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Abnormal Calcification of Cartilage
847
with isoniazid had the same order of toxicity (and was as effective) as P.A.S. with isoniazid. Local conditions may therefore to some extent influence the incidence of toxic effects, and the Madras report suggests that the extensive use of thiacetazone with isoniazid should be preceded by carefully planned pilot studies to investigate, under local conditions, the toxicity and efficacy of the regimen. Another useful finding from Madras is that the progress of tuberculous patients on chemotherapy can be assessed with reasonable accuracy by simple smear examination of the sputum. Hence the methods for controlling tuberculosis on a wide scale are known. The question is when and how they can be applied-and this is not a purely medical matter. The World Health Organisation and the International Union against Tuberculosis continue to do valuable work,12 but, to carry through the large projects that are needed, a lot more money must be provided. The stresses imposed by rapid growth of population, migration, and industrialisation, together with the growing menace of drug resistance,13 make the situation more urgent. What is needed is not only mass medicine but " individual medicine ", as defined by Dr. CICELY WILLIAMS, 14 on a massive scale. This implies more than diagnosis and treatment: it includes prevention, health education, and supervision of contacts; and, as Dr. WILLIAMS pointed out, immunisation, nutrition, and family planning should also be a part. For some countries this objective might seem impossible: it will certainly remain so as long as priorities in allocating resources remain unchanged. But disease and overpopulation, poverty and ignorance, are real and substantial enemies, and in many parts of the world defences against them are pitifully inadequate. Nevertheless, some developing countries allocate half or more of their annual expenditure to military defence, and the leading nations devote to the same cause the equivalent of twothirds or more of the combined national incomes of all developing countries.15 Meanwhile, the prospects not only for health but for an improvement in the quality of life for many millions remain unrealised. Nor will inefficiency, bureaucracy, poor administration, and corruption, which can severely impede the development of adequate health services in many of the poorer countries,16be overcome without determined, systematic, and sustained effort. As LOWELLputs it, " Times change and we must accept the challenge to change with them, otherwise, because of our default, future generations will continue to endure the unnecessary and costly burden of tuberculosis ". In therapy the decisive breakthrough has been achieved by international cooperative effort, both developed and developing countries making their contribution and deriving benefit. For administrators and legislators, the implications-and the example-are
pointed and pertinent. 12. 13. 14. 15. 16.
See Lancet, 1966, i, 303. Br. med. J. Sept. 17, 1966, p. 656.
Lancet, Sept. 3, 1966, p. 544. UNESCO Courier, November, 1964, p. 5. Tuberculosis (International Union against Tuberculosis), July, 1966, no. 16, p. 4.
Abnormal Calcification of Cartilage SOFT tissues become calcified either when the mineral concentrations in tissue-fluids are abnormally high (as in vitamin-D poisoning and primary hyperparathyroidism) or when some local change in the tissues makes them calcify at normal mineral levels (for example, tuberculous lesions, injuries, and degenerating collagen). Calcification of costal cartilage is common in older people, and calcification of other cartilage has also been noted. The mineral deposit has been assumed to be hydroxyapatite. The subject came into prominence when MCCARTY et al.l described a syndrome which they
termed "pseudo-gout". Examining over 200 specimens of synovial fluid from joints with various arthritic disorders, they found 7 patients whose fluid showed a large number of rod-shaped crystals, 1-20 long, which gave a positive sign of birefringence under polarised light. These were obviously not urate crystals, although the clinical picture was that of gout. They suggested, from evidence which was strongly suggestive but not conclusive, that the crystals were calcium pyrophosphate.2 The infra-red spectrophotometric absorption curves were consistent with various pyrophosphate spectra, and the chemical findings were in keeping with calcium pyrophosphate, although on X-ray fluorescence and emission spectroscopy the picture did not correspond with any of the four known types of calcium pyrophosphate. Further work confirmed that the production of acute arthritis in this syndrome and in true gout was due to a synovitis induced by a certain concentration of crystals.33 A review of the literature disclosed 30 men and 21 with what was probably pseudo-gout. Radio-
women
logical calcification was seen in the shoulder-joint in 25 patients, the intervertebral discs in 22, the wrist in 21, the symphysis pubis in 20, the hip in 19, the elbow in 18, and the ankle in 14. The tendons were often found to be calcified. FAiREs et al. suggested that there was some inherited defect of cartilage metabolism and noted that surgery and diuretic therapy produced acute episodes, as they did in gout. A similar, familial, disease has been described by ZITNAN and SIT’AJ4 under the name " chondrocalcinosis ". LOUGHRIDGE and CALNE 5 described a condition, which they believed to be pseudogout, following renal transplantation, but although X-ray examination and biopsy showed periarticular calcification the nature of the material was not discovered. A syndrome producing gout-like episodes of acute localised soft-tissue inflammation had previously been observed in urxmic patients maintained by periodic haemodialysis. 677 By increasing the uric-acid concentration of the dialysis fluid an acute arthritis was produced. Nodular areas of calcification composed of hydroxyapatite developed in soft tissue both in the wake of acute attacks and, more commonly, without related symptoms. The calcinosis was thought to be, for the most part, a separate affair 1. 2. 3. 4. 5. 6. 7.
McCarty, D. J., Kohn, N. N., Faires, J. S. Ann. intern. Med. 1962, 56, 711. Kohn, N. N., Hughes, R. C., McCarty, D. J., Faires, J. S. ibid. p. 738. Faires, J. S., McCarty, D. J. Lancet, 1962, ii, 682. Zitnan, D., Sit’aj, S. Ann. rheum. Dis. 1963, 22, 142. Loughridge, L. W., Calne, R. Y. ibid. 1966, 25, 371. Caner, J. E. Z.. Decker, J. L. Am. J. Med. 1964, 36, 571. Decker, J. L. Arthritis Rheum. 1965, 8, 840.
848
by hyperphosphatsemia. Calcium deposition phatase, but there is no suggestion of a diminished resembling that seen in chondrocalcinosis has also been alkaline-phosphatase level in the serum of these patients. described in the articular cartilage of hyperparathyroid In fact the serum-alkaline-phosphatase was raised in 5 of the 35 cases of CuRREY et al. In synovial fluid from patients.I> CURREY et awl. investigated 35 patients with joint patients with rheumatoid arthritis and osteoarthrosis the symptoms in whom joint calcification was noted radio- level of alkaline phosphatase does not differ significantly logically. 13 had an acute arthritis, 14 had generalised from that in the blood. There may, however, be a osteoarthrosis (7 with acute episodes), and 3 had poly- specific pyrophosphatase, changes of which are not arthritis similar to rheumatoid arthritis but without shown by determination of the total alkaline phosrheumatoid factor in the blood. 3 had gout, and 2 had phatase. The levels of pyrophosphate and phosphatase hyperparathyroidism. Calcification was found in the in normal and diseased joints require further study. menisci of all patients, and other joints showing such radiographic change were, in order of frequency, the pubis and wrist, and the shoulder and elbow. Joints with Annotations arthritis of rheumatoid type suggested the possibility of a crystal synovitis arising simultaneously in many joints THE PINK SPOT: A RED HERRING? -a picture the authors had seen in a patient with classical LAST year1 we reviewed the conflicting reports about gout. They noted that the syndrome was often associated the excretion of (D.M.P.E.) with periarticular calcification. Examination of synovial in the urine of 3,4-dimethoxyphenylethylamine This compound, schizophrenic patients. fluid was possible in 23 patients: 3 had many crystals of which gave a pink colour when analysed chromatocalcium pyrophosphate, 3 had urate crystals, and 5 had graphically, is of particular interest because its structure is calcium-oxalate crystals. Some crystals with theoptical similar to the hallucinogenic drug, mescaline. These properties of calcium pyrophosphate were seen in 13, initial findings stimulated much interest and research in but they have also been found in other arthropathies and many centres, but further reports, which continue to
induced
of classical gout. MOSKOWITZ and KATZ 10 described 4 cases of chondrocalcinosis coincident with other rheumatic diseases, and 3 of these had small numbers of crystals with the morphological and polarising properties of calcium pyrophosphate. It is of course likely that the patients described by CURREY and his colleagues were a heterogeneous group, and calcification in patients with hyperparathyroidism (where plasmacalcium is high) may have a different basis from other cases in which plasma-calcium is normal. Apart from the crystal synovitis, these studies raise interesting problems of calcium metabolism. Calcium pyrophosphate is found in very small quantities throughout the body (the ratio of pyrophosphate/phosphate in the urine is normally about 1/500), and a suggestion that it may appear locally in joint-fluids in quantities large enough to form crystals poses the question of its origin. Moreover, pyrophosphate is a potent inhibitor of calcification.11 12 Indeed, FLEISH and NEUMAN’s hypothesis 13 of calcification in bone depended on the destruction of pyrophosphate by a raised concentration of alkaline phosphatase. It was suggested that at least two mechanisms were involved in the mineralisation of tissues - firstly, the formation of a nucleating collagen; and, secondly, the presence of phosphatase for the local destruction of the inhibitors present in plasma. The calcium salt deposited in the cartilage of pseudo-goul has been assumed to be pyrophosphate itself. The pyrophosphate/phosphate ratio is thought to be the endproduct of the hydrolysis of pyrophosphate by a phos-
in
a case
8. 9. 10. 11.
12. 13.
Bywaters, E. G. L., Dixon, A. St. J., Scott, J. T. Ann. rheum. Dis. 1963, 22, 171. Currey, H. L. F., Key, J. J., Mason, R. M., Sweetenham, K. V. ibid. 1966, 25, 295. Moskowitz, R. W., Katz, D. Ann. intern. Med. 1965, 115, 680. Gutman, A. B., Yu, T. F. Metab. Interrel. Trons. Confs. Josiah Macy jr Fdn, 1950, 2, 167. Thomas, W., Howaid, J. E. Trans. Ass. Am. Physns, 1959, 72, 181. Fleish, H., Neuman, W. F. Am. J. Physiol. 1961, 200, 1296.
appear, made it doubtful whether D.M.P.E. does in fact appear commonly in the urine of schizophrenic patients or
whether it is at all specific to schizophrenia. Kuehl et al. now point out, as others have done, that the " pink spot " as determined by the earlier methods has not been certainly identified with D.M.P.E. It has been shown both in humans3 and in rats4 that a major metabolite of D.M.P.E. in urine is 3, 4-dimethoxyphenylacetic acid. These workers measured the urinary excretion of this compound in normal subjects and in both acute and chronic schizophrenic patients, using thin-layer and gas chromatography and also mass spectrometry to make its identification certain. No significant difference was found between the normal subjects and the patients in the urinary excretion of 3, 4-dimethoxyphenylacetic acid. They also examined5 a number of the urines for D.M.P.E., and, contrary to their earlier findings they did not detect it in any of the samples. They also failed to demonstrate the conversion of dopamine to D.M.P.E. by postmortem specimens of liver and brain from both patients with schizophrenia and mentally normal people. Other investigations have been similarly negative. Williams et al. using two-way thin-layer chromatography, failed to detect D.M.P.E. in the urine.of 22 schizophrenic patients, in 17 of whom the illness was of recent acute onset. None of the patients had received drugs for at least three years, except 3 who had been given some barbiturates. Three new reports also throw doubt on the excretion of D.M.P.E. in schizophrenia.7-9Bell and Somerville8 found the pink spot in only 3 out of 27 samples from schizophrenic patients and the pink spot was not D.M.P.E. but some unidentified compound. Perry et al. gave a 1. 2.
3. 4.
Lancet, 1965, ii, 1169. Kuehl, F. A., Ormond, R. E., Vandenheuval, W. J. A. Nature, Lond. 1966, 211, 606. Friedhoff, A. J., Van Winkle, E. ibid. 1963, 199, 1271. Schweitzer, J. W., Friedhoff, A. J. Biochim. biophys. Acta. 1965, 111,
326. 5. Wagner, A. F., Cirillo, V. J., Meisinger, M. A. P., Ormond, R. E., Kuehl, F. A., Brink, N. G. Nature, Lond. 1966, 211, 604. 6. Williams, C. H., Gibson, J. G., McCormick, W. O. ibid. p. 1195. 7. Boulton, A. A., Felton, C. A. ibid. p. 1404. 8. Bell, C. E., Somerville, A. R. ibid. p. 1405.
with isoniazid had the same order of toxicity (and was as effective) as P.A.S. with isoniazid. Local conditions may therefore to some extent influence the incidence of toxic effects, and the Madras report suggests that the extensive use of thiacetazone with isoniazid should be preceded by carefully planned pilot studies to investigate, under local conditions, the toxicity and efficacy of the regimen. Another useful finding from Madras is that the progress of tuberculous patients on chemotherapy can be assessed with reasonable accuracy by simple smear examination of the sputum. Hence the methods for controlling tuberculosis on a wide scale are known. The question is when and how they can be applied-and this is not a purely medical matter. The World Health Organisation and the International Union against Tuberculosis continue to do valuable work,12 but, to carry through the large projects that are needed, a lot more money must be provided. The stresses imposed by rapid growth of population, migration, and industrialisation, together with the growing menace of drug resistance,13 make the situation more urgent. What is needed is not only mass medicine but " individual medicine ", as defined by Dr. CICELY WILLIAMS, 14 on a massive scale. This implies more than diagnosis and treatment: it includes prevention, health education, and supervision of contacts; and, as Dr. WILLIAMS pointed out, immunisation, nutrition, and family planning should also be a part. For some countries this objective might seem impossible: it will certainly remain so as long as priorities in allocating resources remain unchanged. But disease and overpopulation, poverty and ignorance, are real and substantial enemies, and in many parts of the world defences against them are pitifully inadequate. Nevertheless, some developing countries allocate half or more of their annual expenditure to military defence, and the leading nations devote to the same cause the equivalent of twothirds or more of the combined national incomes of all developing countries.15 Meanwhile, the prospects not only for health but for an improvement in the quality of life for many millions remain unrealised. Nor will inefficiency, bureaucracy, poor administration, and corruption, which can severely impede the development of adequate health services in many of the poorer countries,16be overcome without determined, systematic, and sustained effort. As LOWELLputs it, " Times change and we must accept the challenge to change with them, otherwise, because of our default, future generations will continue to endure the unnecessary and costly burden of tuberculosis ". In therapy the decisive breakthrough has been achieved by international cooperative effort, both developed and developing countries making their contribution and deriving benefit. For administrators and legislators, the implications-and the example-are
pointed and pertinent. 12. 13. 14. 15. 16.
See Lancet, 1966, i, 303. Br. med. J. Sept. 17, 1966, p. 656.
Lancet, Sept. 3, 1966, p. 544. UNESCO Courier, November, 1964, p. 5. Tuberculosis (International Union against Tuberculosis), July, 1966, no. 16, p. 4.
Abnormal Calcification of Cartilage SOFT tissues become calcified either when the mineral concentrations in tissue-fluids are abnormally high (as in vitamin-D poisoning and primary hyperparathyroidism) or when some local change in the tissues makes them calcify at normal mineral levels (for example, tuberculous lesions, injuries, and degenerating collagen). Calcification of costal cartilage is common in older people, and calcification of other cartilage has also been noted. The mineral deposit has been assumed to be hydroxyapatite. The subject came into prominence when MCCARTY et al.l described a syndrome which they
termed "pseudo-gout". Examining over 200 specimens of synovial fluid from joints with various arthritic disorders, they found 7 patients whose fluid showed a large number of rod-shaped crystals, 1-20 long, which gave a positive sign of birefringence under polarised light. These were obviously not urate crystals, although the clinical picture was that of gout. They suggested, from evidence which was strongly suggestive but not conclusive, that the crystals were calcium pyrophosphate.2 The infra-red spectrophotometric absorption curves were consistent with various pyrophosphate spectra, and the chemical findings were in keeping with calcium pyrophosphate, although on X-ray fluorescence and emission spectroscopy the picture did not correspond with any of the four known types of calcium pyrophosphate. Further work confirmed that the production of acute arthritis in this syndrome and in true gout was due to a synovitis induced by a certain concentration of crystals.33 A review of the literature disclosed 30 men and 21 with what was probably pseudo-gout. Radio-
women
logical calcification was seen in the shoulder-joint in 25 patients, the intervertebral discs in 22, the wrist in 21, the symphysis pubis in 20, the hip in 19, the elbow in 18, and the ankle in 14. The tendons were often found to be calcified. FAiREs et al. suggested that there was some inherited defect of cartilage metabolism and noted that surgery and diuretic therapy produced acute episodes, as they did in gout. A similar, familial, disease has been described by ZITNAN and SIT’AJ4 under the name " chondrocalcinosis ". LOUGHRIDGE and CALNE 5 described a condition, which they believed to be pseudogout, following renal transplantation, but although X-ray examination and biopsy showed periarticular calcification the nature of the material was not discovered. A syndrome producing gout-like episodes of acute localised soft-tissue inflammation had previously been observed in urxmic patients maintained by periodic haemodialysis. 677 By increasing the uric-acid concentration of the dialysis fluid an acute arthritis was produced. Nodular areas of calcification composed of hydroxyapatite developed in soft tissue both in the wake of acute attacks and, more commonly, without related symptoms. The calcinosis was thought to be, for the most part, a separate affair 1. 2. 3. 4. 5. 6. 7.
McCarty, D. J., Kohn, N. N., Faires, J. S. Ann. intern. Med. 1962, 56, 711. Kohn, N. N., Hughes, R. C., McCarty, D. J., Faires, J. S. ibid. p. 738. Faires, J. S., McCarty, D. J. Lancet, 1962, ii, 682. Zitnan, D., Sit’aj, S. Ann. rheum. Dis. 1963, 22, 142. Loughridge, L. W., Calne, R. Y. ibid. 1966, 25, 371. Caner, J. E. Z.. Decker, J. L. Am. J. Med. 1964, 36, 571. Decker, J. L. Arthritis Rheum. 1965, 8, 840.
848
by hyperphosphatsemia. Calcium deposition phatase, but there is no suggestion of a diminished resembling that seen in chondrocalcinosis has also been alkaline-phosphatase level in the serum of these patients. described in the articular cartilage of hyperparathyroid In fact the serum-alkaline-phosphatase was raised in 5 of the 35 cases of CuRREY et al. In synovial fluid from patients.I> CURREY et awl. investigated 35 patients with joint patients with rheumatoid arthritis and osteoarthrosis the symptoms in whom joint calcification was noted radio- level of alkaline phosphatase does not differ significantly logically. 13 had an acute arthritis, 14 had generalised from that in the blood. There may, however, be a osteoarthrosis (7 with acute episodes), and 3 had poly- specific pyrophosphatase, changes of which are not arthritis similar to rheumatoid arthritis but without shown by determination of the total alkaline phosrheumatoid factor in the blood. 3 had gout, and 2 had phatase. The levels of pyrophosphate and phosphatase hyperparathyroidism. Calcification was found in the in normal and diseased joints require further study. menisci of all patients, and other joints showing such radiographic change were, in order of frequency, the pubis and wrist, and the shoulder and elbow. Joints with Annotations arthritis of rheumatoid type suggested the possibility of a crystal synovitis arising simultaneously in many joints THE PINK SPOT: A RED HERRING? -a picture the authors had seen in a patient with classical LAST year1 we reviewed the conflicting reports about gout. They noted that the syndrome was often associated the excretion of (D.M.P.E.) with periarticular calcification. Examination of synovial in the urine of 3,4-dimethoxyphenylethylamine This compound, schizophrenic patients. fluid was possible in 23 patients: 3 had many crystals of which gave a pink colour when analysed chromatocalcium pyrophosphate, 3 had urate crystals, and 5 had graphically, is of particular interest because its structure is calcium-oxalate crystals. Some crystals with theoptical similar to the hallucinogenic drug, mescaline. These properties of calcium pyrophosphate were seen in 13, initial findings stimulated much interest and research in but they have also been found in other arthropathies and many centres, but further reports, which continue to
induced
of classical gout. MOSKOWITZ and KATZ 10 described 4 cases of chondrocalcinosis coincident with other rheumatic diseases, and 3 of these had small numbers of crystals with the morphological and polarising properties of calcium pyrophosphate. It is of course likely that the patients described by CURREY and his colleagues were a heterogeneous group, and calcification in patients with hyperparathyroidism (where plasmacalcium is high) may have a different basis from other cases in which plasma-calcium is normal. Apart from the crystal synovitis, these studies raise interesting problems of calcium metabolism. Calcium pyrophosphate is found in very small quantities throughout the body (the ratio of pyrophosphate/phosphate in the urine is normally about 1/500), and a suggestion that it may appear locally in joint-fluids in quantities large enough to form crystals poses the question of its origin. Moreover, pyrophosphate is a potent inhibitor of calcification.11 12 Indeed, FLEISH and NEUMAN’s hypothesis 13 of calcification in bone depended on the destruction of pyrophosphate by a raised concentration of alkaline phosphatase. It was suggested that at least two mechanisms were involved in the mineralisation of tissues - firstly, the formation of a nucleating collagen; and, secondly, the presence of phosphatase for the local destruction of the inhibitors present in plasma. The calcium salt deposited in the cartilage of pseudo-goul has been assumed to be pyrophosphate itself. The pyrophosphate/phosphate ratio is thought to be the endproduct of the hydrolysis of pyrophosphate by a phos-
in
a case
8. 9. 10. 11.
12. 13.
Bywaters, E. G. L., Dixon, A. St. J., Scott, J. T. Ann. rheum. Dis. 1963, 22, 171. Currey, H. L. F., Key, J. J., Mason, R. M., Sweetenham, K. V. ibid. 1966, 25, 295. Moskowitz, R. W., Katz, D. Ann. intern. Med. 1965, 115, 680. Gutman, A. B., Yu, T. F. Metab. Interrel. Trons. Confs. Josiah Macy jr Fdn, 1950, 2, 167. Thomas, W., Howaid, J. E. Trans. Ass. Am. Physns, 1959, 72, 181. Fleish, H., Neuman, W. F. Am. J. Physiol. 1961, 200, 1296.
appear, made it doubtful whether D.M.P.E. does in fact appear commonly in the urine of schizophrenic patients or
whether it is at all specific to schizophrenia. Kuehl et al. now point out, as others have done, that the " pink spot " as determined by the earlier methods has not been certainly identified with D.M.P.E. It has been shown both in humans3 and in rats4 that a major metabolite of D.M.P.E. in urine is 3, 4-dimethoxyphenylacetic acid. These workers measured the urinary excretion of this compound in normal subjects and in both acute and chronic schizophrenic patients, using thin-layer and gas chromatography and also mass spectrometry to make its identification certain. No significant difference was found between the normal subjects and the patients in the urinary excretion of 3, 4-dimethoxyphenylacetic acid. They also examined5 a number of the urines for D.M.P.E., and, contrary to their earlier findings they did not detect it in any of the samples. They also failed to demonstrate the conversion of dopamine to D.M.P.E. by postmortem specimens of liver and brain from both patients with schizophrenia and mentally normal people. Other investigations have been similarly negative. Williams et al. using two-way thin-layer chromatography, failed to detect D.M.P.E. in the urine.of 22 schizophrenic patients, in 17 of whom the illness was of recent acute onset. None of the patients had received drugs for at least three years, except 3 who had been given some barbiturates. Three new reports also throw doubt on the excretion of D.M.P.E. in schizophrenia.7-9Bell and Somerville8 found the pink spot in only 3 out of 27 samples from schizophrenic patients and the pink spot was not D.M.P.E. but some unidentified compound. Perry et al. gave a 1. 2.
3. 4.
Lancet, 1965, ii, 1169. Kuehl, F. A., Ormond, R. E., Vandenheuval, W. J. A. Nature, Lond. 1966, 211, 606. Friedhoff, A. J., Van Winkle, E. ibid. 1963, 199, 1271. Schweitzer, J. W., Friedhoff, A. J. Biochim. biophys. Acta. 1965, 111,
326. 5. Wagner, A. F., Cirillo, V. J., Meisinger, M. A. P., Ormond, R. E., Kuehl, F. A., Brink, N. G. Nature, Lond. 1966, 211, 604. 6. Williams, C. H., Gibson, J. G., McCormick, W. O. ibid. p. 1195. 7. Boulton, A. A., Felton, C. A. ibid. p. 1404. 8. Bell, C. E., Somerville, A. R. ibid. p. 1405.