that this state of unresponsiveness is actively induced by blood-transfusions.8 Although the reason for development ofcytotoxins in some patients and induction of unresponsiveness in others may well be controlled by genes, as speculated by us earlier, the data presented by Dr Oliver and his colleagues do not support the postulate. Furthermore, we might point out that the immuno4. 5. 6.
7. 8. 9.
Hendrickse, R. G., Adeniyi, A., Edington, G. M., Glasgow, E. F., White, R. H. R., Houba, V. Lancet, 1972, i, 1143. Soothill, J. F., Hendrickse, R. G. ibid. 1967, ii, 629. Hoyer, J. R., Raij, L., Vernier, R. L., Simmons, R. L., Najarian, J. S., Michael, A. F. ibid. 1972, ii, 343. Moncrieff, M. W., White, R. H. R., Glasgow, E. F., Winterborn, M. H., Cameron, J. S., Ogg, C. S. Clin. Nephrol. (in the press). Opelz, G., Mickey, M. R., Terasaki, P. I. Lancet, 1972, i, 868. Opelz, G., Sengar, D. P. S., Mickey, M. R., Terasaki, P. I. 4th Congress of the Transplantation Society, San Francisco, September, 1972. Transpl. Proc. (in the press).