BRITISH MEDICAL JOURNAL
233
22 JANUARY 1977
Abnormal calcium metabolism in normocalcaemic sarcoidosis
SIR,-In their otherwise excellent paper on calcium metabolism in sarcoidosis (18 December, p 1473) Dr M Reiner and his colleagues state that total hydroxyproline excretion is increased in acute sarcoidosis and that this indicates increased bone resorption. So far as I know the site of origin of the excess hydroxyproline has never been determined. Although it would seem logical that it is due to increased bone turnover there are at least three other possibilities: (1) It could be due to increased turnover of collagen in the lung parenchyma. (2) It could arise from the sarcoid granulomata themselves-significant amounts of hydroxyproline have been detected in experimental granulomata.' (3) Theoretically it could be due to excess turnover of the Clq component of complement. Total complement levels have been shown to be elevated in sarcoidosis,2 $ particularly in the acute phase.` Lastly, though the reference they quote) and also the work of Pawelec" did show elevated levels of urinary hydroxyproline in sarcoidosis, at least one large series7 failed to show any increase over control values. I would therefore be chary at present of adducing raised hydroxyproline values as confirmation of the degree of bone involvement in sarcoidosis. N J C SNELL Henley-on-Thames, Oxon1 Lovell, D, British Journal of Experimental Pathology, 1966, 47, 228. Buckley, C, Nagaya, H, and Sieker, H, Annals of Internal Medicine, 1966, 64, 508. Sheffer, A, Ruddy, S, and Israel, H, in Proceedinlgs of "5th International Contference oni Sarcoidosis", p 195. Prague, Charles University Press, 1971. Simecek, C, et al, ibid, p 188. Massaro, D, et al, Americani Review of Respiratory Diseases, 1966, 93, 929. Pawelec, D, Polski Tygodnik Lekarski, 1973, 28, 1412. Uitto, J, Tani, P, and Pihko, H, Clinica Chinmica Acta. 1971, 32, 265.
SIR,-Dr M Reiner and his many colleagues (18 December, p 1473) have clarified the calcium disorders sometimes found in patients with sarcoidosis, and these are usually shortlived. Nearly half of their patients had accelerated bone turnover and hypercalciuria, suggesting that a common metabolic factor had caused the alterations in the gut, bones, and kidneys. This factor has been thought to be immunological since 1969.1 In more than 50(), of sarcoid cases, however, calcium metabolism is normal, and one other factor is therefore required to explain the calcium abnormalities adequately. Two patients with sarcoidosis had giant-cell granulomas in the parathyroid glands2 ;; and infiltration also probably caused hypoparathyroidism in three other patients.4 The mechanism by which sarcoidosis sometimes stimulates the parathyroids5 thus appears to be immunological. Although the infiltration is rarely persistent enough to induce "tertiary" hyperparathyroidism, 16 cases have in fact been reported with parathyroid hyperplasia or adenomas.2 Twenty cases of hyperthyroidism8 9 and five cases of Addison's disease" 10 have also occurred in patients with sarcoidosis. Local infiltration of endocrine glands with the granulomas probably generates immunoglobulins, and these can be stimulatory. They usually act only transiently, but occasionally more permanent stimulation may occur, leading rarely to gland failure. For
instance, a 54-year-old man with splenomegaly had a positive Kveim test and developed weight loss and vomiting a year later. He then had hypercalcaemia and hypercalciuria, which remitted during 10 days' treatment with 20 mg of prednisolone daily. Although he was given 50 000 U of vitamin D3 provocatively for three weeks he remained normocalcaemic and has been well for the past four years. He appeared to have transient sarcoid parathyroiditis.)' Another patient with sarcoidosis which remains active after 17 years still has hypercalcaemia every summer. He was reported to have "vitamin D hypersensitivity," accounting for the calcium abnormality and a renal stone,'2 but more probably he now has autonomous hyperparathyroidism. Patients with hypersecretion of parathyroid hormone (PTH) may sometimes develop relative deficiency of vitamin D unless they have ample sunlight. This is presumably the reason for normocalcaemic hyperparathyroidism. Cushard et al found hypercalcaemia in six of their 26 cases of sarcoidosis. Most of these were considered to have functional hypoparathyroidism because the PTH assays were unmeasurably low in all but seven cases. Many of the patients may have had, instead, granulomas in their parathyroids, however, because the "dysproteinaemia" of sarcoidosis is very likely to have interfered with the radioimmunoassay. It is most significant that the interference was partially corrected in the five patients who received corticosteroid treatment. The three additional cases described with hyperparathyroidism probably had more infiltration in the glands or a higher level of immunity locally. The endocrinopathies complicating sarcoidosis remain underdiagnosed because the inflammation is usually temporary and it may often be subclinical. GERALD A MACGREGOR St Luke's Hospital, Guildford, Surrey MacGregor, G A, Lancet, 1969, 1, 730. Van Rijssel, T G, De Ziekte van Besnier-Boech en Bacterieelallergische Otntstekintgs Processen. Utrecht, 1947. 3David, N J, Verner, J V, and Engel, F L, American 2
J7ournal of Medicine, 1962, 33,
88.
4MacGregor, G A, Lancet, 1970, 2, 1257. Dent, C F, Postgraduate Medical J7ournal, 1970, 46, 471. Winnacker, J L, et al, American Jouirnal of Medicine, 1969, 46, 305. Cushard, W G, et al, New! England Journal of Medicine, 1972, 286, 395. MacGregor, G A, Proceedings of the Royal Society of Medicinze, 1974, 67, 22 1. 9 MacGregor, G A, British Medical Jouirnal, 1976, 2, 944. Irvine, W J, unpublished observation. MacGregor, G A, unpublished observation. 12Smith, M J, and Hey, G B, Postgraduate Medical Journal, 1976, 52, 86.
Gowers's advice. "Thirty of the 54 patients . . ." ignores the opinion of O'Connor and Woodford that figures and words should not be mixed in the same sentence. One of the great strengths of the book by O'Connor and Woodford is its sponsorship by the European Association of Editors of Biological Periodicals. I know from personal experience as a member of the editorial committee of a European journal how helpful it has been. P R R CLARKE Middlesbrough, Cleveland O'Connor, M, and Woodford, F P, Writing Scientific Papers in English. Amsterdam, Associated Scientific Publishers, 1975. Fowler, H W, A Dictionary of Modern English Usage, 2nd edn, revised E Gowers. London, Oxford University Press, 1965.
**A move to greater uniformity of style is due to be considered at the First International Conference of Scientific Editors in AprilED, BM7. Insulin: U40, U80, or U100? SIR,-It is painful to find myself in disagreement with the authors of the letter on insulin (27 November, p 1319) since I respect them all and value their judgment, but their proposal comes at an inappropriate time and the case is not convincingly made. Of course it is not difficult to agree that it would be better to have insulin prepared at only one strength but it hardly seems to be an advance to have syringes with different graduations. My personal experience is that mistakes due to confusion between units and marks on the syringe are comparatively uncommon and are mostly made by those who would perpetrate errors in anything calling for measurement. District nurses rarely go wrong, but regrettably hospital staff, including doctors, sometimes do. The most important objection to the proposed change is that the majority of clinics in this country are in the process of changing over to the new very pure preparations of insulin. If these become the standard insulins of the future it is likely that the mean daily dosage will fall considerably so that the preferred strength might become U40, as in Europe. Is it wise to cut ourselves off from our fellow members of the EEC and especially from Denmark, from which so much of the best work on insulin has come and which makes so much of the insulin used in this country ? JOHN MALINS General Hospital,
Birmingham
Better medical writing SIR,-In a leading article (12 April, 1975, p 56) you commended to intending authors Writing Scientific Papers in English by O'Connor and Woodford,' and observed, "If its sales are as wide as they deserve perhaps the millennium may be nearer when all journals will use the same basic style conventions." Unfortunately, your "Instructions to authors" (1 January, p 6) contains examples of departures from the admirable code you have previously recommended. "Et al" without the period is not approved by O'Connor and Woodford or by that splendid authority Sir Ernest Gowers in Fowler's Modern English Usage.2 E coli, with no period after the E, also contravenes
SIR,-Dr B Galandauer (25 December, p 1561) is unfortunately quite incorrect in his remarks about the "completely outdated 'insulin syringes'"; I presume that he refers to the standard BS 1619 insulin syringe, which has the approval of the British Diabetic Association. This syringe is graduated in 20 subdivisions to 1 ml and the word "units" is intentionally omitted. For U40 strength insulin each mark or subdivision represents 2 units, and for U80 strentgh 4 units. Thus 20 units of U40 insulin is 10 marks on the syringe-not 10 units as stated by Dr Galandauer. For many diabetics the term "millilitres" means little or nothing, but most diabetics can
233
22 JANUARY 1977
Abnormal calcium metabolism in normocalcaemic sarcoidosis
SIR,-In their otherwise excellent paper on calcium metabolism in sarcoidosis (18 December, p 1473) Dr M Reiner and his colleagues state that total hydroxyproline excretion is increased in acute sarcoidosis and that this indicates increased bone resorption. So far as I know the site of origin of the excess hydroxyproline has never been determined. Although it would seem logical that it is due to increased bone turnover there are at least three other possibilities: (1) It could be due to increased turnover of collagen in the lung parenchyma. (2) It could arise from the sarcoid granulomata themselves-significant amounts of hydroxyproline have been detected in experimental granulomata.' (3) Theoretically it could be due to excess turnover of the Clq component of complement. Total complement levels have been shown to be elevated in sarcoidosis,2 $ particularly in the acute phase.` Lastly, though the reference they quote) and also the work of Pawelec" did show elevated levels of urinary hydroxyproline in sarcoidosis, at least one large series7 failed to show any increase over control values. I would therefore be chary at present of adducing raised hydroxyproline values as confirmation of the degree of bone involvement in sarcoidosis. N J C SNELL Henley-on-Thames, Oxon1 Lovell, D, British Journal of Experimental Pathology, 1966, 47, 228. Buckley, C, Nagaya, H, and Sieker, H, Annals of Internal Medicine, 1966, 64, 508. Sheffer, A, Ruddy, S, and Israel, H, in Proceedinlgs of "5th International Contference oni Sarcoidosis", p 195. Prague, Charles University Press, 1971. Simecek, C, et al, ibid, p 188. Massaro, D, et al, Americani Review of Respiratory Diseases, 1966, 93, 929. Pawelec, D, Polski Tygodnik Lekarski, 1973, 28, 1412. Uitto, J, Tani, P, and Pihko, H, Clinica Chinmica Acta. 1971, 32, 265.
SIR,-Dr M Reiner and his many colleagues (18 December, p 1473) have clarified the calcium disorders sometimes found in patients with sarcoidosis, and these are usually shortlived. Nearly half of their patients had accelerated bone turnover and hypercalciuria, suggesting that a common metabolic factor had caused the alterations in the gut, bones, and kidneys. This factor has been thought to be immunological since 1969.1 In more than 50(), of sarcoid cases, however, calcium metabolism is normal, and one other factor is therefore required to explain the calcium abnormalities adequately. Two patients with sarcoidosis had giant-cell granulomas in the parathyroid glands2 ;; and infiltration also probably caused hypoparathyroidism in three other patients.4 The mechanism by which sarcoidosis sometimes stimulates the parathyroids5 thus appears to be immunological. Although the infiltration is rarely persistent enough to induce "tertiary" hyperparathyroidism, 16 cases have in fact been reported with parathyroid hyperplasia or adenomas.2 Twenty cases of hyperthyroidism8 9 and five cases of Addison's disease" 10 have also occurred in patients with sarcoidosis. Local infiltration of endocrine glands with the granulomas probably generates immunoglobulins, and these can be stimulatory. They usually act only transiently, but occasionally more permanent stimulation may occur, leading rarely to gland failure. For
instance, a 54-year-old man with splenomegaly had a positive Kveim test and developed weight loss and vomiting a year later. He then had hypercalcaemia and hypercalciuria, which remitted during 10 days' treatment with 20 mg of prednisolone daily. Although he was given 50 000 U of vitamin D3 provocatively for three weeks he remained normocalcaemic and has been well for the past four years. He appeared to have transient sarcoid parathyroiditis.)' Another patient with sarcoidosis which remains active after 17 years still has hypercalcaemia every summer. He was reported to have "vitamin D hypersensitivity," accounting for the calcium abnormality and a renal stone,'2 but more probably he now has autonomous hyperparathyroidism. Patients with hypersecretion of parathyroid hormone (PTH) may sometimes develop relative deficiency of vitamin D unless they have ample sunlight. This is presumably the reason for normocalcaemic hyperparathyroidism. Cushard et al found hypercalcaemia in six of their 26 cases of sarcoidosis. Most of these were considered to have functional hypoparathyroidism because the PTH assays were unmeasurably low in all but seven cases. Many of the patients may have had, instead, granulomas in their parathyroids, however, because the "dysproteinaemia" of sarcoidosis is very likely to have interfered with the radioimmunoassay. It is most significant that the interference was partially corrected in the five patients who received corticosteroid treatment. The three additional cases described with hyperparathyroidism probably had more infiltration in the glands or a higher level of immunity locally. The endocrinopathies complicating sarcoidosis remain underdiagnosed because the inflammation is usually temporary and it may often be subclinical. GERALD A MACGREGOR St Luke's Hospital, Guildford, Surrey MacGregor, G A, Lancet, 1969, 1, 730. Van Rijssel, T G, De Ziekte van Besnier-Boech en Bacterieelallergische Otntstekintgs Processen. Utrecht, 1947. 3David, N J, Verner, J V, and Engel, F L, American 2
J7ournal of Medicine, 1962, 33,
88.
4MacGregor, G A, Lancet, 1970, 2, 1257. Dent, C F, Postgraduate Medical J7ournal, 1970, 46, 471. Winnacker, J L, et al, American Jouirnal of Medicine, 1969, 46, 305. Cushard, W G, et al, New! England Journal of Medicine, 1972, 286, 395. MacGregor, G A, Proceedings of the Royal Society of Medicinze, 1974, 67, 22 1. 9 MacGregor, G A, British Medical Jouirnal, 1976, 2, 944. Irvine, W J, unpublished observation. MacGregor, G A, unpublished observation. 12Smith, M J, and Hey, G B, Postgraduate Medical Journal, 1976, 52, 86.
Gowers's advice. "Thirty of the 54 patients . . ." ignores the opinion of O'Connor and Woodford that figures and words should not be mixed in the same sentence. One of the great strengths of the book by O'Connor and Woodford is its sponsorship by the European Association of Editors of Biological Periodicals. I know from personal experience as a member of the editorial committee of a European journal how helpful it has been. P R R CLARKE Middlesbrough, Cleveland O'Connor, M, and Woodford, F P, Writing Scientific Papers in English. Amsterdam, Associated Scientific Publishers, 1975. Fowler, H W, A Dictionary of Modern English Usage, 2nd edn, revised E Gowers. London, Oxford University Press, 1965.
**A move to greater uniformity of style is due to be considered at the First International Conference of Scientific Editors in AprilED, BM7. Insulin: U40, U80, or U100? SIR,-It is painful to find myself in disagreement with the authors of the letter on insulin (27 November, p 1319) since I respect them all and value their judgment, but their proposal comes at an inappropriate time and the case is not convincingly made. Of course it is not difficult to agree that it would be better to have insulin prepared at only one strength but it hardly seems to be an advance to have syringes with different graduations. My personal experience is that mistakes due to confusion between units and marks on the syringe are comparatively uncommon and are mostly made by those who would perpetrate errors in anything calling for measurement. District nurses rarely go wrong, but regrettably hospital staff, including doctors, sometimes do. The most important objection to the proposed change is that the majority of clinics in this country are in the process of changing over to the new very pure preparations of insulin. If these become the standard insulins of the future it is likely that the mean daily dosage will fall considerably so that the preferred strength might become U40, as in Europe. Is it wise to cut ourselves off from our fellow members of the EEC and especially from Denmark, from which so much of the best work on insulin has come and which makes so much of the insulin used in this country ? JOHN MALINS General Hospital,
Birmingham
Better medical writing SIR,-In a leading article (12 April, 1975, p 56) you commended to intending authors Writing Scientific Papers in English by O'Connor and Woodford,' and observed, "If its sales are as wide as they deserve perhaps the millennium may be nearer when all journals will use the same basic style conventions." Unfortunately, your "Instructions to authors" (1 January, p 6) contains examples of departures from the admirable code you have previously recommended. "Et al" without the period is not approved by O'Connor and Woodford or by that splendid authority Sir Ernest Gowers in Fowler's Modern English Usage.2 E coli, with no period after the E, also contravenes
SIR,-Dr B Galandauer (25 December, p 1561) is unfortunately quite incorrect in his remarks about the "completely outdated 'insulin syringes'"; I presume that he refers to the standard BS 1619 insulin syringe, which has the approval of the British Diabetic Association. This syringe is graduated in 20 subdivisions to 1 ml and the word "units" is intentionally omitted. For U40 strength insulin each mark or subdivision represents 2 units, and for U80 strentgh 4 units. Thus 20 units of U40 insulin is 10 marks on the syringe-not 10 units as stated by Dr Galandauer. For many diabetics the term "millilitres" means little or nothing, but most diabetics can
