- Email: [email protected]
AMITRIPTYLINE POISONING
640 or
vaginal discharge
was a
chief
complaint.
There remained
303 patients in whom the presence of carcinoma-in-situ of the cervix was previously unknown and could have played no role
in
initially causing the patient to seek examination. Therefore, by definition, this group is extremely likely to have sought "
medical aid for rn associated disorder. We estimate that perhaps a fourth of all of our patients with Hashimoto’s thyroiditis have sought medical aid primarily because of the goitrous enlargement of their necks, and one might therefore expect an even higher chance association with other diseases among the less symptomatic group with unsuspected cervical carcinoma. Among the 303 patients with previously unsuspected cervical carcinoma, connective-tissue diseases and syndromes were found in 2 patients who met the criteria of the American Rheumatism Association for definite rheumatoid arthritis and in 1 with probable rheumatoid arthritis, in 2 with rheumatoid spondylitis, in 1 with lupus erythematosus, and in 3 with some features of the syndrome of secondary fibrositis as has been previously defined,7 as follows:
Among our previously reported 506 patients with Hashimoto’s thyroiditis, there were 20 patients (4-0%) with definite or probable rheumatoid arthritis, 2 (0-4%) with rheumatoid spondylitis, 1 (0-2%) with scleroderma, 1 (0-2%) with suspected lupus erythematosus, 1 (0-2%) with the hydralazine syndrome, and 40 (7-9%) patients with fibrositic
symptomatology. We believe that the results of this study of patients with in-situ carcinoma of the cervix support our earlier conclusion that rheumatoid arthritis and musculoskeletal symptoms of a fibrositic character occur with increased frequency among patients with Hashimoto’s thyroiditis. Veterans Administration Hospital, Washington, D.C., and
Mayo Clinic, Rochester, Minnesota.
KENNETH L. BECKER RICHARD H. FERGUSON WILLIAM M. MCCONAHEY.
LOSS OF PARENTS
SIR,-The relation of the upbringing of a child and its total the subsequent personality of the adult is perhaps one of the most important issues in psychiatry. Your annotation (Aug. 21) seems to imply that a deprivation experience in childhood is of less importance than some authorities have suggested.9 10 It is debatable whether medical and surgical outpatients are a suitable normal control group representative of the general population. The age and sex distribution is different." Maclay,12 in her study of 100 medical outpatients, found that only 45 had a structural lesion to account for their symptoms; no such lesion was demonstrated in the other 55 who were diagnosed as functional. Priest,13 in his study of 1000 consecutive medical outpatients, classified 16-2% as psychoneurotic, and in a further 7-6% no organic disease was found; altogether these two groups made up nearly a quarter of the total. Shepherd et al.14 found that a large proportion of patients at general medical and surgical outpatients suffer primarily from psychological disorders. In the work that has been done in this field different workers
environment
to
8. Slocumb, C. H. Ann. rheum. Dis. 1941, 2, 108. 9. Bowlby, J. Am. J. Psychiat. 1961, 118, 481. 10. Brown, F. J. ment. Sci. 1961, 107, 754. 11. Munro, A. Br. J. prev. soc. Med. 1965, 19, 69. 12. Maclay, I. Br. J. Psychiat. 1965, 111, 34. 13. Priest, W. M. Lancet, 1962, ii, 1043. 14. Shepherd, M., Davies, B. M., Culpan, R. H. Acta 1960, 35, 518.
have obtained different results, and their figures have not been collected in a way which makes them comparable 16 In your annotation you cite Munro 11 who seems to suggest that, because the majority of the patients in the control group did not consider that the real deprivation they had experienced had upset them, this deprivation was not significant. Could the process of " selective forgetting " or repression of unpleasant or unacceptable experience be operating here ? The conclusion is, I think, that the matter is still not settled, and much more work needs to be done. Hampstead General Hospital, CONSTANCE M. DENNEHY. London, N.W.3. THE LISTER CENTENARY
SiR,—The issue of the Lister centenary postage stamp
may be an appropriate moment to draw attention to the fact that when 12, Park Crescent, once his home, was restored, his memorial tablet, which was put in place 50 years ago, was removed. The building is now in occupation by the University Grants Committee, but the memorial tablet has not been replaced, although I drew the attention of the Royal College of Surgeons to this omission months ago. It would be a pity if the lack is allowed to go unquestioned. F. M. R. WALSHE. London, W.1.
TREATMENT OF DEPRESSION SIR,-Dr. Roberts and Mr. Broadley 17 proposed a possible biochemical basis for mental depression. They speculated that noradnamine (5-aminomethyl-2, 3, 7, 8-tetrahydroxydibenzo-[a, e]-cycloheptatriene) might be formed in the brain and cause depression, and that the antidepressant activity of iminodibenzyl derivatives may be due to competition with noradnamine, because of their structural similarity to that substance. A possible pathway of noradnamine formation was presented, involving the dehydrative condensation of a molecule of noradrenaline with a molecule of 2(3, 4-dihydroxyphenyl)ethen-l-ol which, it was suggested, arises from 3,
4-dihydroxyphenylglycol. We wish to point out a more direct origin for 2(3, 4dihydroxyphenyl)ethen-l-ol : it is the enol form of, and could be formed by tautomerisation of, 3, 4-dihydroxyphenylacetaldehyde, which is the immediate product of monoamineoxidase (M.A.O.) action on dopamine. In most circumstances, the aldehyde presumably is quickly oxidised to dihydroxyphenylacetic acid by aldehyde dehydrogenase, but it is conceivable that the equilibrium would allow dehydrative condensation of the enol with noradrenaline. Decreased activity of aldehyde dehydrogenase would favour this condensation; malfunction of this enzyme in the brain might be considered as a possible underlying cause of depression. Feldstein et al.18 showed that serotonin given orally to depressed patients was metabolised in the same way as in normal subjects. Since serotonin does not penetrate the blood-brain barrier, however, a possible deficiency of brain aldehyde dehydrogenase would not have been revealed. M.A.O. inhibitors would directly inhibit the formation, from dopamine, of the keto form of 2 (3, 4-dihydroxyphenyl) ethen-1-ol, and this could contribute to their antidepressant action if noradnamine is in fact causally related to mental
depression. The
Lilly Research Laboratories, Lilly and Company, Indianapolis, Indiana, U.S.A. Eli
RAY W. FULLER W. S. MARSHALL.
AMITRIPTYLINE POISONING SIR,-Amitriptyline should be added to the list of drugs which may build up to a toxic level when used in the usual
dosage in renal insufficiency. Pitts, F. N., Meyer, J., Brooks, M., Winokur, G. Am. J. Psychiat. 1965, 121, suppl. p. 1. 16. Gregory, I. ibid. 1958, 115, 432. 17. Roberts, D. J., Broadley, K. J. Lancet, 1965, i, 1219. 18. Feldstein, A., Hoagland, H., Wong, K. K.-K., Oktem, M. R., Freeman, H. Am. J. Psychiat. 1964, 120, 1192. 15.
psychiat. neurol, scand.
641 An elderly patient with moderate nitrogen retention, due to benign prostatic hypertrophy, was treated with amitriptyline, 25 mg. t.d.s., for depression. Within a week he became agitated and tremulous. These symptoms subsided within a few days of stopping the drug.
Regional Urological Centre, Sefton General Hospital, Liverpool, 15.
H. J. GOLDSMITH.
the surviving animals were
suprarenal glands of rats was measured after the injected, 6 hours before they were killed, with heparin, Rol-8307, or thrombocid, two groups of Hungarian workers observed that synthesis of the hormone was distinctly reduced.16 17 Moreover Vallent et al.l8 found that a 10-day course of heparin causes moderate shrinkage of nuclear volume and zone width in the suprarenal zona glomerulosa of rats.
HEPARIN AND OSTEOPOROSIS SIR,-Your annotation (Aug. 21) deserves comment in two respects. The first point is that you state that " heparin has few side-effects. Anaphylactoid reactions, alopecia, and thrombocytopenia are uncommon.... But the pharmacological actions of heparin are not limited to its complex interference with the coagulation mechanism ". One such action, which you did not mention, is the natriuretic and aldosterone-suppressive effect of heparin and most heparinoids. In 1957 my colleagues and I found1 that heparin enhances the urinary excretion of sodium in patients with and without oedema. The effect was delayed for 36-48 hours after the first injection, and the response continued for about 48 hours after therapy had been stopped. In some patients with severe heartfailure, the onset of natriuresis was even delayed until the 4th-8th day of drug administration.2-4 In many patients there was slight potassium retention, usually most pronounced when the natriuresis was considerable. My associates and I have never found enhanced kaluresis,2 6which Vallent and Fachet5 have claimed to have observed. In 1960 Schlatmann et al. reported experiments showing that the heparinoids ’Thrombocid ’ (xylan polysulphuric acid) and Rol-8307 (N-formyl-chitosan polysulphuric acid) have a diuretic action similar to that of natural heparin.7 In later studies of other heparinoids, only those with a relatively low sulphur content appeared to lack a natriuretic action.s The simultaneous occurrence of natriuresis and potassium retention prompted us to study adrenal cortical function during administration of heparin and Rol-8307. Urinary excretion of total 17-hydroxycorticosteroids was not affected,2and this result was confirmed later by Veyrat et awl.9 9 10 Furthermore, administration of heparin did not alter the excretion of 11hydroxycorticosteroids,l1 measured according to Mattingly’s technique.12 When urinary excretion of aldosterone was studied, however,3 6 s 13a rapid fall to very low levels was found during administration of Rol-8307. These results were corroborated by Veyrat et al.,9 " who also found," in two normal subjects on salt-restricted diets, that the secretion-rate of aldosterone during Rol-8307 treatment decreased from 1135 and 1040 !1-g. per 24 hours to 141 and 116 g. per 24 hours, respectively. In my laboratory we have found an analogous suppression of the aldosterone-secretion rate in patients on standard heparin therapy.14 15 In dogs, too, treatment with heparinoids is followed by natriuresis, though so far aldosterone studies have not been done in this species. But when aldosterone production by 1. Majoor, C. L. H., Prenen, H., van Munster, P. J. J., Schlatmann, 2. 3. 4.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14.
15.
R. J. A. F. M. Ned. Tijdschr. Geneesk. 1957, 101, 1301. Majoor, C. L. H., Schlatmann, R. J. A. F. M., Jansen, A. P., Prenen, H. Clinica chim. Acta, 1960, 5, 591. Cejka, V., de Vries, L. A., Smorenberg-Schoorl, M. E., van Daatselaar, J. J., Borst, J. G. G., Majoor, C. L. H. Lancet, 1960, i, 317. Majoor, C. L. H., Jansen, A. P., Schlatmann, R. J. A. F. M., van der Korst, J. K., Prenen, H. Acta cardiol. 1962, 17, 657. Vallent, K., Fachet, J. Klin. Wschr. 1965, 43, 235. Schlatmann, R. J. A. F. M., Jansen, A. P., Prenen, H., van der Korst, J. K., Majoor, C. L. H. J. clin. Endocr. Metab. 1964, 24, 35. Schlatmann, R. J. A. F. M., Prenen, H., Jansen, A. P., Majoor, C. L. H. Lancet, 1960, i, 314. Majoor, C. L. H., Schlatmann, R. J. A. F. M., Jansen, A. P., Frohn, H., Prenen, H. Folia med. Neerl. 1962, 5, suppl. 1, p. 79. Veyrat, R., Fabre, J., Muller, A. F. Helv. med. Acta, 1962, 29, 543. Veyrat, R., Manning, E. L., Fabre, J., Muller, A. F. Revue fr. Étud. clin. biol. 1963, 8, 667. Kloppenborg, P. W. C., Benraad, Th.J. Unpublished. Mattingly, D., Dennis, P. M., Pearson, J., Cope, C. L. Lancet, 1964, ii, 1046. Cejka, V. Folia med. Neerl. 1962, 5, suppl. 1, p. 40. Majoor, C. L. H., Kloppenborg, P. W. C., Benraad, Th.J. 2nd International Congress of Endocrinology. London, 1964. Kloppenborg, P. W. C., Benraad, Th.J., Majoor, C. L. H. Ned. Tijdschr. Geneesk. 1965, 109, 1178.
The pathway by which heparin and heparinoids inhibit aldosterone secretion is by no means clear. Some facts and reflections suggested that heparins might produce their effect by interfering with the renin/angiotensin system.6 But this theory can less convincingly be put forward since Vallent et al.l8 in rats, and Steenbergen and Swaen 19 in dogs, found an increase of renal juxtaglomerular granularity during treatment with heparin, and since Conn et al. 20 found that the heparinoid, RoI-8307, can decrease aldosterone secretion in patients with primary aldosteronism who showed no plasma-renin activity before and during drug administration. Other recent results of importance, that will have to be fitted into an ultimate theory of heparin action on the suprarenal glands, are Laidlaw’s finding of a decrease of the secretion-rate of 18-hydroxycorticosterone and aldosterone during Rol-8307 administration,21 and Kloppenborg’s experiments 14 15 showing that intravenous infusions of angiotensin II in patients on salt-restricted diets cannot stimulate aldosterone secretion when the rate is decreased by heparin administration. The clinical significance of this pharmacological action of heparin and heparinoids is shown by the death from selective hypoaldosteronism of a 38-year-old male who had been treated with 200 mg. of heparin subcutaneously for almost 4 years.22 As courses of heparin of 300 mg. per day for several weeks have become popular recently for patients with severe intravascular clotting, it seems to be appropriate to remember the aldosterone-suppressive action of this drug. The second point that might be made is about your statement that " biochemical investigations in these patients [treated with heparin] revealed no apparent disorder of calcium or phosphate metabolism " Bijvoet et al. 23 found that, during long courses of heparin treatment, the serum-inorganic-phosphate rose to values between 3-7 and 6-4 mg. per 100 ml. In three patients it was found that the ratio of the renal reabsorptive maximal tubular capacity for inorganic phosphate to the glomerular filtration-rate (T.M.P./G.F.R. ratio) also rose distinctly. We feel that these data have to be taken into account when the heparininduced osteoporosis that was reported by Griffith et al. 24 and Jaffe et al. 25 is explained. Department of Medicine, St. Radboud Hospital, University of Nijmegen, The Netherlands.
C. L. H.
MAJOOR.
CONGENITAL MALFORMATIONS AND DIABETES
SiR,—Ihave read with great interest the letter of Dr. Stern colleagues,26 and would like to present here the case of a girl, now 16 years old, who was born with complete absence of the sacrum and L5, and who had the same signs and symptoms as the female infant’s described by these workers. The maternal grandfather had severe diabetes. The mother, now 38 years old, has a persistently high blood-sugar level, despite treatment and diet, which was first discovered a year and his
16. 17. 18. 19. 20. 21.
Glaz, E., Sugár, K. Endocrinology, 1964, 74, 159. Fachet, J., Stark, E., Vallent, K., Palkovits, M. Acta med. hung. 1962, 18, 461. Vallent, K., Fachet, J., Palkovits, M., Dévényi, I. Z. Zellforsch. mikrosk. Anat. 1964, 63, 728. Steenbergen, J., Swaen, G. J. V. Unpublished. Conn, J. W., Rooner, D. R., Cohen, E. L., Klembergs, S. Clin. Res. 1964, 12, 351. Laidlaw, J 2nd International Congress of Endocrinology. London, 1964.
Wilson, J. D., Goetz, F. C. Am. J. Med. 1964, 36, 635. Bijvoet, O. L. M., Jansen, A. P., Prenen, H., Majoor, C. L. H. Water and Electrolyte Metabolism (edited by J. de Graeff and B. Leynse); vol. II, p. 151. Amsterdam, 1964. 24. Griffith, G. C., Nichols, G., Asher, J. D., Flanagan, B. J. Am. med. Ass. 1965, 193, 91. 25. Jaffe, M. D., Willis, P. W. ibid. p. 158. 26. Stern, L., Ramos, A., Light, I. Lancet, 1965, i, 1393. 22. 23.
vaginal discharge
was a
chief
complaint.
There remained
303 patients in whom the presence of carcinoma-in-situ of the cervix was previously unknown and could have played no role
in
initially causing the patient to seek examination. Therefore, by definition, this group is extremely likely to have sought "
medical aid for rn associated disorder. We estimate that perhaps a fourth of all of our patients with Hashimoto’s thyroiditis have sought medical aid primarily because of the goitrous enlargement of their necks, and one might therefore expect an even higher chance association with other diseases among the less symptomatic group with unsuspected cervical carcinoma. Among the 303 patients with previously unsuspected cervical carcinoma, connective-tissue diseases and syndromes were found in 2 patients who met the criteria of the American Rheumatism Association for definite rheumatoid arthritis and in 1 with probable rheumatoid arthritis, in 2 with rheumatoid spondylitis, in 1 with lupus erythematosus, and in 3 with some features of the syndrome of secondary fibrositis as has been previously defined,7 as follows:
Among our previously reported 506 patients with Hashimoto’s thyroiditis, there were 20 patients (4-0%) with definite or probable rheumatoid arthritis, 2 (0-4%) with rheumatoid spondylitis, 1 (0-2%) with scleroderma, 1 (0-2%) with suspected lupus erythematosus, 1 (0-2%) with the hydralazine syndrome, and 40 (7-9%) patients with fibrositic
symptomatology. We believe that the results of this study of patients with in-situ carcinoma of the cervix support our earlier conclusion that rheumatoid arthritis and musculoskeletal symptoms of a fibrositic character occur with increased frequency among patients with Hashimoto’s thyroiditis. Veterans Administration Hospital, Washington, D.C., and
Mayo Clinic, Rochester, Minnesota.
KENNETH L. BECKER RICHARD H. FERGUSON WILLIAM M. MCCONAHEY.
LOSS OF PARENTS
SIR,-The relation of the upbringing of a child and its total the subsequent personality of the adult is perhaps one of the most important issues in psychiatry. Your annotation (Aug. 21) seems to imply that a deprivation experience in childhood is of less importance than some authorities have suggested.9 10 It is debatable whether medical and surgical outpatients are a suitable normal control group representative of the general population. The age and sex distribution is different." Maclay,12 in her study of 100 medical outpatients, found that only 45 had a structural lesion to account for their symptoms; no such lesion was demonstrated in the other 55 who were diagnosed as functional. Priest,13 in his study of 1000 consecutive medical outpatients, classified 16-2% as psychoneurotic, and in a further 7-6% no organic disease was found; altogether these two groups made up nearly a quarter of the total. Shepherd et al.14 found that a large proportion of patients at general medical and surgical outpatients suffer primarily from psychological disorders. In the work that has been done in this field different workers
environment
to
8. Slocumb, C. H. Ann. rheum. Dis. 1941, 2, 108. 9. Bowlby, J. Am. J. Psychiat. 1961, 118, 481. 10. Brown, F. J. ment. Sci. 1961, 107, 754. 11. Munro, A. Br. J. prev. soc. Med. 1965, 19, 69. 12. Maclay, I. Br. J. Psychiat. 1965, 111, 34. 13. Priest, W. M. Lancet, 1962, ii, 1043. 14. Shepherd, M., Davies, B. M., Culpan, R. H. Acta 1960, 35, 518.
have obtained different results, and their figures have not been collected in a way which makes them comparable 16 In your annotation you cite Munro 11 who seems to suggest that, because the majority of the patients in the control group did not consider that the real deprivation they had experienced had upset them, this deprivation was not significant. Could the process of " selective forgetting " or repression of unpleasant or unacceptable experience be operating here ? The conclusion is, I think, that the matter is still not settled, and much more work needs to be done. Hampstead General Hospital, CONSTANCE M. DENNEHY. London, N.W.3. THE LISTER CENTENARY
SiR,—The issue of the Lister centenary postage stamp
may be an appropriate moment to draw attention to the fact that when 12, Park Crescent, once his home, was restored, his memorial tablet, which was put in place 50 years ago, was removed. The building is now in occupation by the University Grants Committee, but the memorial tablet has not been replaced, although I drew the attention of the Royal College of Surgeons to this omission months ago. It would be a pity if the lack is allowed to go unquestioned. F. M. R. WALSHE. London, W.1.
TREATMENT OF DEPRESSION SIR,-Dr. Roberts and Mr. Broadley 17 proposed a possible biochemical basis for mental depression. They speculated that noradnamine (5-aminomethyl-2, 3, 7, 8-tetrahydroxydibenzo-[a, e]-cycloheptatriene) might be formed in the brain and cause depression, and that the antidepressant activity of iminodibenzyl derivatives may be due to competition with noradnamine, because of their structural similarity to that substance. A possible pathway of noradnamine formation was presented, involving the dehydrative condensation of a molecule of noradrenaline with a molecule of 2(3, 4-dihydroxyphenyl)ethen-l-ol which, it was suggested, arises from 3,
4-dihydroxyphenylglycol. We wish to point out a more direct origin for 2(3, 4dihydroxyphenyl)ethen-l-ol : it is the enol form of, and could be formed by tautomerisation of, 3, 4-dihydroxyphenylacetaldehyde, which is the immediate product of monoamineoxidase (M.A.O.) action on dopamine. In most circumstances, the aldehyde presumably is quickly oxidised to dihydroxyphenylacetic acid by aldehyde dehydrogenase, but it is conceivable that the equilibrium would allow dehydrative condensation of the enol with noradrenaline. Decreased activity of aldehyde dehydrogenase would favour this condensation; malfunction of this enzyme in the brain might be considered as a possible underlying cause of depression. Feldstein et al.18 showed that serotonin given orally to depressed patients was metabolised in the same way as in normal subjects. Since serotonin does not penetrate the blood-brain barrier, however, a possible deficiency of brain aldehyde dehydrogenase would not have been revealed. M.A.O. inhibitors would directly inhibit the formation, from dopamine, of the keto form of 2 (3, 4-dihydroxyphenyl) ethen-1-ol, and this could contribute to their antidepressant action if noradnamine is in fact causally related to mental
depression. The
Lilly Research Laboratories, Lilly and Company, Indianapolis, Indiana, U.S.A. Eli
RAY W. FULLER W. S. MARSHALL.
AMITRIPTYLINE POISONING SIR,-Amitriptyline should be added to the list of drugs which may build up to a toxic level when used in the usual
dosage in renal insufficiency. Pitts, F. N., Meyer, J., Brooks, M., Winokur, G. Am. J. Psychiat. 1965, 121, suppl. p. 1. 16. Gregory, I. ibid. 1958, 115, 432. 17. Roberts, D. J., Broadley, K. J. Lancet, 1965, i, 1219. 18. Feldstein, A., Hoagland, H., Wong, K. K.-K., Oktem, M. R., Freeman, H. Am. J. Psychiat. 1964, 120, 1192. 15.
psychiat. neurol, scand.
641 An elderly patient with moderate nitrogen retention, due to benign prostatic hypertrophy, was treated with amitriptyline, 25 mg. t.d.s., for depression. Within a week he became agitated and tremulous. These symptoms subsided within a few days of stopping the drug.
Regional Urological Centre, Sefton General Hospital, Liverpool, 15.
H. J. GOLDSMITH.
the surviving animals were
suprarenal glands of rats was measured after the injected, 6 hours before they were killed, with heparin, Rol-8307, or thrombocid, two groups of Hungarian workers observed that synthesis of the hormone was distinctly reduced.16 17 Moreover Vallent et al.l8 found that a 10-day course of heparin causes moderate shrinkage of nuclear volume and zone width in the suprarenal zona glomerulosa of rats.
HEPARIN AND OSTEOPOROSIS SIR,-Your annotation (Aug. 21) deserves comment in two respects. The first point is that you state that " heparin has few side-effects. Anaphylactoid reactions, alopecia, and thrombocytopenia are uncommon.... But the pharmacological actions of heparin are not limited to its complex interference with the coagulation mechanism ". One such action, which you did not mention, is the natriuretic and aldosterone-suppressive effect of heparin and most heparinoids. In 1957 my colleagues and I found1 that heparin enhances the urinary excretion of sodium in patients with and without oedema. The effect was delayed for 36-48 hours after the first injection, and the response continued for about 48 hours after therapy had been stopped. In some patients with severe heartfailure, the onset of natriuresis was even delayed until the 4th-8th day of drug administration.2-4 In many patients there was slight potassium retention, usually most pronounced when the natriuresis was considerable. My associates and I have never found enhanced kaluresis,2 6which Vallent and Fachet5 have claimed to have observed. In 1960 Schlatmann et al. reported experiments showing that the heparinoids ’Thrombocid ’ (xylan polysulphuric acid) and Rol-8307 (N-formyl-chitosan polysulphuric acid) have a diuretic action similar to that of natural heparin.7 In later studies of other heparinoids, only those with a relatively low sulphur content appeared to lack a natriuretic action.s The simultaneous occurrence of natriuresis and potassium retention prompted us to study adrenal cortical function during administration of heparin and Rol-8307. Urinary excretion of total 17-hydroxycorticosteroids was not affected,2and this result was confirmed later by Veyrat et awl.9 9 10 Furthermore, administration of heparin did not alter the excretion of 11hydroxycorticosteroids,l1 measured according to Mattingly’s technique.12 When urinary excretion of aldosterone was studied, however,3 6 s 13a rapid fall to very low levels was found during administration of Rol-8307. These results were corroborated by Veyrat et al.,9 " who also found," in two normal subjects on salt-restricted diets, that the secretion-rate of aldosterone during Rol-8307 treatment decreased from 1135 and 1040 !1-g. per 24 hours to 141 and 116 g. per 24 hours, respectively. In my laboratory we have found an analogous suppression of the aldosterone-secretion rate in patients on standard heparin therapy.14 15 In dogs, too, treatment with heparinoids is followed by natriuresis, though so far aldosterone studies have not been done in this species. But when aldosterone production by 1. Majoor, C. L. H., Prenen, H., van Munster, P. J. J., Schlatmann, 2. 3. 4.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14.
15.
R. J. A. F. M. Ned. Tijdschr. Geneesk. 1957, 101, 1301. Majoor, C. L. H., Schlatmann, R. J. A. F. M., Jansen, A. P., Prenen, H. Clinica chim. Acta, 1960, 5, 591. Cejka, V., de Vries, L. A., Smorenberg-Schoorl, M. E., van Daatselaar, J. J., Borst, J. G. G., Majoor, C. L. H. Lancet, 1960, i, 317. Majoor, C. L. H., Jansen, A. P., Schlatmann, R. J. A. F. M., van der Korst, J. K., Prenen, H. Acta cardiol. 1962, 17, 657. Vallent, K., Fachet, J. Klin. Wschr. 1965, 43, 235. Schlatmann, R. J. A. F. M., Jansen, A. P., Prenen, H., van der Korst, J. K., Majoor, C. L. H. J. clin. Endocr. Metab. 1964, 24, 35. Schlatmann, R. J. A. F. M., Prenen, H., Jansen, A. P., Majoor, C. L. H. Lancet, 1960, i, 314. Majoor, C. L. H., Schlatmann, R. J. A. F. M., Jansen, A. P., Frohn, H., Prenen, H. Folia med. Neerl. 1962, 5, suppl. 1, p. 79. Veyrat, R., Fabre, J., Muller, A. F. Helv. med. Acta, 1962, 29, 543. Veyrat, R., Manning, E. L., Fabre, J., Muller, A. F. Revue fr. Étud. clin. biol. 1963, 8, 667. Kloppenborg, P. W. C., Benraad, Th.J. Unpublished. Mattingly, D., Dennis, P. M., Pearson, J., Cope, C. L. Lancet, 1964, ii, 1046. Cejka, V. Folia med. Neerl. 1962, 5, suppl. 1, p. 40. Majoor, C. L. H., Kloppenborg, P. W. C., Benraad, Th.J. 2nd International Congress of Endocrinology. London, 1964. Kloppenborg, P. W. C., Benraad, Th.J., Majoor, C. L. H. Ned. Tijdschr. Geneesk. 1965, 109, 1178.
The pathway by which heparin and heparinoids inhibit aldosterone secretion is by no means clear. Some facts and reflections suggested that heparins might produce their effect by interfering with the renin/angiotensin system.6 But this theory can less convincingly be put forward since Vallent et al.l8 in rats, and Steenbergen and Swaen 19 in dogs, found an increase of renal juxtaglomerular granularity during treatment with heparin, and since Conn et al. 20 found that the heparinoid, RoI-8307, can decrease aldosterone secretion in patients with primary aldosteronism who showed no plasma-renin activity before and during drug administration. Other recent results of importance, that will have to be fitted into an ultimate theory of heparin action on the suprarenal glands, are Laidlaw’s finding of a decrease of the secretion-rate of 18-hydroxycorticosterone and aldosterone during Rol-8307 administration,21 and Kloppenborg’s experiments 14 15 showing that intravenous infusions of angiotensin II in patients on salt-restricted diets cannot stimulate aldosterone secretion when the rate is decreased by heparin administration. The clinical significance of this pharmacological action of heparin and heparinoids is shown by the death from selective hypoaldosteronism of a 38-year-old male who had been treated with 200 mg. of heparin subcutaneously for almost 4 years.22 As courses of heparin of 300 mg. per day for several weeks have become popular recently for patients with severe intravascular clotting, it seems to be appropriate to remember the aldosterone-suppressive action of this drug. The second point that might be made is about your statement that " biochemical investigations in these patients [treated with heparin] revealed no apparent disorder of calcium or phosphate metabolism " Bijvoet et al. 23 found that, during long courses of heparin treatment, the serum-inorganic-phosphate rose to values between 3-7 and 6-4 mg. per 100 ml. In three patients it was found that the ratio of the renal reabsorptive maximal tubular capacity for inorganic phosphate to the glomerular filtration-rate (T.M.P./G.F.R. ratio) also rose distinctly. We feel that these data have to be taken into account when the heparininduced osteoporosis that was reported by Griffith et al. 24 and Jaffe et al. 25 is explained. Department of Medicine, St. Radboud Hospital, University of Nijmegen, The Netherlands.
C. L. H.
MAJOOR.
CONGENITAL MALFORMATIONS AND DIABETES
SiR,—Ihave read with great interest the letter of Dr. Stern colleagues,26 and would like to present here the case of a girl, now 16 years old, who was born with complete absence of the sacrum and L5, and who had the same signs and symptoms as the female infant’s described by these workers. The maternal grandfather had severe diabetes. The mother, now 38 years old, has a persistently high blood-sugar level, despite treatment and diet, which was first discovered a year and his
16. 17. 18. 19. 20. 21.
Glaz, E., Sugár, K. Endocrinology, 1964, 74, 159. Fachet, J., Stark, E., Vallent, K., Palkovits, M. Acta med. hung. 1962, 18, 461. Vallent, K., Fachet, J., Palkovits, M., Dévényi, I. Z. Zellforsch. mikrosk. Anat. 1964, 63, 728. Steenbergen, J., Swaen, G. J. V. Unpublished. Conn, J. W., Rooner, D. R., Cohen, E. L., Klembergs, S. Clin. Res. 1964, 12, 351. Laidlaw, J 2nd International Congress of Endocrinology. London, 1964.
Wilson, J. D., Goetz, F. C. Am. J. Med. 1964, 36, 635. Bijvoet, O. L. M., Jansen, A. P., Prenen, H., Majoor, C. L. H. Water and Electrolyte Metabolism (edited by J. de Graeff and B. Leynse); vol. II, p. 151. Amsterdam, 1964. 24. Griffith, G. C., Nichols, G., Asher, J. D., Flanagan, B. J. Am. med. Ass. 1965, 193, 91. 25. Jaffe, M. D., Willis, P. W. ibid. p. 158. 26. Stern, L., Ramos, A., Light, I. Lancet, 1965, i, 1393. 22. 23.