- Email: [email protected]
SYSTEMIC LUPUS ERYTHEMATOSUS AND MALIGNANT HISTIOCYTOSIS
1305
expected and does not imply that naloxone negates the placebo
ently
effect.
crease
et
given
D,
response to
al. use data on patients who and D2. Irrespective of their resubjects were allocated according to their re-
Subsequently,
Levine
received placebo both
at
sponses D1, sponses at D2 as placebo responders or placebo non-responders. The non-responders fared exactly as did those who had placebo at Dl and naloxone at D2. The conclusion reached is, again, that naloxone prevents the expression of the placebo response. The main difficulty here seems to be that in 17 patients who had placebo at both Dland D2, the response-rate at D2 was unexpectedly high (65%). Usual placebo responses are about 35%, and the patients given saline at Dl had a 39% response. (The figure of 65% is taken from the legend to fig. 4; in the text different figures are given [5 of 14, or 36%] but these do not accord with data given in Methods.) The naloxone results might not have been significantly different from those of a "normal" placebo group. It is also not clear whether drugs were given at 2 and 3 h after surgery (as in Methods) or at 3 and 4 h (as in Summary). Allocation was supposed to be at random, but the numbers in the treatment group differed markedly. In summary, many data in this paper are unclear, missing, or given erroneously. The conclusions are based on false assumptions of the existence of people who are consistent placebo responders, and on the observation of placebo analgesia in 65% of 17 patients. The problem under investigation is very important and answers to these points would be welcome. at
AMOS D. KORCZYN
** This letter has been shown
to
Dr Levine and Dr
Fields,
whose reply follows.-ED. L we
can
answer
the
points
that Dr
Korczyn raises. First, he suggests that we directly compare naloxone and placebo, given at the same time. In fact, we have published just such data. Using a crossover design we showed that naloxone produces hyperalgesia relative to placebo at 3 and 4 h after surgery. That study demonstrated naloxone-inducible hyperalgesia in opiate-naive subjects. That design, however, cannot, in contrast to Korczyn’s suggestion, demonstrate naloxone reversul of placebo. To make a statement about endorphin involvement in the placebo response, it is necessary to separate patients into placebo reactors and non-reactors. However, Korczyn criticises our attempts to define these two groups in our clinical paradigm. Thus, we are criticised for our selection of 60 min postdrug to assess the response to placebo, yet several studies of the "pharmacology" of placeb023 indicate that its peak effect is at approximately 1 h. Given this timing, it is really only necessary to test at 60 min to establish a significant effect. We do not argue whether consistent placebo reactors can be identified. However, we believe two points are worth stressing. The time course of the study was 4 h after the start of surgery onset and treatments were given at 2 and 3 h (and the time course of placebo is at least 3 h in most studies). Thus a positive placebo response should extend past the second administration of placebo. Furthermore, when we compared the responses to placebo given twice consecutively to a single patient, approximately two-thirds have the same response (or nonresponse) to both placebo administrations. The basic observation upon which our conclusion is based is that placebo responders (a group which we defined independ1.
Levine, J. D., Gordon, N. C., Jones, R. T., Fields, H. L. Nature, 1978, 272,
2.
Houde,
3.
Lasagna, L., Laties, V. G., Dohan, J. L. J. clin. Invest. 1958, 37, 533.
826. R.
placebo could, as suggested by Korczyn, explain finding. If our finding of naloxone hyperalgesia is accepted, figs 3 and 4 illustrate that the entire naloxone effect can be accounted for by an action on placebo responders. The bimodality of fig. 2 seems obvious to us, though it
this
would be difficult to find a statistical test to prove it. We did plot the data using several different band widths and boundaries without abolishing the apparent bimodality. The data simply support our contention that our definition of placebo reactor and non-reactor was not arbitrary. Korczyn’s point about the caption of fig. 4 is valid. The number of placebo responders should be 6 and the number of non-responders 11 (these were reversed in the final article and we failed to pick up this error). The number of positive placebo responders is thus 6/17 or 35% (not 5 or 14 given in the text). We discovered another error in rechecking our paper. In fig. 3, p<0-123 should read p
JON D. LEVINE HOWARD L. FIELDS
SYSTEMIC LUPUS ERYTHEMATOSUS AND MALIGNANT HISTIOCYTOSIS
SIR,-Dr Green and his colleagues (Oct. 7,
p. 753) report association between systemic lupus erythematosus (S.L.E.) and malignant lymphoma in four cases. We have seen a case of malignant histiocytosis diagnosed 9 months after the onset OfS.L.E. In October, 1973, a 24-year-old man presented with polyarthralgia, fever, and facial erythema. No abnormality of the lymphoid system was noted. Erythrocyte-sedimentation rate was 26 mm/h. Antinuclear antibodies were found at 1/4000 dilution. High titres of antibodies to single-stranded and double-stranded D.N.A.’ were present in serum. S.L.E. was diagnosed and anti-inflammatory therapy (profenic acid) was started. 9 months later, recurrence of fever and poor general condition led to another examination which revealed facial erythema, cutaneous infarcts of the fingertips, pleural effusion, generalised lymphadenopathy, hepatomegaly, and massive splenomegaly. Besides antinuclear and anti-D.N.A. antibodies, a direct Coombs’ test was positive. There was proteinuria (0.15 g/24 h). Kidney biopsy revealed focal proliferative glomerulonephritis with wire-loop type lesions and IgG and C3 deposits. Two lymph-node biopsies were done. In both lymphnode architecture was only partly obliterated. Pericapsular soft tissue was affected. Many lymphatic sinuses remained visible. Some of them were distended with atypical large cells with abundant, often basophilic, cytoplasm. Erythrophagocytic activity was noted in some cells. Malignant cells were also found in cortical and medullary areas among lymphocytes and rare plasmocytes. Mitotic figures were common. These lesions are consistent with malignant histiocytosis.1 3 Despite therapy (prednisone, cytarabine, cyclophosphamide, vincristine) the patient died in November, 1974. Malignant histiocytosis could perhaps be included in the spectrum of lymphoreticular malignancy associated with S.L.E. Early biopsy of suspect lymph-nodes is recommended in s.L.E. by Green et al. However, malignant lesions are rare while lymph-node enlargement occurs in about half of patients with S.L.E.4 In our experience non-specific reactive follicular hyperplasia, sometimes simulating nodular lymphoma, is the most an
Department of Neurology, Mount Sinai Medical School, New York, N.Y. 10029, U.S.A.
SIR,-We feel that
of response to naloxone) showed a much greater inin pain than did non-responders when naloxone was as D2. It is difficult to understand how inconsistency of
W., Wallenstein, S. L., Rogers, A. Clin. Pharmac. Ther. 1960, 1,
163.
common
finding.
In this
patient symptoms and signs of
S.L.E.
preceded
the
Wold, R. T., Young, F. E., Tan, E. M., Farr, R. S. Science, 1968, 161, 806. Byrne, G. E., Rappaport, H. Gann Monogr. Cancer Res. 1973, 15, 145. 3. Warnke, R. A., Kim, H., Dorfman, R. F. Cancer, 1975, 35, 215.
1. 2. 4.
Dubois,
E. L.
Lupus Erythematosus; p. 238.
Los
Angeles,
1974.
,
1306 clinical
onset
of
malignant symptoms by
9 months. No im-
munosuppressive therapy was given before the malignant histiocytosis developed. However, the timing invites speculation about the induction of autoimmune disorders in association with malignancy and the induction of both diseases by the same aetiological agent (virus ?). Laboratoire d’Immunopathologie Rénale, Service de Néphrologie et d’Hémodialyse, C.H.U. Toulouse-Purpan, 31052 Toulouse, France
GILBERT J. FOURNIE JEAN J. CONTE
Laboratoire d’Anatomie Pathologique, C.H.U. Toulouse-Purpan
GEORGES DELSOL JEAN FABRE
Service de Pneumologie, C.H.U. Toulouse-Rangueil
JEAN MIGUERES
ANDRÉ JOVER
MAINTENANCE AZATHIOPRINE IN CROHN’S DISEASE some comments on the interesting paper by Dr and O’Donoghue colleagues (Nov. 4, p. 955). O’Donoghue et al. do not mention any side-effects of azathioprine other than a case of fatal pancytopenia. Have they observed any other side-effects? The cumulative clinical recurrence-rate for patients who had been in hospital was found to be 17% by Greenstein et al.,1 a percentage that Greenstein et al. found to be high in comparison with other series. Others2 found a cumulative recurrence risk of 10% in the first year after excisional surgery with ileostomy for Crohn’s colitis and 5% yearly thereafter. Although the patients O’Donoghue et al. studied were not strictly comparable with these other two series I wonder why the cumulative recurrence risk for their placebo group was as high as 41% in one year, especially since their patients were in a "stable clinical state" when they entered the trial. The criteria for relapse were mainly clinical, with no radiological or histological data, and this can occasionally lead to
SIR,-I have
misinterpretation.
Singleton3 showed that azathioprine was no better than plaat 1 or 2 years, in preventing recurrence in patients who had either quiescent disease or had had surgical resection of all
cebo,
affected bowel in the year before entry. Moreover, azathioprine was potentially more dangerous than sulphasalazine or
prednisone. It could be argued that azathioprine is a dangerous drug (1 of 24 patients in O’Donoghue’s series died) with very
out
doubtful benefits in the long-term maintenance therapy of Crohn’s disease. It is therefore reassuring that O’Donoghue et al. do not give a firm recommendation for its use. General Hospital, Birmingham B4 6NH
** This letter has been shown whose reply follows.-ED. L.
GEORGE KITIS
to
the
Bart’s/St Mark’s group,
SIR,-Side-effects from azathioprine are seen in patients with Crohn’s disease, as in patients with other disorders treated with this drug. However, these adverse reactions, such as nausea, abdominal pain (including pancreatitis), fever, rash, or arthralgia, tend to develop within days or weeks of starting treatment. Our patients had been taking azathioprine for more than 6 months, and it is not therefore surprising that the sideeffects observed were limited to the one case reported. Exact comparability of treatment groups is difficult to achieve in a disorder as diverse in its clinical manifestations as Crohn’s disease. The relapse-rates observed at both hospitals 1. Greenstein, A. J., and others New Engl. J. Med. 2. Steinberg, D. M., and others Gut, 1974, 15, 845.
3.
Singleton, J. W. Gastroenterology, 1977, 72, 1133.
1975, 293, 685.
involved in this trial were closely similar. It seems unlikely that the small differences between the two treatment groups described by Dr Kitis affected the large difference in therapeutic response observed in the two groups. The papers on relapse-rate referred to by Kitis describe results after surgical treatment, and are not applicable to the patients with established disease in our trial. The term "stable clinical state" to describe the condition of the patients at the start of the trial was carefully chosen to indicate a group of patients whose disease was well controlled but not necessarily inactive. As pointed out in our paper, the dose of azathioprine used as a maintenance treatment in the American National Cooperative Crohn’s Disease Study was half that used in our trial, which may account for the different results. Azathioprine has been used in the treatment of approximately 300 patients with Crohn’s disease at our two hospitals without any fatality, other than the one described in our report. The drug does have potentially serious side-effects but, used cautiously and sensibly, it has a place in the treatment of some patients with Crohn’s disease. St Bartholomew’s London EC1
Hospital,
St. Mark’s Hospital, London EC1
D. P. O’DONOGHUE A. M. DAWSON
J. POWELL-TUCK R. L. BOWN J. E. LENNARD-JONES
COLONIC BACTERIA, GALLSTONES, AND DEOXYCHOLATE SiR,—Ishare Dr Low-Beer’s view that colonic bacteria play a major role in the pathogenesis of cholesterol gallstones, and his paper of Nov. 18 (p. 1063) provides important support for this belief. He and his co-worker found that the reduction in anaerobic bacterial activity in the colon as a result of metronidazole administration reduces the cholesterol saturation of bile and consequently the tendency to form gallstones. He suggests that this change is the result of the demonstrated decrease in the proportion of deoxycholate in the bile, yet nowhere in the paper does he show the causal nature of this association. The suggestion that deoxycholate selectively suppresses the synthesis of the gallstone-dissolving bile acid chenodeoxycholate is unconvincing since chenodeoxycholate is degraded by bacteria to lithocholate and is not, therefore, even the precur1 sor of deoxycholate. Furthermore, Low-Beer’s earlier work,’ cited in support of this suggestion, has not been confirmed.2 Similarly, whilst it is now established that bran causes a fall in both the deoxycholate content and cholesterol saturation of bile,3-5 no other study than the one he cites3 has shown that it increases the proportion of chenodeoxycholate. Any argument based on the percentage composition of a bile-acid pool of variable and unquantified size must be incomplete. What we need to know is the absolute amount of each bile acid perfusing the liver and thereby regulating bile-acid synthesis. Thus, whilst lithocholate constitutes only a small percentage of biliary bile, this is a consequence of its rapid excretion after hepatic sulphation, and it has been calculated that a greater amount of lithocholate than deoxycholate perfuses the liver each day.6 Low-Beer has clearly shown the colonic flora facilitate gall1. Pomare, E. W., Low-Beer, T. S. Clin. Sci. mol. Med. 1975, 48, 315. 2. La Russo, N. F., Szczepanik, P. A., Hofmann, A. F. Gastroenterology,
1977, 72, 132. 3. Pomare, E. W., Heaton, K. W., Low-Beer, T. S., Espiner, H. J. Am. J. dig. Dis. 1976, 21, 521. 4. Tarpila, S., Miettinen, T. A., Metsaranta, L. Gut, 1978, 19, 137. 5. Watts, J. McK., Jablonski, P., Toouii, J. Am. J. Surg. 1978, 135, 321. 6. Vlahcevic, Z. R., Prugh, M. F., Gregory, D. H., Swell, L. Clins Gastroent. 1977, 6, 25.
expected and does not imply that naloxone negates the placebo
ently
effect.
crease
et
given
D,
response to
al. use data on patients who and D2. Irrespective of their resubjects were allocated according to their re-
Subsequently,
Levine
received placebo both
at
sponses D1, sponses at D2 as placebo responders or placebo non-responders. The non-responders fared exactly as did those who had placebo at Dl and naloxone at D2. The conclusion reached is, again, that naloxone prevents the expression of the placebo response. The main difficulty here seems to be that in 17 patients who had placebo at both Dland D2, the response-rate at D2 was unexpectedly high (65%). Usual placebo responses are about 35%, and the patients given saline at Dl had a 39% response. (The figure of 65% is taken from the legend to fig. 4; in the text different figures are given [5 of 14, or 36%] but these do not accord with data given in Methods.) The naloxone results might not have been significantly different from those of a "normal" placebo group. It is also not clear whether drugs were given at 2 and 3 h after surgery (as in Methods) or at 3 and 4 h (as in Summary). Allocation was supposed to be at random, but the numbers in the treatment group differed markedly. In summary, many data in this paper are unclear, missing, or given erroneously. The conclusions are based on false assumptions of the existence of people who are consistent placebo responders, and on the observation of placebo analgesia in 65% of 17 patients. The problem under investigation is very important and answers to these points would be welcome. at
AMOS D. KORCZYN
** This letter has been shown
to
Dr Levine and Dr
Fields,
whose reply follows.-ED. L we
can
answer
the
points
that Dr
Korczyn raises. First, he suggests that we directly compare naloxone and placebo, given at the same time. In fact, we have published just such data. Using a crossover design we showed that naloxone produces hyperalgesia relative to placebo at 3 and 4 h after surgery. That study demonstrated naloxone-inducible hyperalgesia in opiate-naive subjects. That design, however, cannot, in contrast to Korczyn’s suggestion, demonstrate naloxone reversul of placebo. To make a statement about endorphin involvement in the placebo response, it is necessary to separate patients into placebo reactors and non-reactors. However, Korczyn criticises our attempts to define these two groups in our clinical paradigm. Thus, we are criticised for our selection of 60 min postdrug to assess the response to placebo, yet several studies of the "pharmacology" of placeb023 indicate that its peak effect is at approximately 1 h. Given this timing, it is really only necessary to test at 60 min to establish a significant effect. We do not argue whether consistent placebo reactors can be identified. However, we believe two points are worth stressing. The time course of the study was 4 h after the start of surgery onset and treatments were given at 2 and 3 h (and the time course of placebo is at least 3 h in most studies). Thus a positive placebo response should extend past the second administration of placebo. Furthermore, when we compared the responses to placebo given twice consecutively to a single patient, approximately two-thirds have the same response (or nonresponse) to both placebo administrations. The basic observation upon which our conclusion is based is that placebo responders (a group which we defined independ1.
Levine, J. D., Gordon, N. C., Jones, R. T., Fields, H. L. Nature, 1978, 272,
2.
Houde,
3.
Lasagna, L., Laties, V. G., Dohan, J. L. J. clin. Invest. 1958, 37, 533.
826. R.
placebo could, as suggested by Korczyn, explain finding. If our finding of naloxone hyperalgesia is accepted, figs 3 and 4 illustrate that the entire naloxone effect can be accounted for by an action on placebo responders. The bimodality of fig. 2 seems obvious to us, though it
this
would be difficult to find a statistical test to prove it. We did plot the data using several different band widths and boundaries without abolishing the apparent bimodality. The data simply support our contention that our definition of placebo reactor and non-reactor was not arbitrary. Korczyn’s point about the caption of fig. 4 is valid. The number of placebo responders should be 6 and the number of non-responders 11 (these were reversed in the final article and we failed to pick up this error). The number of positive placebo responders is thus 6/17 or 35% (not 5 or 14 given in the text). We discovered another error in rechecking our paper. In fig. 3, p<0-123 should read p
JON D. LEVINE HOWARD L. FIELDS
SYSTEMIC LUPUS ERYTHEMATOSUS AND MALIGNANT HISTIOCYTOSIS
SIR,-Dr Green and his colleagues (Oct. 7,
p. 753) report association between systemic lupus erythematosus (S.L.E.) and malignant lymphoma in four cases. We have seen a case of malignant histiocytosis diagnosed 9 months after the onset OfS.L.E. In October, 1973, a 24-year-old man presented with polyarthralgia, fever, and facial erythema. No abnormality of the lymphoid system was noted. Erythrocyte-sedimentation rate was 26 mm/h. Antinuclear antibodies were found at 1/4000 dilution. High titres of antibodies to single-stranded and double-stranded D.N.A.’ were present in serum. S.L.E. was diagnosed and anti-inflammatory therapy (profenic acid) was started. 9 months later, recurrence of fever and poor general condition led to another examination which revealed facial erythema, cutaneous infarcts of the fingertips, pleural effusion, generalised lymphadenopathy, hepatomegaly, and massive splenomegaly. Besides antinuclear and anti-D.N.A. antibodies, a direct Coombs’ test was positive. There was proteinuria (0.15 g/24 h). Kidney biopsy revealed focal proliferative glomerulonephritis with wire-loop type lesions and IgG and C3 deposits. Two lymph-node biopsies were done. In both lymphnode architecture was only partly obliterated. Pericapsular soft tissue was affected. Many lymphatic sinuses remained visible. Some of them were distended with atypical large cells with abundant, often basophilic, cytoplasm. Erythrophagocytic activity was noted in some cells. Malignant cells were also found in cortical and medullary areas among lymphocytes and rare plasmocytes. Mitotic figures were common. These lesions are consistent with malignant histiocytosis.1 3 Despite therapy (prednisone, cytarabine, cyclophosphamide, vincristine) the patient died in November, 1974. Malignant histiocytosis could perhaps be included in the spectrum of lymphoreticular malignancy associated with S.L.E. Early biopsy of suspect lymph-nodes is recommended in s.L.E. by Green et al. However, malignant lesions are rare while lymph-node enlargement occurs in about half of patients with S.L.E.4 In our experience non-specific reactive follicular hyperplasia, sometimes simulating nodular lymphoma, is the most an
Department of Neurology, Mount Sinai Medical School, New York, N.Y. 10029, U.S.A.
SIR,-We feel that
of response to naloxone) showed a much greater inin pain than did non-responders when naloxone was as D2. It is difficult to understand how inconsistency of
W., Wallenstein, S. L., Rogers, A. Clin. Pharmac. Ther. 1960, 1,
163.
common
finding.
In this
patient symptoms and signs of
S.L.E.
preceded
the
Wold, R. T., Young, F. E., Tan, E. M., Farr, R. S. Science, 1968, 161, 806. Byrne, G. E., Rappaport, H. Gann Monogr. Cancer Res. 1973, 15, 145. 3. Warnke, R. A., Kim, H., Dorfman, R. F. Cancer, 1975, 35, 215.
1. 2. 4.
Dubois,
E. L.
Lupus Erythematosus; p. 238.
Los
Angeles,
1974.
,
1306 clinical
onset
of
malignant symptoms by
9 months. No im-
munosuppressive therapy was given before the malignant histiocytosis developed. However, the timing invites speculation about the induction of autoimmune disorders in association with malignancy and the induction of both diseases by the same aetiological agent (virus ?). Laboratoire d’Immunopathologie Rénale, Service de Néphrologie et d’Hémodialyse, C.H.U. Toulouse-Purpan, 31052 Toulouse, France
GILBERT J. FOURNIE JEAN J. CONTE
Laboratoire d’Anatomie Pathologique, C.H.U. Toulouse-Purpan
GEORGES DELSOL JEAN FABRE
Service de Pneumologie, C.H.U. Toulouse-Rangueil
JEAN MIGUERES
ANDRÉ JOVER
MAINTENANCE AZATHIOPRINE IN CROHN’S DISEASE some comments on the interesting paper by Dr and O’Donoghue colleagues (Nov. 4, p. 955). O’Donoghue et al. do not mention any side-effects of azathioprine other than a case of fatal pancytopenia. Have they observed any other side-effects? The cumulative clinical recurrence-rate for patients who had been in hospital was found to be 17% by Greenstein et al.,1 a percentage that Greenstein et al. found to be high in comparison with other series. Others2 found a cumulative recurrence risk of 10% in the first year after excisional surgery with ileostomy for Crohn’s colitis and 5% yearly thereafter. Although the patients O’Donoghue et al. studied were not strictly comparable with these other two series I wonder why the cumulative recurrence risk for their placebo group was as high as 41% in one year, especially since their patients were in a "stable clinical state" when they entered the trial. The criteria for relapse were mainly clinical, with no radiological or histological data, and this can occasionally lead to
SIR,-I have
misinterpretation.
Singleton3 showed that azathioprine was no better than plaat 1 or 2 years, in preventing recurrence in patients who had either quiescent disease or had had surgical resection of all
cebo,
affected bowel in the year before entry. Moreover, azathioprine was potentially more dangerous than sulphasalazine or
prednisone. It could be argued that azathioprine is a dangerous drug (1 of 24 patients in O’Donoghue’s series died) with very
out
doubtful benefits in the long-term maintenance therapy of Crohn’s disease. It is therefore reassuring that O’Donoghue et al. do not give a firm recommendation for its use. General Hospital, Birmingham B4 6NH
** This letter has been shown whose reply follows.-ED. L.
GEORGE KITIS
to
the
Bart’s/St Mark’s group,
SIR,-Side-effects from azathioprine are seen in patients with Crohn’s disease, as in patients with other disorders treated with this drug. However, these adverse reactions, such as nausea, abdominal pain (including pancreatitis), fever, rash, or arthralgia, tend to develop within days or weeks of starting treatment. Our patients had been taking azathioprine for more than 6 months, and it is not therefore surprising that the sideeffects observed were limited to the one case reported. Exact comparability of treatment groups is difficult to achieve in a disorder as diverse in its clinical manifestations as Crohn’s disease. The relapse-rates observed at both hospitals 1. Greenstein, A. J., and others New Engl. J. Med. 2. Steinberg, D. M., and others Gut, 1974, 15, 845.
3.
Singleton, J. W. Gastroenterology, 1977, 72, 1133.
1975, 293, 685.
involved in this trial were closely similar. It seems unlikely that the small differences between the two treatment groups described by Dr Kitis affected the large difference in therapeutic response observed in the two groups. The papers on relapse-rate referred to by Kitis describe results after surgical treatment, and are not applicable to the patients with established disease in our trial. The term "stable clinical state" to describe the condition of the patients at the start of the trial was carefully chosen to indicate a group of patients whose disease was well controlled but not necessarily inactive. As pointed out in our paper, the dose of azathioprine used as a maintenance treatment in the American National Cooperative Crohn’s Disease Study was half that used in our trial, which may account for the different results. Azathioprine has been used in the treatment of approximately 300 patients with Crohn’s disease at our two hospitals without any fatality, other than the one described in our report. The drug does have potentially serious side-effects but, used cautiously and sensibly, it has a place in the treatment of some patients with Crohn’s disease. St Bartholomew’s London EC1
Hospital,
St. Mark’s Hospital, London EC1
D. P. O’DONOGHUE A. M. DAWSON
J. POWELL-TUCK R. L. BOWN J. E. LENNARD-JONES
COLONIC BACTERIA, GALLSTONES, AND DEOXYCHOLATE SiR,—Ishare Dr Low-Beer’s view that colonic bacteria play a major role in the pathogenesis of cholesterol gallstones, and his paper of Nov. 18 (p. 1063) provides important support for this belief. He and his co-worker found that the reduction in anaerobic bacterial activity in the colon as a result of metronidazole administration reduces the cholesterol saturation of bile and consequently the tendency to form gallstones. He suggests that this change is the result of the demonstrated decrease in the proportion of deoxycholate in the bile, yet nowhere in the paper does he show the causal nature of this association. The suggestion that deoxycholate selectively suppresses the synthesis of the gallstone-dissolving bile acid chenodeoxycholate is unconvincing since chenodeoxycholate is degraded by bacteria to lithocholate and is not, therefore, even the precur1 sor of deoxycholate. Furthermore, Low-Beer’s earlier work,’ cited in support of this suggestion, has not been confirmed.2 Similarly, whilst it is now established that bran causes a fall in both the deoxycholate content and cholesterol saturation of bile,3-5 no other study than the one he cites3 has shown that it increases the proportion of chenodeoxycholate. Any argument based on the percentage composition of a bile-acid pool of variable and unquantified size must be incomplete. What we need to know is the absolute amount of each bile acid perfusing the liver and thereby regulating bile-acid synthesis. Thus, whilst lithocholate constitutes only a small percentage of biliary bile, this is a consequence of its rapid excretion after hepatic sulphation, and it has been calculated that a greater amount of lithocholate than deoxycholate perfuses the liver each day.6 Low-Beer has clearly shown the colonic flora facilitate gall1. Pomare, E. W., Low-Beer, T. S. Clin. Sci. mol. Med. 1975, 48, 315. 2. La Russo, N. F., Szczepanik, P. A., Hofmann, A. F. Gastroenterology,
1977, 72, 132. 3. Pomare, E. W., Heaton, K. W., Low-Beer, T. S., Espiner, H. J. Am. J. dig. Dis. 1976, 21, 521. 4. Tarpila, S., Miettinen, T. A., Metsaranta, L. Gut, 1978, 19, 137. 5. Watts, J. McK., Jablonski, P., Toouii, J. Am. J. Surg. 1978, 135, 321. 6. Vlahcevic, Z. R., Prugh, M. F., Gregory, D. H., Swell, L. Clins Gastroent. 1977, 6, 25.