Commentary
BILE SALTS AND THE SKIN J, L, BURTON, B.Sc,, M,D,, M.R.C.P. From the Department of Dermatology, Bristol Royal Infirmary, Bristol, Fngland
The ancient Greeks believed that symptoms were due to imbalance of the bilious humors. Ideas change, but most authors still believe that bile salts are responsible for the pruritis of obstructive jaundice. The best evidence for this belief was provided by Schoenfield et al,' who recovered bile salts from the skin of jaundiced patients with pruritis. The concent>-ations of the recovered bile salts were higher than in similar patients without pruritis, and the levels decreased to normal on the same day that the pruritis disappeared. However, the evidence has not been completely convincing because the correlation between the total circulating bile salt concentration and the severity of pruritis is poor,^ and several attempts to induce itching by applying bile salts to the skin topically or by iontophoresis have been unsuccessful. Moreover, the intravenous and the oral administration of pure cholate has not provoked itching,•'•'* although crude bile salt ingestion did exacerbate pruritis in a few patients with biliary cirrhosis,^ These discrepancies could be explained if the various bile salts differed in their ability to provoke pruritis, and two groups have recently produced evidence to support this idea, Varadi*" found chen-
odeoxycholate to be more effective than cholate in producing pruritis when it was applied under occlusion to keratin-stripped skin, and Kirby et al,,' using the blister-base technique, confirmed that dihydroxy bile salts such as chenodeoxycholate and deoxycholate are more effective pruritogens than the trihydroxy salts such as cholates. The ratio of chenodeoxycholate to cholate tends to increase in cholestasis,^ and cholestyramine, which relieves the pruritis of obstructive jaundice, has been shown to bind the dihydroxy bile salts preferentially.** It is possible, therefore, that a change in the proportion of the dihydroxy bile salts could account for the discrepancy observed between total bile salt concentration and the severity of the pruritis. Mechanism The mechanism by which bile salts might cause cutaneous irritation is speculative, but they are toxic to various cell preparations in vitro, and this nonspecific cytotoxicity is thought to relate to their detergent effect on lipid membranes.^ The dihydroxy salts are more cytotoxic than the trihydroxy salts and the increased toxicity correlates with the increased surface activity of the dihydroxy salts. Bile salts liberate small quantities of histamine on perfusion of animal skin,'" and blood histamine levels increase in experimental obstructive jaundice,'^ but the poor cor-
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relation between pruritis and plasma histamine in liver disease'" and the poor therapeutic response to antihistamines suggests that histamine is not the major mediator of pruritis in obstructive jaundice. The most toxic bile salts such as lithocholate have been shown to be capable of disrupting (ysosomes in vitro, and lysosomal damage results in the release of proteolytic enzymes, which are potent pruritogens. McGuire'-' has suggested that proteolytic enzymes may also produce pigmentation by activating epidermal tyrosinase. If this is so, it is possible that the continued release of low concentrations of proteolytic enzymes in the skin due to the toxic detergent effects of bile salts could account for both the pigmentation and the pruritis of patients with chronic obstructive jaundice. References 1. Schoenfield, I. |., Sjovall, L, and Perman, E., Bile acids on the skin of patients with pruritic hepato-biliary disease. Nature 213:93, 1967. 2. Neale, G., Lewis, B., Weaver, V., and Panveliwella, D., Serum bile acids in liver disease. 12:145, 1971. 3. Carey, |. B., The serum trihydroxy-dihydroxy
4.
5.
6. 7. 8.
9. 10. 11. 12. 13.
Burton
199
bile acid ratio in liver and biliary tract disease. ). Clin. Invest. 37:1494, 1958. Osborn, E. C, Da Silva, L. C, Sher(ock, Sheila, and Wooton, I. D. P., Serum bileacid levels in liver disease. Lancet 2:1049, 1959. Ahrens, H. H., Jr., Payne, M. A., Kunkel, H. C , Eisenmenger, W. J., and Blondheim, S. H., Primary biliary cirrhosis. Medicine 29: 299, 1950. Varadi, D. P., Pruritus induced by Crude Bile and Purified Bile Acids Archives of Dermatology, 109:678. Kirby, J., Heaton, K. W., and Burton, J. L., Pruritic effect of bile salts. Br. Med. J. 4:693, 1974. Johns, W. H., and Bates, T. R., Quantification of the binding tendencies of cholestyramine: II. Mechanism of interaction with bile salt and fatty acid salt anions. |. Pharm. Sci. 59:329, 1970. Heaton, K. W., Bile Salts in Health and Disease. London, Churchill Livingstone, 1972, p. 117. Schachter, M., The release of histamine by pethidine, atropine, quinine and other drugs. Br. J. Pharmacol. 7:646, 1952. Anrep, G. V., and Barsoum, G. S., Blood histamine in experimental obstruction of the common bile duct. J. Physiol. 120:427, 1953. Mitchell, R. G., Butt, H. R., and Code, C. F., Histamine metabolism in diseases of tbe liver. J. of Clin. InvesL 33:1199, 1954. McGuire, J. S., Activation of epidermal tyrosinase. Invest. Dermatol. 56:249, 1971.
Demodex Folliculorum. P. Megnin publishes a memoir on this parasite. The Demodex folliculorum belongs to the order of acari, but not to the family of the sarcoptides, to which latter the itch insect belongs. It constitutes, according to the author and Prof. Cervais, the only genus of a family of demodicides. There are different species upon different animals; the demodex of man differs from that of the dog, cat, sheep, etc. This difference can only be made out in the larval state, since the adult mites resemble each other in a high degree.—Arch. Dermatol. 4:168, 1879.
BILE SALTS AND THE SKIN J, L, BURTON, B.Sc,, M,D,, M.R.C.P. From the Department of Dermatology, Bristol Royal Infirmary, Bristol, Fngland
The ancient Greeks believed that symptoms were due to imbalance of the bilious humors. Ideas change, but most authors still believe that bile salts are responsible for the pruritis of obstructive jaundice. The best evidence for this belief was provided by Schoenfield et al,' who recovered bile salts from the skin of jaundiced patients with pruritis. The concent>-ations of the recovered bile salts were higher than in similar patients without pruritis, and the levels decreased to normal on the same day that the pruritis disappeared. However, the evidence has not been completely convincing because the correlation between the total circulating bile salt concentration and the severity of pruritis is poor,^ and several attempts to induce itching by applying bile salts to the skin topically or by iontophoresis have been unsuccessful. Moreover, the intravenous and the oral administration of pure cholate has not provoked itching,•'•'* although crude bile salt ingestion did exacerbate pruritis in a few patients with biliary cirrhosis,^ These discrepancies could be explained if the various bile salts differed in their ability to provoke pruritis, and two groups have recently produced evidence to support this idea, Varadi*" found chen-
odeoxycholate to be more effective than cholate in producing pruritis when it was applied under occlusion to keratin-stripped skin, and Kirby et al,,' using the blister-base technique, confirmed that dihydroxy bile salts such as chenodeoxycholate and deoxycholate are more effective pruritogens than the trihydroxy salts such as cholates. The ratio of chenodeoxycholate to cholate tends to increase in cholestasis,^ and cholestyramine, which relieves the pruritis of obstructive jaundice, has been shown to bind the dihydroxy bile salts preferentially.** It is possible, therefore, that a change in the proportion of the dihydroxy bile salts could account for the discrepancy observed between total bile salt concentration and the severity of the pruritis. Mechanism The mechanism by which bile salts might cause cutaneous irritation is speculative, but they are toxic to various cell preparations in vitro, and this nonspecific cytotoxicity is thought to relate to their detergent effect on lipid membranes.^ The dihydroxy salts are more cytotoxic than the trihydroxy salts and the increased toxicity correlates with the increased surface activity of the dihydroxy salts. Bile salts liberate small quantities of histamine on perfusion of animal skin,'" and blood histamine levels increase in experimental obstructive jaundice,'^ but the poor cor-
198
No. 3
BILE SALTS AND THE SKIN
relation between pruritis and plasma histamine in liver disease'" and the poor therapeutic response to antihistamines suggests that histamine is not the major mediator of pruritis in obstructive jaundice. The most toxic bile salts such as lithocholate have been shown to be capable of disrupting (ysosomes in vitro, and lysosomal damage results in the release of proteolytic enzymes, which are potent pruritogens. McGuire'-' has suggested that proteolytic enzymes may also produce pigmentation by activating epidermal tyrosinase. If this is so, it is possible that the continued release of low concentrations of proteolytic enzymes in the skin due to the toxic detergent effects of bile salts could account for both the pigmentation and the pruritis of patients with chronic obstructive jaundice. References 1. Schoenfield, I. |., Sjovall, L, and Perman, E., Bile acids on the skin of patients with pruritic hepato-biliary disease. Nature 213:93, 1967. 2. Neale, G., Lewis, B., Weaver, V., and Panveliwella, D., Serum bile acids in liver disease. 12:145, 1971. 3. Carey, |. B., The serum trihydroxy-dihydroxy
4.
5.
6. 7. 8.
9. 10. 11. 12. 13.
Burton
199
bile acid ratio in liver and biliary tract disease. ). Clin. Invest. 37:1494, 1958. Osborn, E. C, Da Silva, L. C, Sher(ock, Sheila, and Wooton, I. D. P., Serum bileacid levels in liver disease. Lancet 2:1049, 1959. Ahrens, H. H., Jr., Payne, M. A., Kunkel, H. C , Eisenmenger, W. J., and Blondheim, S. H., Primary biliary cirrhosis. Medicine 29: 299, 1950. Varadi, D. P., Pruritus induced by Crude Bile and Purified Bile Acids Archives of Dermatology, 109:678. Kirby, J., Heaton, K. W., and Burton, J. L., Pruritic effect of bile salts. Br. Med. J. 4:693, 1974. Johns, W. H., and Bates, T. R., Quantification of the binding tendencies of cholestyramine: II. Mechanism of interaction with bile salt and fatty acid salt anions. |. Pharm. Sci. 59:329, 1970. Heaton, K. W., Bile Salts in Health and Disease. London, Churchill Livingstone, 1972, p. 117. Schachter, M., The release of histamine by pethidine, atropine, quinine and other drugs. Br. J. Pharmacol. 7:646, 1952. Anrep, G. V., and Barsoum, G. S., Blood histamine in experimental obstruction of the common bile duct. J. Physiol. 120:427, 1953. Mitchell, R. G., Butt, H. R., and Code, C. F., Histamine metabolism in diseases of tbe liver. J. of Clin. InvesL 33:1199, 1954. McGuire, J. S., Activation of epidermal tyrosinase. Invest. Dermatol. 56:249, 1971.
Demodex Folliculorum. P. Megnin publishes a memoir on this parasite. The Demodex folliculorum belongs to the order of acari, but not to the family of the sarcoptides, to which latter the itch insect belongs. It constitutes, according to the author and Prof. Cervais, the only genus of a family of demodicides. There are different species upon different animals; the demodex of man differs from that of the dog, cat, sheep, etc. This difference can only be made out in the larval state, since the adult mites resemble each other in a high degree.—Arch. Dermatol. 4:168, 1879.
