- Email: [email protected]
INTESTINAL ABSORPTION OF CALCIUM IN FASTING PATIENTS
616 have therefore demonstrated that a dose of oestrogen which is approximately five times greater than that in the contraceptive pill is necessary in order to produce sufficient squamous metaplasia in order to prevent rupture of the telangiectasia and to induce healing of aphthous mouth ulcers. A relatively small dose of cestrogen might produce capillary dilatation without squamous metaplasia. Dr. Rowley and his colleagues do not state whether their patients bled during oral contraceptive therapy, or during the week between successive courses of the pill; but in either event the bleeding tendency would presumably depend on the relative balance between dilatation of the telangiectasia and the degree of squamous metaplasia present. A case could therefore be made out for prescribing substantially larger doses of oestrogen—e.g., 0.25 mg. of ethinyloestradiol daily-as a contraceptive agent in women with H.H.T. Guy’s Hospital, P. W. R. HARRIS. London S.E.1.
SiR,—The report by Dr. Rowley and others that the disease of three women with hereditary hxmorrhagic telangiectasia (H.H.T.) may have been aggravated by oral cestrogens is of interest because it adds to the controversy in the field of hormonal therapy of H.H.T. While, on the one hand, oral oestrogens have controlled epistaxis in H.H.T.1on the other, some authors have not found oestrogens of benefit in H.H.T.5,6 Certainly, treatment of H.H.T. with oestrogens may have unpredictable effects. Thus, for example, one of our male patients with H.H.T. developed severe pustular acne of the neck on two separate occasions when treated with chlorotrianisene.4 Neither ethinyloestradiol nor diethylstilboestrol produces this phenomenon. The acne is surprising and unexplained because it is generally believed that androgens are the important hormonal factors necessary for the development of sebaceous glands and therefore for the production of acne.7 University Department of Hæmatology, The Royal Infirmary, E. K. BLACKBURN. Sheffield.
STAGING OF BREAST CANCER
SIR,-Sir John Bruce and his colleagues (Feb. 28, stress the limitations of clinical staging of breast
p. 433) cancer,
bone-scan evidence of distant metastases in clinically " early " cases. They do not comment on the value of such staging for purposes of comparison between different centres, many of which will not have facilities for routine bone scans, nor on the remarkable correlation (which operability cannot explain) between clinical staging and survival-rates. No matter how often bone scans, or other sophisticated techniques of the future, reveal that an apparently " early " case is really " advanced ", we are still left with the surprising fact that comparatively minor local variations (for example, in the size of the primary tumour or in the exact site and extent of axillary-node involvement) are associated with major differences in the chance of long survival. Since death is usually due to distant metastases, why should a woman whose primary
pointing
1. 2. 3. 4. 5.
6. 7.
to
H. J., Escher, G. C., Lewis, J. S. J. Am. med. Ass. 1952, 149, 1376. Harrison, D. F. N. Q. Jl Med. 1964, 33, 25. Blackburn, E. K. Br. med. J. 1963, ii, 159. Blackburn, E. K. Hémostase. 1965, 5, 37. Stefanini, M., Dameshek, W. The Hemorrhagic Disorders; p. 53. New York, 1955. Israëls, M. C. G. Diagnosis and Treatment of Blood Diseases; p. 162. London, 1963. Strauss, J. S., Kligman, A. M., Pochi, P. E. J. invest. Derm. 1962, 39, 139.
Koch,
6 cm. in diameter have a much worse whose primary tumour measures 3 cm. ? prognosis Such observations, reported from several centres and tumour measures
than
one
seriously challenged by none, are surely complementary the emphasis placed by Sir John Bruce and his colleagues on the synchronous appearance of local recurrence and distant metastases. Both sets of observations provide plenty of food for thought for anyone interested in the
to
natural history and management of breast cancer. Glasgow Institute for Radiotherapy, T. B. BREWIN. Glasgow W.1.
INTESTINAL ABSORPTION OF CALCIUM IN FASTING PATIENTS
SIR,-It has been demonstrated in animals 1-3 as well as in man 4-11 that the rate of intestinal absorption of calcium is inversely related to the calcium content of the diet. This led us to suspect that the rate of intestinal absorption of calcium would be greatly increased during total therapeutic
fasting. TABLE I-INTESTINAL ABSORPTION OF
4’Ca
IN FASTING PATIENTS
Serum level of "Ca expressed as percentage of dose of "Ca per g. serum-calcium per 1’73 sq. m.
We conducted an experimental study with two groups: (a) four obese patients (free from any disease of mineral metabolism) who were given a daily diet consisting only of 2500 ml. of distilled water with 60 meq. of potassium; and (b) five normal controls who were given a 2000-calorie diet containing 800 to 1000 mg. of calcium. The age of the patients in the first group ranged from 26 to 36 years, and their weight from 74-2 to 102-5 kg.; those in the control group were aged between 39 and 44 years and weighed
from 59-0 to 75-4 kg. On the 9th day of fasting, 40 fLCi of 47Ca was administered to each of the obese patients in 200 ml. of milk. The same dose was given to the controls who had eaten nothing in the preceding 12 hours. Serum samples were taken 60,120, 180, and 240 minutes after administration of the radioisotope. The intestinal absorption of calcium, evaluated indirectly, was expressed as a percentage of the administered 47Ca dose per g. 40Ca in serum, corrected to 1-73 sq. m.12 1.
Nicolaysen, R., Eeg-Larsen, N., Malm, O. J. Physiol. Rev. 1953, 33, 424.
Kimberg, D. V., Schachter, D. V., Schenker, H. Am. J. Physiol. 1961, 200, 1256. 3. Wasserman, R. H., Comar, C. L. Endocrinology, 1961, 89, 1074. 4. Malm, O. Scand. J. clin. Lab. Invest. 1958, 10 (suppl. 36), 1. 5. Robinson, C. J., Gutteridge, D. H., Joplin, G. F., Belcher, E. H., Fraser, R. Medical Uses of 47Ca: Second Panel Report. International Atomic Energy Agency, Vienna, 1964. 6. De Grazia, J. A., Rich, C. Metabolism, 1964, 11, 650. 7. Bronner, F., Harris, R. S. Ann. N.Y. Acad Sci. 1956, 64, 314. 8. Avioli, L. V., McDonald, J. E., Singer, J. E., Henneman, P. H. J. clin. Invest. 1965, 44, 128. 9. Kinney, V. R., Tauxe, W. N., Dearing, W. H. J. Lab. clin. Med. 1965, 66, 187. 10. Rich, C., Ivanovich P. NW Med., Seattle, 1964, 63, 792. 11. Spencer, H., Lewin, I., Fowler, J., Samachson, J. Am. J. Med. 1969, 46, 197. 12. Litvak, J., Oberhauser, E., Vukusic, A., Zanzi, I., López, O., Alliende, I., Armendaris, R. Rev. med. Chile, 1966, 94, 415. 2.
617 TABLE II-INTESTINAL ABSORPTION OF
47Ca
IN FASTING PATIENTS
AND CONTROLS
lise later. It is for this
reason
that I recommend routine pro-
phylaxis for all adults, not excluding those under 40 years of age. As for the problem of heparin and bleeding, as stated, I merely attempt to maintain normocoagulation with subcutaneous heparin. I must agree that most surgeons have been reluctant at first to try the method for fear of hxmorrhage. But now, having used the method with almost comin close on 700 often high-risk patients, our satisfied that they have not lost patients as a result of haemorrhage but know they have lost many whom they failed to heparinise. I am informed that Mr. Lanning (personal communication), of the Lady Gibson Hospital in Johannesburg, South Africa, also has had equally good success using my method and is satisfied that he would risk some bleeding just so long as his patients lived. In this I
plete
success
surgeons
..
Units
as
in table
i.
Table I shows the values for intestinal absorption in the four fasting patients, and table II shows the difference between the averages of absorption in the fasting group and in the controls. Even taking into consideration the doubts about the usefulness of an indirect method of evaluation,9,13,14 and the small number of cases included in this study, it is evident that the intestinal absorption of calcium in patients undergoing therapeutic fasting not only was not higher than in the control group, but was lower at 60 and 120 minutes, and showed no appreciable difference at 180 and 240 minutes
(table II). Possibly the absence of an increase in intestinal absorption of calcium in the fasting group could be due to atrophy of the intestinal papillae 15 or to a lack of aminoacids or other factors needed for the normal calcium absorption during the fasting oeriod.16 Department of Endocrinology, Surgery Institute of the Province of Buenos Aires, Haedo, Argentina. Section of
GÜNTHER A. FROMM.
Endocrinology
and Nuclear Medicine, Department of Medicine,
José J. Aguirre Hospital, University of Chile, Santiago, Chile. Nuclear Medicine Center of the José de San Martin Teaching Hospital, Argentine Atomic Energy Commission and Faculty of Medicine, University of Buenos Aires, Argentina.
JORGE LITVAK.
OSVALDO J. DEGROSSI.
PREVENTION OF VENOUS THROMBOSIS SIR,-Iwish to correct a statement in your editorial (Feb. 21, p. 395) in which you refer to my most recent report.17 I have never, as implied in the editorial, used the LeeWhite coagulation test, nor any other test, for determining which surgical patients should receive prophylactic heparin to prevent venous thrombosis and possible fatal embolism. I do use the modified Dale and Laidlaw coagulometer merely as a control of heparin prophylaxis in adjusting the subcutaneous heparin dosage if the patient has a greatly shortened or prolonged blood-coagulation time. I find that there is no test which can accurately predict just who is vulnerable and will become hypercoagulable and require heparin prophylaxis. If this were possible, how simple the problem would be. I long ago abandoned the Lee-White coagulation-time after checking it against the Dale and Laidlaw test, finding it totally unreliable as stated in my last report. My earlier study 18 indicated that our potentially most critical hypercoagulable period is any period of stress, as in the perioperative period when leg-vein thrombosis is most likely to develop and become immediately embolic or embo13. Jaworski, Z. F., Brown, E. M., Fedoruk, S., Seitz, H. New Engl. J. Med. 1963, 269, 1103. 14. Mautalen, C., Medicina, B. Aires, 1968, 28, 290. 15. Thomson, T. J., Rencie, J., Miller, V. Lancet, 1966, ii, 992. 16. Stewart, W. K., Fleming, L. W., Robertson, P. C. Am. J. Med. 1966, 40, 967. 17. Lancet 1969, ii, 292. 18. Surgery Gynec. Obstet. 1966, 123, 303.
heartily
are
concur.
Department of Pathology, Mount Vernon Hospital, Mount Vernon, New York
J. G. SHARNOFF.
PAROXYSMAL NOCTURNAL HÆMOGLOBINURIA WITH CHROMOSOME ABNORMALITIES: POSSIBLE PRELEUKÆMIA SIR,-There have been few reports of chromosomal investigation of patients with paroxysmal nocturnal hsmoglobinuria (P.N.H.) 1-4; and such patients as have been studied had no apparent chromosomal abnormalities. We recently observed a patient with P.N.H. who had chromosome aberrations in the bone-marrow cells. The patient was a 52-year-old Japanese man who had been in good health until 1961, when he developed recurrent mild anaemia. There was no history of exposure to radiation or myelotoxic drugs. Sternal-marrow examinations in June and October, 1968, and February and July, 1969, revealed a hypercellular marrow with erythroid hyperplasia. Binucleated, trinucleated, and megaloblastoid erythroblasts were occasionally seen. The cells of the myeloid series were decreased in absolute numbers, showing apparent maturation arrest at the stage of younger myelocytes. In February, 1969, the Ham’s test and sugar-water test were positive, and the neutrophil-alkaline-phosphatase activity It was at this time that nocturnal hasmoglobinuria was low. became obvious. DETAILS OF CELLS ANALYSED
Nos. of cells with minute chromosome
are
in
parentheses.
Cytogenetic examination, using the direct bone-marrow was performed on four occasions (see accompanying table). On each occasion a minute chromosome was found in most of the cells examined, which appeared to be a group-G chromosome with deletion of long arms, or a condensed, abnormally small, chromosome. There were, moreover, frequent abnormalities of the chromosome method,
by loss of C and/or G group chromosomes. Examination of 3-day lymphocyte cultures in February, 1969, revealed no abnormalities. Three well-documented cases of P.N.H. terminating in, or score, caused
Beutler, C., Goldenburg, E. W., Ohno, S., Yettra, M. Blood, 1964, 24, 160. 2. Bottura, C., Ferrari, I. Acta hœmat. 1962, 28, 20. 3. Goh, K. O., Swisher, S. N. Clin. Res. 1963, 11, 194. 4. Ross, J. D., Rosenbaum, E. Am. J. Med. 1964, 37, 130. 1.
SiR,—The report by Dr. Rowley and others that the disease of three women with hereditary hxmorrhagic telangiectasia (H.H.T.) may have been aggravated by oral cestrogens is of interest because it adds to the controversy in the field of hormonal therapy of H.H.T. While, on the one hand, oral oestrogens have controlled epistaxis in H.H.T.1on the other, some authors have not found oestrogens of benefit in H.H.T.5,6 Certainly, treatment of H.H.T. with oestrogens may have unpredictable effects. Thus, for example, one of our male patients with H.H.T. developed severe pustular acne of the neck on two separate occasions when treated with chlorotrianisene.4 Neither ethinyloestradiol nor diethylstilboestrol produces this phenomenon. The acne is surprising and unexplained because it is generally believed that androgens are the important hormonal factors necessary for the development of sebaceous glands and therefore for the production of acne.7 University Department of Hæmatology, The Royal Infirmary, E. K. BLACKBURN. Sheffield.
STAGING OF BREAST CANCER
SIR,-Sir John Bruce and his colleagues (Feb. 28, stress the limitations of clinical staging of breast
p. 433) cancer,
bone-scan evidence of distant metastases in clinically " early " cases. They do not comment on the value of such staging for purposes of comparison between different centres, many of which will not have facilities for routine bone scans, nor on the remarkable correlation (which operability cannot explain) between clinical staging and survival-rates. No matter how often bone scans, or other sophisticated techniques of the future, reveal that an apparently " early " case is really " advanced ", we are still left with the surprising fact that comparatively minor local variations (for example, in the size of the primary tumour or in the exact site and extent of axillary-node involvement) are associated with major differences in the chance of long survival. Since death is usually due to distant metastases, why should a woman whose primary
pointing
1. 2. 3. 4. 5.
6. 7.
to
H. J., Escher, G. C., Lewis, J. S. J. Am. med. Ass. 1952, 149, 1376. Harrison, D. F. N. Q. Jl Med. 1964, 33, 25. Blackburn, E. K. Br. med. J. 1963, ii, 159. Blackburn, E. K. Hémostase. 1965, 5, 37. Stefanini, M., Dameshek, W. The Hemorrhagic Disorders; p. 53. New York, 1955. Israëls, M. C. G. Diagnosis and Treatment of Blood Diseases; p. 162. London, 1963. Strauss, J. S., Kligman, A. M., Pochi, P. E. J. invest. Derm. 1962, 39, 139.
Koch,
6 cm. in diameter have a much worse whose primary tumour measures 3 cm. ? prognosis Such observations, reported from several centres and tumour measures
than
one
seriously challenged by none, are surely complementary the emphasis placed by Sir John Bruce and his colleagues on the synchronous appearance of local recurrence and distant metastases. Both sets of observations provide plenty of food for thought for anyone interested in the
to
natural history and management of breast cancer. Glasgow Institute for Radiotherapy, T. B. BREWIN. Glasgow W.1.
INTESTINAL ABSORPTION OF CALCIUM IN FASTING PATIENTS
SIR,-It has been demonstrated in animals 1-3 as well as in man 4-11 that the rate of intestinal absorption of calcium is inversely related to the calcium content of the diet. This led us to suspect that the rate of intestinal absorption of calcium would be greatly increased during total therapeutic
fasting. TABLE I-INTESTINAL ABSORPTION OF
4’Ca
IN FASTING PATIENTS
Serum level of "Ca expressed as percentage of dose of "Ca per g. serum-calcium per 1’73 sq. m.
We conducted an experimental study with two groups: (a) four obese patients (free from any disease of mineral metabolism) who were given a daily diet consisting only of 2500 ml. of distilled water with 60 meq. of potassium; and (b) five normal controls who were given a 2000-calorie diet containing 800 to 1000 mg. of calcium. The age of the patients in the first group ranged from 26 to 36 years, and their weight from 74-2 to 102-5 kg.; those in the control group were aged between 39 and 44 years and weighed
from 59-0 to 75-4 kg. On the 9th day of fasting, 40 fLCi of 47Ca was administered to each of the obese patients in 200 ml. of milk. The same dose was given to the controls who had eaten nothing in the preceding 12 hours. Serum samples were taken 60,120, 180, and 240 minutes after administration of the radioisotope. The intestinal absorption of calcium, evaluated indirectly, was expressed as a percentage of the administered 47Ca dose per g. 40Ca in serum, corrected to 1-73 sq. m.12 1.
Nicolaysen, R., Eeg-Larsen, N., Malm, O. J. Physiol. Rev. 1953, 33, 424.
Kimberg, D. V., Schachter, D. V., Schenker, H. Am. J. Physiol. 1961, 200, 1256. 3. Wasserman, R. H., Comar, C. L. Endocrinology, 1961, 89, 1074. 4. Malm, O. Scand. J. clin. Lab. Invest. 1958, 10 (suppl. 36), 1. 5. Robinson, C. J., Gutteridge, D. H., Joplin, G. F., Belcher, E. H., Fraser, R. Medical Uses of 47Ca: Second Panel Report. International Atomic Energy Agency, Vienna, 1964. 6. De Grazia, J. A., Rich, C. Metabolism, 1964, 11, 650. 7. Bronner, F., Harris, R. S. Ann. N.Y. Acad Sci. 1956, 64, 314. 8. Avioli, L. V., McDonald, J. E., Singer, J. E., Henneman, P. H. J. clin. Invest. 1965, 44, 128. 9. Kinney, V. R., Tauxe, W. N., Dearing, W. H. J. Lab. clin. Med. 1965, 66, 187. 10. Rich, C., Ivanovich P. NW Med., Seattle, 1964, 63, 792. 11. Spencer, H., Lewin, I., Fowler, J., Samachson, J. Am. J. Med. 1969, 46, 197. 12. Litvak, J., Oberhauser, E., Vukusic, A., Zanzi, I., López, O., Alliende, I., Armendaris, R. Rev. med. Chile, 1966, 94, 415. 2.
617 TABLE II-INTESTINAL ABSORPTION OF
47Ca
IN FASTING PATIENTS
AND CONTROLS
lise later. It is for this
reason
that I recommend routine pro-
phylaxis for all adults, not excluding those under 40 years of age. As for the problem of heparin and bleeding, as stated, I merely attempt to maintain normocoagulation with subcutaneous heparin. I must agree that most surgeons have been reluctant at first to try the method for fear of hxmorrhage. But now, having used the method with almost comin close on 700 often high-risk patients, our satisfied that they have not lost patients as a result of haemorrhage but know they have lost many whom they failed to heparinise. I am informed that Mr. Lanning (personal communication), of the Lady Gibson Hospital in Johannesburg, South Africa, also has had equally good success using my method and is satisfied that he would risk some bleeding just so long as his patients lived. In this I
plete
success
surgeons
..
Units
as
in table
i.
Table I shows the values for intestinal absorption in the four fasting patients, and table II shows the difference between the averages of absorption in the fasting group and in the controls. Even taking into consideration the doubts about the usefulness of an indirect method of evaluation,9,13,14 and the small number of cases included in this study, it is evident that the intestinal absorption of calcium in patients undergoing therapeutic fasting not only was not higher than in the control group, but was lower at 60 and 120 minutes, and showed no appreciable difference at 180 and 240 minutes
(table II). Possibly the absence of an increase in intestinal absorption of calcium in the fasting group could be due to atrophy of the intestinal papillae 15 or to a lack of aminoacids or other factors needed for the normal calcium absorption during the fasting oeriod.16 Department of Endocrinology, Surgery Institute of the Province of Buenos Aires, Haedo, Argentina. Section of
GÜNTHER A. FROMM.
Endocrinology
and Nuclear Medicine, Department of Medicine,
José J. Aguirre Hospital, University of Chile, Santiago, Chile. Nuclear Medicine Center of the José de San Martin Teaching Hospital, Argentine Atomic Energy Commission and Faculty of Medicine, University of Buenos Aires, Argentina.
JORGE LITVAK.
OSVALDO J. DEGROSSI.
PREVENTION OF VENOUS THROMBOSIS SIR,-Iwish to correct a statement in your editorial (Feb. 21, p. 395) in which you refer to my most recent report.17 I have never, as implied in the editorial, used the LeeWhite coagulation test, nor any other test, for determining which surgical patients should receive prophylactic heparin to prevent venous thrombosis and possible fatal embolism. I do use the modified Dale and Laidlaw coagulometer merely as a control of heparin prophylaxis in adjusting the subcutaneous heparin dosage if the patient has a greatly shortened or prolonged blood-coagulation time. I find that there is no test which can accurately predict just who is vulnerable and will become hypercoagulable and require heparin prophylaxis. If this were possible, how simple the problem would be. I long ago abandoned the Lee-White coagulation-time after checking it against the Dale and Laidlaw test, finding it totally unreliable as stated in my last report. My earlier study 18 indicated that our potentially most critical hypercoagulable period is any period of stress, as in the perioperative period when leg-vein thrombosis is most likely to develop and become immediately embolic or embo13. Jaworski, Z. F., Brown, E. M., Fedoruk, S., Seitz, H. New Engl. J. Med. 1963, 269, 1103. 14. Mautalen, C., Medicina, B. Aires, 1968, 28, 290. 15. Thomson, T. J., Rencie, J., Miller, V. Lancet, 1966, ii, 992. 16. Stewart, W. K., Fleming, L. W., Robertson, P. C. Am. J. Med. 1966, 40, 967. 17. Lancet 1969, ii, 292. 18. Surgery Gynec. Obstet. 1966, 123, 303.
heartily
are
concur.
Department of Pathology, Mount Vernon Hospital, Mount Vernon, New York
J. G. SHARNOFF.
PAROXYSMAL NOCTURNAL HÆMOGLOBINURIA WITH CHROMOSOME ABNORMALITIES: POSSIBLE PRELEUKÆMIA SIR,-There have been few reports of chromosomal investigation of patients with paroxysmal nocturnal hsmoglobinuria (P.N.H.) 1-4; and such patients as have been studied had no apparent chromosomal abnormalities. We recently observed a patient with P.N.H. who had chromosome aberrations in the bone-marrow cells. The patient was a 52-year-old Japanese man who had been in good health until 1961, when he developed recurrent mild anaemia. There was no history of exposure to radiation or myelotoxic drugs. Sternal-marrow examinations in June and October, 1968, and February and July, 1969, revealed a hypercellular marrow with erythroid hyperplasia. Binucleated, trinucleated, and megaloblastoid erythroblasts were occasionally seen. The cells of the myeloid series were decreased in absolute numbers, showing apparent maturation arrest at the stage of younger myelocytes. In February, 1969, the Ham’s test and sugar-water test were positive, and the neutrophil-alkaline-phosphatase activity It was at this time that nocturnal hasmoglobinuria was low. became obvious. DETAILS OF CELLS ANALYSED
Nos. of cells with minute chromosome
are
in
parentheses.
Cytogenetic examination, using the direct bone-marrow was performed on four occasions (see accompanying table). On each occasion a minute chromosome was found in most of the cells examined, which appeared to be a group-G chromosome with deletion of long arms, or a condensed, abnormally small, chromosome. There were, moreover, frequent abnormalities of the chromosome method,
by loss of C and/or G group chromosomes. Examination of 3-day lymphocyte cultures in February, 1969, revealed no abnormalities. Three well-documented cases of P.N.H. terminating in, or score, caused
Beutler, C., Goldenburg, E. W., Ohno, S., Yettra, M. Blood, 1964, 24, 160. 2. Bottura, C., Ferrari, I. Acta hœmat. 1962, 28, 20. 3. Goh, K. O., Swisher, S. N. Clin. Res. 1963, 11, 194. 4. Ross, J. D., Rosenbaum, E. Am. J. Med. 1964, 37, 130. 1.