378
plasma from patients with Christmas disease very little. The shortening of the clotting-times of haemophilia-A plasma was much more pronounced. Such a discrepancy is difficult to ascribe to thromboplastin. E. J. W. BOWIE C. A. OWEN
Mayo Clinic and Foundation, Rochester, Minnesota 55901, U.S.A.
***This letter has been shown
face immunoglobulin level was high when the sample was tested fresh and low after posting, but after trypsinisation and culture the cells failed to regenerate immunoglobulin. This strongly suggests the need for this test to separate out those cells to which circulating immunoglobulin adheres, including non-B leukaemic cells which themselves are not producing immunoglobulin, from the true B-lymphoid type. These two patients both had lymphomas with leukaemic transformation and both had high lymphocyte-counts and low blast-counts. Accumulating evidence on cell-surface markers stresses the need for a whole battery of tests, the results being considered together before the leukaemic-cell type is decided on. We are not yet in a position to tailor treatment to cell type, but that time is fast approaching; furthermore subcategorisation is essential for discussing prognosis with the family and for analysis of survival curves.
to
Dr
Blecher, whose reply fol-
lows.-ED.L.
SiR,—The claim by Dr Bowie and Dr Owen that they pre-
viously demonstrated the synthesis of factor vm coagulant by leucocytes is most directly refuted by the evidence in their own
papers.l2 In these it is specifically stated2 that the "factor vm activity" was not reduced by incubation with an anti-factor-vm antibody. It is also stated that "in the leucocyte cultures, factor vm levels were reduced to virtually zero by centrifugation for 30 min at 25,000 g" and that "the activity was stable for 24 h at room temperature". These are not the properties of factor vm; they are compatible with those of leucocyte thromboplastin. The evidence that the activity they found might have been factor vm was that it shortened the clottingtime of factor vm-dencient plasma. This, however, leucocyte thromboplastin does equally well, and since their papers appeared it has been shown convincingly by several workers, including their co-author Dr Zacharski, that leucocytes or fibroblasts incubated in similar manner to that in their experiments develop a potent tissue-factor-like thromboplastin activity.3-6 We cannot explain the discrepancy they mention: that the activity they found hardly shortened the clotting-time of factor ix-deficient plasma. Their observation, however, is in conflict with all the subsequent studies, including those of their former co-author two years later6 and ourselves (unpublished). These studies have shown that when leucocytes3 47 or fibroblasts5 6 are incubated, activity develops within them which shortens the clotting-times of both factor-viii-deficient and factorix-deficient plasmas. For these reasons, and in view of their own evidence quoted above showing clearly that their activity was not factor vm, Bowie and Owen’s claim to have made the "original observation that leucocytes synthesise factor vm coagulant activity" ’
does not seem to be at all well founded. Department of Hæmatology, Hospital, Nottingham NG1 6HA General
T. E. BLECHER
Department of Child Life and Health,
O. B. EDEN
University of Edinburgh, Edinburgh EH9 1UW
E. M. INNES
DOSE OF CHENODEOXYCHOLIC ACID FOR GALLSTONE DISSOLUTION
SIR,-Now that doctors in Britain
are
free
to
prescribe
chenodeoxycholic acid (C.D.C.A.) for their gallstone patients, an article from a reputable department about the dose of C.D.C.A. is indeed timely (May 27, p. 1112). Unfortunately, however, the views expressed are, to say the least, controversial. Dr Bateson and his colleagues’ main theme is that patients should be given fixed doses of C.D.C.A. unrelated to body-weight. We believe that, on this advice, some patients will receive inadeamounts of C.D.C.A. which could result in months, or years, of ineffective treatment. By citing, and often misquoting, a few selected and nonrepresentative references in their introduction, the authors create the impression that there is widespread confusion about the doses of C.D.C.A. recommended by others. In fact, there is a large body of agreement among investigators throughout the world about how the dose should be tailored to the patient’s needs. They give four references, two of which came from our own unit at different stages in the evolution of our knowledge about C.D.C.A. Contrary to what they suggest, in an out-of-date study’ which was published in these columns four years ago, we did not find significant changes in biliary cholesterol saturation with 250-375 mg C.D.c.A./day. Indeed in that paper, although we talked about absolute doses of C.D.C.A., we also showed for the first time that there was a significant relationship between biliary cholesterol saturation and the dose of C.D.C.A. related to body-weight. Our second references in this
quate even
-
again misrepresented by the implication that we in favour of doses of 750-1000 mg/day. However, based on an analysis of those factors which we found influenced C.D.C.A.’s efficacy in dissolving gallstones, we stressed that the dose of C.D.C.A. should be related to body-weight and that the optimal dose was 14-15 mg C.D.C.A. kg-lday-1. Since then, this recommendation has been amply confirmed by other major investigators throughout the world. 3-5 There may be no a-priori reason for believing that the dose must be related to body-weight, but we emphatically deny that basing the daily dose of C.D.C.A. on body-weight is "an unnecessary complication". Until recently, the Dundee workers were reluctant to concede that it was ever necessary to use more than 750 mg C.D.c.A./day. Only now (since January, context was were
CELL-SURFACE MARKERS IN LYMPHOBLASTIC LEUKÆMIA two comments on the letter by Dr Kumar colleagues (July 15, p. 164). B-cell numbers falling with delay from time of sampling of the blood has happened to us in four cases this year. The first two patients certainly had B-cell leukxmia, with more than 80% staining with surface immunoglobulin in both instances; in posted samples the percentage staining was negligible. In both instances the cells regenerated surface immunoglobulin after trypsinisation and culture overnight. In the second two samples, the initial sur-
SIR,-We have
and
Zacharski, L. R., Bowie, E. J. W., Titus, J. L., Owen, C. A., Jr. Proc. Staff Meet. Mayo Clin. 1968, 43, 617. 2. Zacharski, L. R., Bowie, E. J. W., Titus, J. L., Owen, C. A., Jr. ibid. 1969, 44, 784. 3. Lerner, R. G., Goldstein, R., Cummings, G. Proc, Soc. exp. Biol. Med. 1971, 1.
138, 145. Loeb, W.F., Wall, R.L.J. Lab. clin. Med. 1972, 79, 778. 5. Green, D., Ryan, C., Malandruccolo, N., Nadler, H. L. Blood, 1971, 37, 47. 6. Zacharski, L. R., McIntyre, O. R. Thromb. Diath. hæmorrh. 1971, 26, 493. 7. Niemetz, J. Proc. Soc. exp. Biol. Med. 1972, 139, 1276. 4.
Mok, H. Y. I., Bell, G. D., Dowling, R. H. Lancet, 1974, ii, 253. Iser, J. H., Dowling, R. H., Mok, H. Y. I., Bell, G. D. New Engl. J. Med. 1975, 293, 378. 3. Thistle, J. L., Hofmann, A. F., Ott, B. J., Stephens, D. H.J. Am. med. Ass. 1978, 239, 1041. 4. Barbara, L., Roda, E., Roda, A., et al. Digestion, 1976, 14, 209. 5. Fromm, H., Erbler, H. C., Eschler, A., Schmidt, F. W. Klin. Wschr. 1976, 54, 1125. 6. Bateson, M. C., Ross, P. E., Murison, J., Bouchier, I. A. D. Gut, 1977, 18, A419, A976. 1. 2.
379
1977) that they have triedadose of 1000 mg/day do they find that they too are achieving more successful gallstone dissolution rates than before. 46-6% of their patients treated with the 1000 mg C.D.C.A. dose "responded to dissolution therapy" compared with 30% given the 750 mg dose despite the fact that 61% of their patients (17 out of 28) given 1000 mg c.D.c.A./day had "large" gallstones compared with only 37.5% (15 out of 40) given 750 mg/day. Since the 1000 mg C.D.C.A. dose corresponds to mean levels of 14.7-14.9 mg kg-’day-1, one could, with equal validity, argue that Bateson and his col- ’ leagues have finally come to the same conclusion reached by Iser et al. three years ago! Indeed it seems that they have had to increase their C.D.C.A. doses to levels equivalent to 14-15 mg kg-lday-1 in 24 of their patients because their gallstones persisted despite treatment with lower C.D.C.A. doses. No-one debates that small doses of C.D.C.A. (250-500 day) will occasionally dissolve gallstones. But surely we need to define not the minimum dose of C.D.C.A. (which works in only the occasional patient) but the optimum dose which will be effective in the large majority of patients. In support of their claims about the efficacy of smaller C.D.C.A. doses, Bateson et al. quote a widely misunderstood abstract by Danzingerfrom Winnipeg. But, as the authors must now be aware. Danziger himself stated publicly at a recent International Bile Acid Meeting in Freiburg that he too believed the optimum dose of C.D.C.A. to be not 250-500 mg or even 3-4 mg C.D.C.A. kg-1day-’(again doses which occasionally dissolve stones) but 12-15 mgkg-1day-1. We agree that there are occasional exceptions to the rule that gallstones dissolve only when fasting duodenal bile has been rendered unsaturated in cholesterol by treatment. But, provided that one considers only "concentrated" samples of duodenal bile arbitrarily containing >20 mmol/1 bile salts, in our experience these exceptions are very rare. However, it is unreasonable to imply, as Bateson and colleagues do, that gallstone "dissolution may occur in the absence of pronounced or indeed any change in cholesterol content" of bile. (Cholesterol content is an imprecise phrase since neither cholesterol concentration nor moles percent cholesterol adequately describe the saturation of bile with cholesterol). Of the three references which the authors quote to support this statement, one was the original 1972 study8 from the Mayo Clinic based on only 7patients, while the other two were from the senior author’s own studies. Indeed the results of bile-lipid analyses in one of these previous studies9 are so much at variance with the findings in other published work, and indeed with the pattern of results in the present article, that one must seriously question the validity of the methods used by the authors at that time. Furthermore, in the present study bile lipids were measured before and during treatment in only 14 out of 45 patients treated with 750 mg C.D.C.A. and in only 6 out of 40 patients who were given 1000 mg C.D.c.A./day. Can one really argue against the usefulness of bile lipid analysis as a predictor of subsequent gallstone dissolution when this was studied in just 6 patients given the 1000 mg dose? How can the authors justify such statements as "biliary lipid analysis only (our italics) leads to conclusions about groups"? This is completely contrary to our experience. Although we too think that it is both impractical and unnecessary for non-specialist units to monitor. the bile-lipid response to C.D.C.A. in all gallstone patients, nonetheless such analyses have yielded invaluable information in individual cases and have helped to define groups of patients who do not respond predictably to the usual recommended doses of C.D.C.A.IO 11
mg/
7. 8.
Danzinger, R. G. Gastroenterology, 1977, 72, 1042 (abst). Danzinger, R. G., Hofmann, A. F., Schoenfield, L. H., Thistle, J. L. New Engl.J. Med. 1972, 286, 1. 9. James, O., Cullen, J., Bouchier, I. A. D. Q.Jl. Med. 1975, 44, 349. 10. Iser, J H., Maton, P. N., Murphy, G. M., Dowling, R. H. Br. med. J. 1978, i, 1509. 11. Maton, P. N., Dowling, R. H. Eur.J. clin. Invest. (in the press).
Bateson and his colleagues come to the surprising conclusion that gallstone size did not influence the response to C.D.C.A. treatment. Not only is this finding contrary to first principles but it also conflicts with a large body of published evidence from around the world which shows that the smaller the gallstone, the more rapid its dissolution.
Gastroenterology Unit, Department of Medicine, Guy’s Hospital and Medical School,
R. HERMON DOWLING PAUL N. MATON
London SE1 9RT
*** This letter has been shown whose reply follows.-ED. L.
to
Dr Bateson and
colleagues
SIR,-We are grateful to Professor Dowling and Dr Maton for their comments on’our paper dealing with a comparison of fixed doses of C.D.C.A. It is a serious allegation to be accused of misquoting the literature and we take this opportunity to reply. Our interpretation of the paper by Mpk et al.l is that 4 of 7 patients receiving 250 mg of C.D.C.A. daily showed an improvement in biliary cholesterol saturation. This may not be "significant" statistically but it is impressive clinically. On rereading the paper by Iser et al. we believe that the authors stated quite clearly that they favoured a maintenance dose of C.D.C.A. of 750-1000 mg daily. Dowling’s views and ours do not differ on the dose of C.D.C.A. required for the typical patient with gallstones. Our communication made it clear that we no longer believe that 750 mg/day is adequate and now favour 1000 mg/day. This is the equivalent of 14-15 mg/kg body-weight/day for many patients and Dowling is correct in saying that we have come to the same conclusions as Iser et awl. It is a matter of opinion whether it is easier to prescribe according to body-weight or by a fixed dose, but in our experience a dose of 1000 mg will be sufficient for the great majority of patients. As Dowling well knows, the exceptionally obese patient appears to be resistant to "conventional" doses of C.D.C.A., however prescribed. We find it difficult to follow the argument regarding the therapeutic effect of 250-500 mg/day because at no time have we recommended this dose. Dowling criticises the conclusions of our 19753 paper. Having the benefit of greater experience we agree that these results were surprising. The reason is not invalid methodology, as suggested by Dowling and Maton, but rather that we did not then discard "dilute" samples of duodenal aspirate as we, and other workers including Dowling, do now. A review of the published data on C.D.C.A. therapy makes it clear that many workers have had individual patients whose gallstones appear to dissolve but in whom "spot" samples of fasting duodenal bile have not been consistently unsaturated. Indeed the reverse has also been observed and an example can be found in the paper by Iser et awl. This is the point we wished to emphasise in our paper. We would not deny that cholesterol unsaturation of bile is a prerequisite for gallstone dissolution and the data for the group as a whole bears this out. It is recognised that a spot sample does not necessarily reflect the composition of bile throughout the 24 h and it is quite likely that a fasting early morning specimen is indicative of the highest degree of biliary cholesterol saturation in the patient during the 24 h period. We too are surprised that gallstone size does not influence the response to C.D.C.A. therapy. There is no immediate explanation for this but we wonder whether the anomaly does not reflect the relative inaccuracy of attempting to document gallstone size radiologically. M. C. BATESON P. E. Ross University Department of Medicine, Ninewells Hospital, J. MURISON Dundee DD1 9SY
I. A. D. BOUCHIER
1. Mok, H. Y. I., Bell, G. D., Dowling, R. H. Lancet, 1974, ii, 253. 2. Iser, J. H., Dowling, R. H., Mok, H. Y. I., Bell, G. D. New
1975, 293, 379. 3. James, O., Cullen, J., Bouchier,
I. A. D.
Engl. J.
Q. Jl Med. 1975, 44, 349.
Med.
plasma from patients with Christmas disease very little. The shortening of the clotting-times of haemophilia-A plasma was much more pronounced. Such a discrepancy is difficult to ascribe to thromboplastin. E. J. W. BOWIE C. A. OWEN
Mayo Clinic and Foundation, Rochester, Minnesota 55901, U.S.A.
***This letter has been shown
face immunoglobulin level was high when the sample was tested fresh and low after posting, but after trypsinisation and culture the cells failed to regenerate immunoglobulin. This strongly suggests the need for this test to separate out those cells to which circulating immunoglobulin adheres, including non-B leukaemic cells which themselves are not producing immunoglobulin, from the true B-lymphoid type. These two patients both had lymphomas with leukaemic transformation and both had high lymphocyte-counts and low blast-counts. Accumulating evidence on cell-surface markers stresses the need for a whole battery of tests, the results being considered together before the leukaemic-cell type is decided on. We are not yet in a position to tailor treatment to cell type, but that time is fast approaching; furthermore subcategorisation is essential for discussing prognosis with the family and for analysis of survival curves.
to
Dr
Blecher, whose reply fol-
lows.-ED.L.
SiR,—The claim by Dr Bowie and Dr Owen that they pre-
viously demonstrated the synthesis of factor vm coagulant by leucocytes is most directly refuted by the evidence in their own
papers.l2 In these it is specifically stated2 that the "factor vm activity" was not reduced by incubation with an anti-factor-vm antibody. It is also stated that "in the leucocyte cultures, factor vm levels were reduced to virtually zero by centrifugation for 30 min at 25,000 g" and that "the activity was stable for 24 h at room temperature". These are not the properties of factor vm; they are compatible with those of leucocyte thromboplastin. The evidence that the activity they found might have been factor vm was that it shortened the clottingtime of factor vm-dencient plasma. This, however, leucocyte thromboplastin does equally well, and since their papers appeared it has been shown convincingly by several workers, including their co-author Dr Zacharski, that leucocytes or fibroblasts incubated in similar manner to that in their experiments develop a potent tissue-factor-like thromboplastin activity.3-6 We cannot explain the discrepancy they mention: that the activity they found hardly shortened the clotting-time of factor ix-deficient plasma. Their observation, however, is in conflict with all the subsequent studies, including those of their former co-author two years later6 and ourselves (unpublished). These studies have shown that when leucocytes3 47 or fibroblasts5 6 are incubated, activity develops within them which shortens the clotting-times of both factor-viii-deficient and factorix-deficient plasmas. For these reasons, and in view of their own evidence quoted above showing clearly that their activity was not factor vm, Bowie and Owen’s claim to have made the "original observation that leucocytes synthesise factor vm coagulant activity" ’
does not seem to be at all well founded. Department of Hæmatology, Hospital, Nottingham NG1 6HA General
T. E. BLECHER
Department of Child Life and Health,
O. B. EDEN
University of Edinburgh, Edinburgh EH9 1UW
E. M. INNES
DOSE OF CHENODEOXYCHOLIC ACID FOR GALLSTONE DISSOLUTION
SIR,-Now that doctors in Britain
are
free
to
prescribe
chenodeoxycholic acid (C.D.C.A.) for their gallstone patients, an article from a reputable department about the dose of C.D.C.A. is indeed timely (May 27, p. 1112). Unfortunately, however, the views expressed are, to say the least, controversial. Dr Bateson and his colleagues’ main theme is that patients should be given fixed doses of C.D.C.A. unrelated to body-weight. We believe that, on this advice, some patients will receive inadeamounts of C.D.C.A. which could result in months, or years, of ineffective treatment. By citing, and often misquoting, a few selected and nonrepresentative references in their introduction, the authors create the impression that there is widespread confusion about the doses of C.D.C.A. recommended by others. In fact, there is a large body of agreement among investigators throughout the world about how the dose should be tailored to the patient’s needs. They give four references, two of which came from our own unit at different stages in the evolution of our knowledge about C.D.C.A. Contrary to what they suggest, in an out-of-date study’ which was published in these columns four years ago, we did not find significant changes in biliary cholesterol saturation with 250-375 mg C.D.c.A./day. Indeed in that paper, although we talked about absolute doses of C.D.C.A., we also showed for the first time that there was a significant relationship between biliary cholesterol saturation and the dose of C.D.C.A. related to body-weight. Our second references in this
quate even
-
again misrepresented by the implication that we in favour of doses of 750-1000 mg/day. However, based on an analysis of those factors which we found influenced C.D.C.A.’s efficacy in dissolving gallstones, we stressed that the dose of C.D.C.A. should be related to body-weight and that the optimal dose was 14-15 mg C.D.C.A. kg-lday-1. Since then, this recommendation has been amply confirmed by other major investigators throughout the world. 3-5 There may be no a-priori reason for believing that the dose must be related to body-weight, but we emphatically deny that basing the daily dose of C.D.C.A. on body-weight is "an unnecessary complication". Until recently, the Dundee workers were reluctant to concede that it was ever necessary to use more than 750 mg C.D.c.A./day. Only now (since January, context was were
CELL-SURFACE MARKERS IN LYMPHOBLASTIC LEUKÆMIA two comments on the letter by Dr Kumar colleagues (July 15, p. 164). B-cell numbers falling with delay from time of sampling of the blood has happened to us in four cases this year. The first two patients certainly had B-cell leukxmia, with more than 80% staining with surface immunoglobulin in both instances; in posted samples the percentage staining was negligible. In both instances the cells regenerated surface immunoglobulin after trypsinisation and culture overnight. In the second two samples, the initial sur-
SIR,-We have
and
Zacharski, L. R., Bowie, E. J. W., Titus, J. L., Owen, C. A., Jr. Proc. Staff Meet. Mayo Clin. 1968, 43, 617. 2. Zacharski, L. R., Bowie, E. J. W., Titus, J. L., Owen, C. A., Jr. ibid. 1969, 44, 784. 3. Lerner, R. G., Goldstein, R., Cummings, G. Proc, Soc. exp. Biol. Med. 1971, 1.
138, 145. Loeb, W.F., Wall, R.L.J. Lab. clin. Med. 1972, 79, 778. 5. Green, D., Ryan, C., Malandruccolo, N., Nadler, H. L. Blood, 1971, 37, 47. 6. Zacharski, L. R., McIntyre, O. R. Thromb. Diath. hæmorrh. 1971, 26, 493. 7. Niemetz, J. Proc. Soc. exp. Biol. Med. 1972, 139, 1276. 4.
Mok, H. Y. I., Bell, G. D., Dowling, R. H. Lancet, 1974, ii, 253. Iser, J. H., Dowling, R. H., Mok, H. Y. I., Bell, G. D. New Engl. J. Med. 1975, 293, 378. 3. Thistle, J. L., Hofmann, A. F., Ott, B. J., Stephens, D. H.J. Am. med. Ass. 1978, 239, 1041. 4. Barbara, L., Roda, E., Roda, A., et al. Digestion, 1976, 14, 209. 5. Fromm, H., Erbler, H. C., Eschler, A., Schmidt, F. W. Klin. Wschr. 1976, 54, 1125. 6. Bateson, M. C., Ross, P. E., Murison, J., Bouchier, I. A. D. Gut, 1977, 18, A419, A976. 1. 2.
379
1977) that they have triedadose of 1000 mg/day do they find that they too are achieving more successful gallstone dissolution rates than before. 46-6% of their patients treated with the 1000 mg C.D.C.A. dose "responded to dissolution therapy" compared with 30% given the 750 mg dose despite the fact that 61% of their patients (17 out of 28) given 1000 mg c.D.c.A./day had "large" gallstones compared with only 37.5% (15 out of 40) given 750 mg/day. Since the 1000 mg C.D.C.A. dose corresponds to mean levels of 14.7-14.9 mg kg-’day-1, one could, with equal validity, argue that Bateson and his col- ’ leagues have finally come to the same conclusion reached by Iser et al. three years ago! Indeed it seems that they have had to increase their C.D.C.A. doses to levels equivalent to 14-15 mg kg-lday-1 in 24 of their patients because their gallstones persisted despite treatment with lower C.D.C.A. doses. No-one debates that small doses of C.D.C.A. (250-500 day) will occasionally dissolve gallstones. But surely we need to define not the minimum dose of C.D.C.A. (which works in only the occasional patient) but the optimum dose which will be effective in the large majority of patients. In support of their claims about the efficacy of smaller C.D.C.A. doses, Bateson et al. quote a widely misunderstood abstract by Danzingerfrom Winnipeg. But, as the authors must now be aware. Danziger himself stated publicly at a recent International Bile Acid Meeting in Freiburg that he too believed the optimum dose of C.D.C.A. to be not 250-500 mg or even 3-4 mg C.D.C.A. kg-1day-’(again doses which occasionally dissolve stones) but 12-15 mgkg-1day-1. We agree that there are occasional exceptions to the rule that gallstones dissolve only when fasting duodenal bile has been rendered unsaturated in cholesterol by treatment. But, provided that one considers only "concentrated" samples of duodenal bile arbitrarily containing >20 mmol/1 bile salts, in our experience these exceptions are very rare. However, it is unreasonable to imply, as Bateson and colleagues do, that gallstone "dissolution may occur in the absence of pronounced or indeed any change in cholesterol content" of bile. (Cholesterol content is an imprecise phrase since neither cholesterol concentration nor moles percent cholesterol adequately describe the saturation of bile with cholesterol). Of the three references which the authors quote to support this statement, one was the original 1972 study8 from the Mayo Clinic based on only 7patients, while the other two were from the senior author’s own studies. Indeed the results of bile-lipid analyses in one of these previous studies9 are so much at variance with the findings in other published work, and indeed with the pattern of results in the present article, that one must seriously question the validity of the methods used by the authors at that time. Furthermore, in the present study bile lipids were measured before and during treatment in only 14 out of 45 patients treated with 750 mg C.D.C.A. and in only 6 out of 40 patients who were given 1000 mg C.D.c.A./day. Can one really argue against the usefulness of bile lipid analysis as a predictor of subsequent gallstone dissolution when this was studied in just 6 patients given the 1000 mg dose? How can the authors justify such statements as "biliary lipid analysis only (our italics) leads to conclusions about groups"? This is completely contrary to our experience. Although we too think that it is both impractical and unnecessary for non-specialist units to monitor. the bile-lipid response to C.D.C.A. in all gallstone patients, nonetheless such analyses have yielded invaluable information in individual cases and have helped to define groups of patients who do not respond predictably to the usual recommended doses of C.D.C.A.IO 11
mg/
7. 8.
Danzinger, R. G. Gastroenterology, 1977, 72, 1042 (abst). Danzinger, R. G., Hofmann, A. F., Schoenfield, L. H., Thistle, J. L. New Engl.J. Med. 1972, 286, 1. 9. James, O., Cullen, J., Bouchier, I. A. D. Q.Jl. Med. 1975, 44, 349. 10. Iser, J H., Maton, P. N., Murphy, G. M., Dowling, R. H. Br. med. J. 1978, i, 1509. 11. Maton, P. N., Dowling, R. H. Eur.J. clin. Invest. (in the press).
Bateson and his colleagues come to the surprising conclusion that gallstone size did not influence the response to C.D.C.A. treatment. Not only is this finding contrary to first principles but it also conflicts with a large body of published evidence from around the world which shows that the smaller the gallstone, the more rapid its dissolution.
Gastroenterology Unit, Department of Medicine, Guy’s Hospital and Medical School,
R. HERMON DOWLING PAUL N. MATON
London SE1 9RT
*** This letter has been shown whose reply follows.-ED. L.
to
Dr Bateson and
colleagues
SIR,-We are grateful to Professor Dowling and Dr Maton for their comments on’our paper dealing with a comparison of fixed doses of C.D.C.A. It is a serious allegation to be accused of misquoting the literature and we take this opportunity to reply. Our interpretation of the paper by Mpk et al.l is that 4 of 7 patients receiving 250 mg of C.D.C.A. daily showed an improvement in biliary cholesterol saturation. This may not be "significant" statistically but it is impressive clinically. On rereading the paper by Iser et al. we believe that the authors stated quite clearly that they favoured a maintenance dose of C.D.C.A. of 750-1000 mg daily. Dowling’s views and ours do not differ on the dose of C.D.C.A. required for the typical patient with gallstones. Our communication made it clear that we no longer believe that 750 mg/day is adequate and now favour 1000 mg/day. This is the equivalent of 14-15 mg/kg body-weight/day for many patients and Dowling is correct in saying that we have come to the same conclusions as Iser et awl. It is a matter of opinion whether it is easier to prescribe according to body-weight or by a fixed dose, but in our experience a dose of 1000 mg will be sufficient for the great majority of patients. As Dowling well knows, the exceptionally obese patient appears to be resistant to "conventional" doses of C.D.C.A., however prescribed. We find it difficult to follow the argument regarding the therapeutic effect of 250-500 mg/day because at no time have we recommended this dose. Dowling criticises the conclusions of our 19753 paper. Having the benefit of greater experience we agree that these results were surprising. The reason is not invalid methodology, as suggested by Dowling and Maton, but rather that we did not then discard "dilute" samples of duodenal aspirate as we, and other workers including Dowling, do now. A review of the published data on C.D.C.A. therapy makes it clear that many workers have had individual patients whose gallstones appear to dissolve but in whom "spot" samples of fasting duodenal bile have not been consistently unsaturated. Indeed the reverse has also been observed and an example can be found in the paper by Iser et awl. This is the point we wished to emphasise in our paper. We would not deny that cholesterol unsaturation of bile is a prerequisite for gallstone dissolution and the data for the group as a whole bears this out. It is recognised that a spot sample does not necessarily reflect the composition of bile throughout the 24 h and it is quite likely that a fasting early morning specimen is indicative of the highest degree of biliary cholesterol saturation in the patient during the 24 h period. We too are surprised that gallstone size does not influence the response to C.D.C.A. therapy. There is no immediate explanation for this but we wonder whether the anomaly does not reflect the relative inaccuracy of attempting to document gallstone size radiologically. M. C. BATESON P. E. Ross University Department of Medicine, Ninewells Hospital, J. MURISON Dundee DD1 9SY
I. A. D. BOUCHIER
1. Mok, H. Y. I., Bell, G. D., Dowling, R. H. Lancet, 1974, ii, 253. 2. Iser, J. H., Dowling, R. H., Mok, H. Y. I., Bell, G. D. New
1975, 293, 379. 3. James, O., Cullen, J., Bouchier,
I. A. D.
Engl. J.
Q. Jl Med. 1975, 44, 349.
Med.
