805
Chenodeoxycholic-acid therapy is most effective patients with mild symptoms, a functioning gallbladder, and an unobstructed biliary tract. in
dissolution may take two years or "chenotherapy" is not suitable for patients
Because more,
stone
with colic, Six years ago K. J. ISSELBACHER asked, "Is prolonged chenodeoxycholic acid therapy safe?". We can now answer with a qualified "Yes". Fears that the feeding of this primary bile-salt would lead to accumulation of cholesterol within the body appear unfounded: bile-salt administration is accompanied by a reduction in bile-salt synthesis;2 there is no increase in total exchangeable body cholesterol. The other concern was that hepatotoxic lithocholic acid, the major bacterial degradation product of chenodeoxycholic acid, might accumulate. There are minor alterations in tests of conventional liver function but no consistent histological changes on light microscopy. The meaning of the increase in sinusoidal lipocytes observed on electron microscopy is uncertain.4-6 The safety of chenodeoxycholic acid in man seems to be related to the ability of human liver to sulphate any lithocholic acid which has been absorbed. Sulphated lithocholate is excreted readily into bile and, being water-soluble, is excreted in the faeces.6A second factor reducing the toxic potential of chenodeoxycholic acid is its epimerisation to ursodeoxycholic acid,which is not a preferred precursor for lithocholic acid. Chenodeoxycholic acid is rapidly and completely absorbed and is effectively excreted by the liver .8 It acts to reduce the hepatic secretory rate of cholesterol, thereby converting saturated bile to bile that is unsaturated with cholesterol. No constant or important influence has been observed on bile-saltpool size and secretion or on phospholipid secretion.9-10 The decreased cholesterol secretion is ascribed to a direct effect of the bile-acid on the enzyme which is rate-limiting for the biosynthesis of cholesterol,l1 although this interpretation has been challenged.12 The improved ability of the bile to solubilise cholesterol provides the milieu within which cholesterol stones can dissolve. There is no evidence that either pigment stones or stones containing much calcium are favourably affected. 1. Isselbacher, K. J. New Engl. J. Med. 1972, 286, 40. 2. Wilson, J. D. Archs intern. Med. 1972, 130, 493. 3. Pedersen, L., Arnfald, T., Thnysen, E. H. Scand. J. Gastroent. 1974, 9, 787. 4. Bell, G. D., Mok, H. Y. I., Thive, M., Murphy, G. M., Henry, K., Dowling, R. H. Gut, 1974, 15, 165. 5. Bateson, M. C., Hopwood, D., Bouchier, I. A. D. Am. J. dig. Dis. 1977, 22, 293. 6. Allan, R. N., Thistle, J. L., Hofmann, A. F., Carter, J. A., Yu, P. Y. S. Gut,
1976, 17, 405. 7. Salen, G., Tint, G. S., Eliav, B., et al. J. clin. Invest. 1974, 53, 612. 8. Van Berge-Henegouwen, G. P., Hofmann, A. F. Gastroenterology,
1977, 73,
300.
9. Adler,
R. D., Bennion, L. J., 326. 10. La Russo, N. F., Hoffman, N. J.L. ibid. 1975, 69, 1301.
Duane, W. C., Grundy, S. M. ibid. 1975, 68, E., Hofmann, A. F., Northfield, T. D., Thistle,
11. Shefer, S., Hauser, S., Lapur, V., Mosbach, E. H. J. Lipid Res. 1973, 14, 573. 12. Carrella, M., Dietschy, J. M.Am.J. dig. Dis. 1977, 22, 318.
or acute
cholecystitis.
How
know that the stones are cholesterol? Firstly, they should be radiolucent-though pigment stones can be non-radio-opaque, accounting for some treatment failures. Secondly, the stones are likely to consist of cholesterol if bile obtained by duodenal drainage is saturated with cholesterol. The aim of therapy is to render hepatic bile unsaturated with cholestetol and this can usually be achieved with a daily dose of 750-1000 mg or 15 mg chenodeoxycholic acid per kg.14 Some patients need less than 15 mg per kg per day, others more. Obesity is probably one of several factors inducing resistance to therapy.14,15 Intermittent therapy is ineffective.16 The only common side-effect is diarrhoea, which responds promptly to reduction in the dose. Several issues remain to be resolved. How is the effect of chenodeoxycholic acid to be judged? Regular cholecystography is necessary, probably at sixmonthly intervals. Bile obtained by duodenal drainage will show whether chenodeoxycholic acid has become the major biliary bile-salt and whether bile is unsaturated with cholesterol-i.e., whether the bile-acid is being taken in effective dosage-but do all patients need to be evaluated in this way? Opinions differ too on the wisdom of chenodeoxycholic acid treatment in women of childbearing age and in women taking the contraceptive pill. There is uncertainty about what to do once the stones have dissolved, because gallstones may recur when therapy stopS:14 should they carry on with full doses, reduce the dose, or take intermittent courses? These regimens have not been compared for safety. Chenodeoxycholic acid may prove useful for other purposes than dissolving cholesterol gallstones. The bile-salt is effective in treating hyper:iípidaemia,17,18 and there is a report suggesting an effect on migraine.19 Several investigators have noted regression of abdominal symptoms early during treatment. The reason is not clear, but let us hope that this valuable drug will not fall into disrepute because it is prescribed indiscriminately for the host of gastrointestinal complaints which are attributed, in the absence of radiological or biochemical abnormality, to some mystical disorder of hepatobiliary function. does
Chenodeoxycholic Acid
cholangitis,
one
13. Brunsgaard, A., Malver, E., Pedersen, L. R., Schlieting, P., Sylvest, J. Scand. J. Gastroent. 1977, 12, 97. 14. Dowling, R. H. Clins Gastroent. 1977, 6, 141. 15. Bateson, M. C., Ross, P. E., Murison, J., Bouchier, I. A. D. Gut, 1977, 18, 599. 16. Iser, J. H., Murphy, G. M., Dowling, R. H. ibid. p. 7. 17. Miller, N. E., Nestel, P. J. Lancet, 1974, ii, 929. 18. Bateson, M. C., Maclean, D., Evans, J. R., Bouchier, I. A. D. Br. J. clin. Pharm. 1978, 5, 249. 19. Lévy, V. G., Nusinovici, V., Rosner, D., Darnis, F. New Engl. J. Med. 1978,
298, 630.
Chenodeoxycholic-acid therapy is most effective patients with mild symptoms, a functioning gallbladder, and an unobstructed biliary tract. in
dissolution may take two years or "chenotherapy" is not suitable for patients
Because more,
stone
with colic, Six years ago K. J. ISSELBACHER asked, "Is prolonged chenodeoxycholic acid therapy safe?". We can now answer with a qualified "Yes". Fears that the feeding of this primary bile-salt would lead to accumulation of cholesterol within the body appear unfounded: bile-salt administration is accompanied by a reduction in bile-salt synthesis;2 there is no increase in total exchangeable body cholesterol. The other concern was that hepatotoxic lithocholic acid, the major bacterial degradation product of chenodeoxycholic acid, might accumulate. There are minor alterations in tests of conventional liver function but no consistent histological changes on light microscopy. The meaning of the increase in sinusoidal lipocytes observed on electron microscopy is uncertain.4-6 The safety of chenodeoxycholic acid in man seems to be related to the ability of human liver to sulphate any lithocholic acid which has been absorbed. Sulphated lithocholate is excreted readily into bile and, being water-soluble, is excreted in the faeces.6A second factor reducing the toxic potential of chenodeoxycholic acid is its epimerisation to ursodeoxycholic acid,which is not a preferred precursor for lithocholic acid. Chenodeoxycholic acid is rapidly and completely absorbed and is effectively excreted by the liver .8 It acts to reduce the hepatic secretory rate of cholesterol, thereby converting saturated bile to bile that is unsaturated with cholesterol. No constant or important influence has been observed on bile-saltpool size and secretion or on phospholipid secretion.9-10 The decreased cholesterol secretion is ascribed to a direct effect of the bile-acid on the enzyme which is rate-limiting for the biosynthesis of cholesterol,l1 although this interpretation has been challenged.12 The improved ability of the bile to solubilise cholesterol provides the milieu within which cholesterol stones can dissolve. There is no evidence that either pigment stones or stones containing much calcium are favourably affected. 1. Isselbacher, K. J. New Engl. J. Med. 1972, 286, 40. 2. Wilson, J. D. Archs intern. Med. 1972, 130, 493. 3. Pedersen, L., Arnfald, T., Thnysen, E. H. Scand. J. Gastroent. 1974, 9, 787. 4. Bell, G. D., Mok, H. Y. I., Thive, M., Murphy, G. M., Henry, K., Dowling, R. H. Gut, 1974, 15, 165. 5. Bateson, M. C., Hopwood, D., Bouchier, I. A. D. Am. J. dig. Dis. 1977, 22, 293. 6. Allan, R. N., Thistle, J. L., Hofmann, A. F., Carter, J. A., Yu, P. Y. S. Gut,
1976, 17, 405. 7. Salen, G., Tint, G. S., Eliav, B., et al. J. clin. Invest. 1974, 53, 612. 8. Van Berge-Henegouwen, G. P., Hofmann, A. F. Gastroenterology,
1977, 73,
300.
9. Adler,
R. D., Bennion, L. J., 326. 10. La Russo, N. F., Hoffman, N. J.L. ibid. 1975, 69, 1301.
Duane, W. C., Grundy, S. M. ibid. 1975, 68, E., Hofmann, A. F., Northfield, T. D., Thistle,
11. Shefer, S., Hauser, S., Lapur, V., Mosbach, E. H. J. Lipid Res. 1973, 14, 573. 12. Carrella, M., Dietschy, J. M.Am.J. dig. Dis. 1977, 22, 318.
or acute
cholecystitis.
How
know that the stones are cholesterol? Firstly, they should be radiolucent-though pigment stones can be non-radio-opaque, accounting for some treatment failures. Secondly, the stones are likely to consist of cholesterol if bile obtained by duodenal drainage is saturated with cholesterol. The aim of therapy is to render hepatic bile unsaturated with cholestetol and this can usually be achieved with a daily dose of 750-1000 mg or 15 mg chenodeoxycholic acid per kg.14 Some patients need less than 15 mg per kg per day, others more. Obesity is probably one of several factors inducing resistance to therapy.14,15 Intermittent therapy is ineffective.16 The only common side-effect is diarrhoea, which responds promptly to reduction in the dose. Several issues remain to be resolved. How is the effect of chenodeoxycholic acid to be judged? Regular cholecystography is necessary, probably at sixmonthly intervals. Bile obtained by duodenal drainage will show whether chenodeoxycholic acid has become the major biliary bile-salt and whether bile is unsaturated with cholesterol-i.e., whether the bile-acid is being taken in effective dosage-but do all patients need to be evaluated in this way? Opinions differ too on the wisdom of chenodeoxycholic acid treatment in women of childbearing age and in women taking the contraceptive pill. There is uncertainty about what to do once the stones have dissolved, because gallstones may recur when therapy stopS:14 should they carry on with full doses, reduce the dose, or take intermittent courses? These regimens have not been compared for safety. Chenodeoxycholic acid may prove useful for other purposes than dissolving cholesterol gallstones. The bile-salt is effective in treating hyper:iípidaemia,17,18 and there is a report suggesting an effect on migraine.19 Several investigators have noted regression of abdominal symptoms early during treatment. The reason is not clear, but let us hope that this valuable drug will not fall into disrepute because it is prescribed indiscriminately for the host of gastrointestinal complaints which are attributed, in the absence of radiological or biochemical abnormality, to some mystical disorder of hepatobiliary function. does
Chenodeoxycholic Acid
cholangitis,
one
13. Brunsgaard, A., Malver, E., Pedersen, L. R., Schlieting, P., Sylvest, J. Scand. J. Gastroent. 1977, 12, 97. 14. Dowling, R. H. Clins Gastroent. 1977, 6, 141. 15. Bateson, M. C., Ross, P. E., Murison, J., Bouchier, I. A. D. Gut, 1977, 18, 599. 16. Iser, J. H., Murphy, G. M., Dowling, R. H. ibid. p. 7. 17. Miller, N. E., Nestel, P. J. Lancet, 1974, ii, 929. 18. Bateson, M. C., Maclean, D., Evans, J. R., Bouchier, I. A. D. Br. J. clin. Pharm. 1978, 5, 249. 19. Lévy, V. G., Nusinovici, V., Rosner, D., Darnis, F. New Engl. J. Med. 1978,
298, 630.
