Alan F. Hofmann,


of bile and cholesterol with chenodeoxycholic M.D.


In Western European adults, fasting-state gallbladder bile is frequently saturated or supersaturated with cholesterol. The reason for this is unknown, but may relate to a high calorie high fat, high cholesterol intake as well as an eating pattern that often involves a 12- to 14-hr interval between the evening meal and breakfast the next morning. Genetic factors may also be important. Little information is available on the epidemiology of saturated or supersaturated fastingstate gall bladder bile because analysis of biliary lipids is a relatively recent technique, and collection of bile requires duodenal intubation. Indeed, we have little information on the epidemiology of cholesterol gallstone disease either in the past or at present We do not know whether the extremely high prevalence today in the western world estimated at nearly 10 % applies to the rest of the world, or whether there has been a marked increase in gallstone disease in recent years in this population This ignorance in part rebates to the relatively recent development of cholecystography, since cholelithiasis could not be diagnosed without baparotomy until this technique was available. Cholelithiasis, in its very early stages, is a benign pathological process, and current opinion is that the disease does not become symptomatic until the stones are of sufficient size that they can obstruct the cystic duct. Accordingly, the therapeutic approach for chobebithiasis has been to treat symptomatic advanced disease evidenced by cholecystitis or nonvisualization of the gablbladder, or both. In contrast to elevated blood cholesterol, which is treated without any evidence of arterial disease, elevated bile cholesterol is currently not treated, not only because its natural history is unknown but ,









The American


gallstone acid1’ 2



30: JUNE

because even if overt disease is demonstrated, treatment is deemed unnecessary unless symptoms occur or there is evidence that the surrounding organ the gallbladder is also diseased. Seven years ago, it was discovered that ingestion of one of the primary bile acids, chenodeoxychobic acid, causes desaturation of bile in gallstone patients (1). This discovery, which was not predicted, has bed to extensive clinical trials concerned with the efficacy and safety of chenodeoxychobic acid as a cholelitholytic agent In brief, based on experience in some 5000 patients, it now seems clear that chenodeoxycholic acid is an efficacious agent for cholesterol gallstone dissolution in the majority of patients, and, that indeed it will induce desaturation of bile in most patients (2). Therefore, if gallstones are composed of cholesterol, and if their cholesterol portions are accessible to bile then they will slowly dissolve The drug appears to be quite safe, but has not yet been acclaimed with enthusiasm because its effect on the saturation of bile is transient, and promptly stops when the drug is discontinued. Gallstone recurrence occurs in some patients when chenodeoxycholic acid treatment is stopped, and because of this, and also because of continuing questions about -












whether medical treatment will replace surgical treatment for this common disease. The purpose of this presentation is to review the rationale, efficacy, safety, and potential of chenodeoxycholic acid when used for the treatment of cholesterol gallstones. 1From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901. 2 The work reported here has been supported by Mayo Foundation, AM 16770.


pp. 993-1000.

and by NIH



in U.S.A.





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Desaturation dissolution











Bile acids are formed in the liver from cholesterol and are its water soluble excretory products. However, in man, the majority of cholesterol is excreted as such, and the conversion of cholesterol to bile acids is bimited. Indeed, man differs from a number of other animals in that dietary cholesterol is poorly absorbed, and the absorption of increased amounts of cholesterol is not associated with increased bile acid formation. Although less than half of the cholesterol which is excreted is in the chemical form of bile acids, biiary secretion of bile acids is 10 to 20 times that of cholesterol, since bile acids, in contrast to cholesterol, are efficiently reabsorbed from the intestine As a result, a barge pool (2 to 4 g) of bile acids circulates about twice with each meal. In man, two primary bile acids are formed from cholesterol, chobic acid and chenodeoxycholic acid. These are each conjugated with glycine or taurine and are excreted in bile As bile acids move through the liver cell, they induce the secretion of lecithin and cholesterol (6). Bile acids, after leaving the liver, are stored in the gallbladder, but little is known about the factors .








in the



intestine, but pass to the distal ileum, where an active transport site exists and is responsible for conservation of at least 90 % of the bile acid pool. The bile acids pass into the portal blood where they are largely bound to albumin On reaching the liver, they are efficiently extracted, single pass clearance for conjugated bile acids varying from probably 70 to 90 % The bile acids pass rapidly through the hepatocyte, again induce the secretion of lecithin and cholesterol, and the mixed bile acid-lecithin micelle is now present in the biiary canaliculus. The cyclical movement from intestine to liver to bile and back into the intestine is termed the “enterohepatic circulation.” Bile acids are lost rather slowly from the enterohepatic circulation, about one-third to one-fourth being lost daily. Accordingly, the mass of circulating bile acids composes a “pool” and its size may be determined by isotope dilution When this is done the specific activity decay curve shows a first-order decay, and from it one may calculate the .




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Bile is a concentrated micelbar solution in which cholesterol is solubilized in bile acidlecithin micelles. Extensive studies of model systems have defined the solubiity limits for varying concentrations of the two solubilizing lipids (3 4) and have indicated that the solubility of cholesterol in bile can be attributed essentially entirely to bile acids and lecithin (4). Complete bile analysis requires determination of bile acids, lecithin, and cholesterol, and when these values are known for any bile sample, it is possible to calculate the percentage saturation, using simple equations (5). Clearly, for cholesterol gallstones to form bile must be supersaturated with chobesterol. Cholesterol must nucleate The crystals must remain in the gallbladder, and must aggregate to form gallstones. Little is known about nucleation factors, crystal retention factors, and crystal aggregation factors.

determining the partitioning of bile between the gallbladder and the intestinal lumen. During the night, bile flow is less, and most bile acids are stored in the gallbladder. In man, when bile acid flow falls below 10 mol/kg per hr, such as occurs during overnight fasting, bile becomes supersaturated, not only in gallstone patients, but also in normal individuals (7). A key question, therefore is to what extent the supersaturated nocturnal bile is stored in the gaibbladder. Obviously, this depends on the tone of the sphincter of Oddi, but at present little information is available. With eating, cholecystokinin is released and the gallbladder contracts. Bile acids enter the small intestine as mixed bile acidlecithin-cholesterol micelles. Here the lecithin is partially hydrolyzed to lysolecithin and fatty acid, which are absorbed (8). The cholesterol is in part precipitated and part absorbed. The micelle changes its composition and new micelles, composed of bile acids, fatty acids, and monoglyceride, are formed. These mixed bile micebles serve to accelerate diffusion of the triglyceride digestion products through the unstirred layer up to the mucosab cell (9). The majority of bile








in individuals, but in general is 1 to 5 % and in many individuals it is the fourth most common bile acid in bile. ,

Bile secretion

in patients

with cholelithiasis

Patients with cholesterol cholelithiasis tend to have supersaturated fasting-state gallbladder bile, whereas patients without gallstones generally do not (14). It is not known whether the presence of supersaturated fasting-state gallbladder bile represents the storage of a greater fraction of nocturnal supersaturated bile, or whether the nocturnal bile is in fact far more saturated in gallstone patients than in patients without gallstones. Obesity is associated with excessive biiary cholesterol secretion (15 16), and it is tempting to speculate that nonobese gallstone patients have a decreased bile acid secretion ; but at the moment, the experimental results which have been obtained are equivocal (7). Perfusion techniques have now been developed for quantitating biliary lipid secretion, and we can expect extensive studies aimed at quantitating biiary lipid secretion in health and bibiary disease. ,




Chenodeoxycholic rationale





In the early 1960’s, preliminary evidence suggested that cholic acid might regulate cholesterol synthesis in man (17), and led Scott Grundy and me to plan experiments in which chenodeoxychobic acid would be fed. Chenodeoxycholic acid did not become commercially available until 1967, when Weddel Pharmaceuticals London arranged the synthesis of 2 kg of chenodeoxycholic acid for studies at the Mayo Clinic which were aimed at testing the effects of various bile acids on bile saturation These experiments, planned and conducted by Leslie Schoenfleld and Johnson Thistle, included careful measurements of bile saturation in duodenal bile samples before and after four months of administration of several bile acids. Early in 1969 they found that the four women who had received chenodoxycholic acid had bile which was less saturated, and in November, 1969, they reported their findings at a meeting of the M



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input of unlabeled bile acids into the pool, which is considered to be the synthetic rate (10). About one-third to one-fourth of the bile acid pool is lost each day. Bacterial biotransformations form new bile acids that are termed secondary bile acids, and these are reabsorbed in part to enter the enterohepatic circulation and join with the primary bile acids. Cholic acid is 7-dehydroxylated to form deoxycholic acid, and about onethird to one-half of this is absorbed and conjugated with glycine or taurine in the liver (1 1). Thus, in addition to the four primary bile acid conjugates, bile also contains the secondary bile acid conjugates, deoxycholyiglycine and deoxycholyltaurine. Chenodeoxycholic acid is 7-dehydroxylated to lithocholic acid, but this monohydroxy acid, in contrast to other bile acids, is quite insoluble at body temperature Only about one-fifth of that formed is absorbed from the colon, and when it passes through the liver, it is not only conjugated with glycine or taurine but also sulfated at the 3 position to form two new conjugates, sulfolithocholylglycine and sulfobithocholybtaurine (12, 1 3). Sulfation is not complete so that about two-thirds of the bithochobate occurring in bile is present as the sulfated conjugates and about one-third as the unsulfated conjugates. Chenodeoxycholic acid conjugates may also be dehydrogenated at the 7 position to form 3-hydroxy-7 keto-cholanoic acid. When this is absorbed from the small intestine it is reduced in part to an epimer of chenodeoxycholic acid, ursodeoxycholic acid (3a,7/3-dihydroxy-5f3-cholanoic acid), as well as to chenodeoxycholic acid The ursodeoxychobyb conjugates (and the chenodeoxycholyl conjugates) are also dehydrogenated at the 7 position, and when these newly formed 3-hydroxy-7 keto compounds are reabsorbed, they are again reduced to ursodeoxycholic acid and chenodeoxycholic acid. Thus, the chenodeoxycholic acid present in bile has two origins, one from hepatic biotransformation of cholesterol and the other from a 7 keto precursor, which is formed in the intestine by bacterial enzymes either from chenodeoxycholic acid or its epimer, ursodeoxycholic acid. The proportion of ursodeoxychobic acid in bile varies greatly




) ,



Mechanism acid





The daily excretion of cholesterol in bile can be quantitated by an intestinal perfusion technique and using this, Northfield and associates (30) showed that the ingestion of chenodeoxycholic acid decreases cholesterol secretion in bile by about 40 % but does not ,

cause any consistent change in bile acid or phospholipid secretion The effect of chenodeoxycholic acid cannot be explained by expansion of the pool size or increased bile acid secretion, since these do not occur in every patient taking chenodeoxychobic acid (18); further, expansion of the bile acid pool and increased bile acid secretion may also be induced with cholic acid, without the induction of bile desaturation or gallstone dissolution (31). Patients with gallstones appear to have elevated hepatic cholesterol synthesis, or at beast an elevated hepatic cholesterol synthe.

sis relative

to the


of bile



based on measurement of hepatic enzymes. Several groups, working independently, have reported that gallstone patients had a high ratio of hydroxymethyb glutarate-coenzyme A (HMG-CoA) reductase the ratelimiting enzyme for cholesterol synthesis, to cholesterol 7a-hydroxybase the rate-limiting enzyme for bile acid synthesis (32, 33). Administration of chenodeoxycholic acid causes the HMG-CoA reductase levels to return to that observed in healthy individuabs, and the current view is that chenodeoxycholic acid works by suppressing the synthesis or activation of hepatic HMGCoA reductase. The limited studies which are available suggest that chenodeoxycholic acid has no effect on blood levels of cholesterol and little effect, if any, on exchangeable pools of cholesterol (34, 35). Serum triglyceride bevels also do not change or may fall slightly. ,





It is now clear that chenodeoxycholic acid is completely absorbed from the gastrointestinal tract after oral ingestion (36). It passes to the liver where it is conjugated with glycine or taurine, and the chenodeoxycholyl conjugates circulate in the enterohepatic circubation. With continued feeding of chenodeoxychobic acid, the bile acids become composed predominantly of chenodeoxycholic acid, the proportion varying from 6090%, depending on the dosage (18). When the bile acid pool becomes composed of about 70% of chenodeoxycholyl conjugates, bile becomes unsaturated in the nonobese individual (28). The chenodeoxy-

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Central Society for Clinical Research (1) and subsequently in more detail in 1971 (18). In 1970, we began isotope dilution studies aimed at quantitating the effect of chenodeoxycholic acid on bile acid pool size and synthesis rate. These experiments, which were carried out largely by Danzinger (19), took place over about 18 months, during which time one patient was observed to show unequivocal gallstone dissolution. Thistle had also been continuing administration of chenodeoxycholic acid to several patients who had taken part in his original study, so that early in 1972 we (20) could report successful gallstone dissolution in four of seven patients. These initial results encouraged Thistle and myself to seek and subsequently obtain government support for a controlled trial which would compare chenodeoxycholic acid with chobic acid and placebo. This study, which has now been published (21 showed that the majority of patients taking chenodeoxycholic acid did dissolve their gallstones, whereas there was no response in the patients receiving cholic acid or placebo. Since our initial controlled study, there have been a number of studies published throughout the world (21-27). Based on dose response studies relating change in saturation to dosage (28), as well as clinical response it now appears that a dose of 1 2 to 1 5 mg/kg is necessary, even in the nonobese individual. Efficacy in patients who have received that dose is SQ to 70 % whereas efficacy in patients who have received lower doses is less. The majority of studies that have been reported have not been controlled, that is, have not contained a placebo group, but the incidence of spontaneous gallstone dissolution is quite low (29), and the ability of chenodeoxycholic acid to desaturate bile and induce gallstone dissolution is a certainty.








administration is still unclear, at least some of the liver damage appears attributable to lithocholic acid The rhesus monkey sulfates lithocholic acid quite poorly (42), and for a given dose, the proportion of lithocholic acid is much higher in the rhesus monkey than in man (43). Additional evidence implicating lithocholic acid in chenodeoxychobic acid-induced liver disease is a positive correlation between the proportion of lithocholic acid in bile and the extent of liver disease in rabbits (44), and the important observation that the liver damage may be decreased by the simultaneous administration of antibiotics with chenodeoxychobic acid (45). .

Safety No significant toxic effects of chenodeoxycholic acid have been observed to date in experience with over 3000 patients with gallstones, other than a single case of transient jaundice (2 38). Transaminase elevations have occurred in about one-fourth of the patients, but the mechanism of this is unclear. Since the enzyme elevation is not associated with elevation of other enzymes commonly considered to signal hepatic disease, and since no morphological damage has been observed in over 200 liver biopsies, the enzyme elevation appears to be a “false positive” test. It has been tempting to assign the mechanism of the elevated transaminase to lithocholate the bacterial metabobite of chenodeoxycholic acid, which is a potent hepatoxin in experimental animals (39). This is unlikely to be true in man, since there is no relationship between the transaminase elevation and the very slight increase in the proportion of bithochobic acid in biiary bile acids (40). Further, the administration of deoxycholic acid to normal volunteers also causes a transaminase elevation, and such individuals have virtually no bithocholic acid circulating in their enterohepatic circulation (41). Expansion of clinical trials with chenodeoxycholic acid has been slowed because of unequivocal toxicity in the rhesus monkey and baboon when these nonhuman primates were fed a dose comparable to that used in man, i.e. 40 mg/kg. Although the mechanism of liver damage induced in the nonhuman primate by chenodeoxycholic acid ,


Recurrence The

expanded slowly but now that chenodeoxycholic acid is licensed as an ethical drug in a number of countries, extensive information on efficacy, safety, and recurrence should soon become available Recurrence rates in the Mayo Clinic group and the Guy’s Hospital study, directed by R. Hermon Dowbing, are about 25 % and this figure can be expected to increase somewhat with time (46 47). When gallstones do recur, they respond promptly to chenodeoxybecause



of the














agement for patients with recurrent after a previous successful medical ment has not yet been defined. Other


of man-

stones treat-


A number of agents have now been claimed to induce gallstone dissolution in man, but at present, the only agent that has clearly induced gallstone dissolution is ursodeoxychobic acid, the 7/3 epimer of chenodeoxycholic acid (48). This finding, first reported by Makino, is of great interest since it provides information on the structural requirements for bile desaturation and is also of practical significance since ursodeoxycholic acid is apparently devoid of secretory properties in animal and an (49). Therefore, the diarrhea tht some patients observe when taking chenodeoxycholic acid should not be present when ursodeoxycholic acid is taken. Unfortunately, this acid will probably be more expensive to produce than chenodeox-

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cholic acid which escapes from the enterohepatic circulation is 7-dehydroxybated to form bithocholic acid, this event presumably occurring in the cecum About one-fifth of the lithochobic acid which is formed is absorbed, and as discussed above is completely conjugated and mostly sulfated (13). The sulfated lithocholyl conjugates are poorly reabsorbed from the small intestine, so that sulfation causes rapid fecal excretion. Admittedly, there is some desulfation and deconjugation during colonic passage, and a very small part of the lithocholic acid is absorbed once again to re-enter the enterohepatic circulation (37).




The future

modern medicine Chenodeoxycholic acid is an enterohepatic drug which acts specifically on hepatic synthesis of cholesterol. We must wonder whether there are classes of drugs yet to be discovered that will have a similar effect on peripheral synthesis of cholesterol. The discovery of such drugs would be of great therapeutic significance. .


In many ways, the discovery that chenodeoxychobic acid desaturates bile is analgous to the discovery that an extract of the adrenal cortex had striking anti-inflammatory properties in patients with rheumatoid arthritis. In each case an important pharmacologic property of a naturally occurring compound or class of compound was demonstrated. With the adrenal steroids, this bed to extensive structure-function relationships, and ultimately, to the synthesis of potent steroids which could be manufactured at low cost, and for which patent protection could be obtained The challenge now is to find such a patentable analogue for chenodeoxycholic acid, which can be produced at bow cost, and which will become a standard drug. The story of chenodeoxychobic acid has been a fascinating one for many reasons, one of the most important of which has been its differing toxicities in man and nonhuman primates. It seems likely that our ignorance of the pharmacological properties of chenodeoxychobic acid stemmed from the initial decision of Wieland and Windhaus to obtain their bile acids from ox bile, which contains little chenodeoxycholic acid. Had these pioneers in bile acid research used bile from another animal such as the hog, whose bile acids are rich in chenodeoxycholic acid, then chenodeoxychobic acid might have been a standard laboratory chemical, and its pharmacological properties discovered some decades previously. But at the moment, chenodeoxycholic acid is a potent drug useful for treating a common disease Since this common disease is also treated safely and permanently by cholecystectomy, we can expect a continuing debate about the relative merits of these two procedures, both of which appear to be examples of important achievements of ,



The feeding of one of the major biliary bile acids, chenodeoxycholic acid, at a dose of 1 0 to 1 5mg/kg per day causes the circubating bile acid pool to become greatly enriched in this bile acid. When chenodeoxycholic acid composes more than 70% of the biiary bile acids, the amount of cholesterol secreted in bile falls, and bile becomes unsaturated in cholesterol. If cholesterol gallstones are present and are exposed to this unsaturated bile, they will dissolve in 4 to 24 months in the majority of patients. Extensive clinical experience indicates that such medical therapy is safe despite unequivocal toxicity of chenodeoxycholic acid in several nonhuman primates. When therapy is stopped, bile resaturates, and stones may recur. Since chobecystecomy is a rapid, safe, effective and usually permanent treatment for all gallstones, the value of medical therapy remains uncertain at present, except for patients in whom surgery is inadvisable. Nonetheless, the demonstration that chenodeoxycholic acid ingestion will desaturate bile and induce gallstone dissolution would appear to be an important pharmacological advance. ,


The work summarized talented labors of numerous are cited in the bibliography. conducted entirely by Dr. responsible for much of the able today on efficacy and

here has resulted from the associates, most of whom Clinical studies have been Johnson L. Thistle, who is information currently availsafety.

References 1 . TmsmE, alteration lelithiasis. (abstr.).


J. L. , AND L. J. SCHOENFIELD. Induced of bile composition in humans with choJ. Lab. Clin. Med. 74: 1020, 1969.


odeoxycholic date, 1975. 1975.


F., AND G. PAUMGARTNER. ChenAcid Therapy of Gallstones: UpNew York: F. K. Schattauer Verlag,

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ychobic acid, and as yet relatively little information is available on either efficacy or safety. Early claims that phenobarbital induces bile desaturation have not been substantiated, although another enzyme inducer, Zanchol, has also been claimed to desaturate bile in preliminary experiments (50).


cholesterol lecithin.


F. G., AND in aqueous

H. D*is. solutions



The solubility of of bile salts and

Z Ernahrungswissenschaft





BORGSTR#{212}M, B. Phospholipid Lipid Absorption: Biochemical pects, edited by K. Rommel and


and Clinical H.




is regulated

by bile


J. Clin.









caster: MTP Press, 1976, pp. 65-70. 9. HOFMANN, A. F. Fat digestion: the interaction of lipid digestion products with micellar bile acid solutions. In: Lipid Absorption: Biochemical and Clinical Aspects, edited by K. Rommel and H. Goebell. Lancaster: MTP Press, 1976, pp. 3-18. 10. Hoi’.ii, A. F., AND N. E. HOFFMAN. Measurement of bile acid kinetics by isotope dilution in man. Gastroenterology 67: 314, 1974. 1 1 . HOFMANN, A. F. The enterohepatic circulation of bile acids in man. Adv. Internal. Med. 21: 501, 1976. 12. COWEN, A. E., M. G. KORMAN, A. F. HOFMANN AND 0. W. CASS. Metabolism of lithocholate in man . I . Biotransformation and biliary excretion of intravenously administered lithocholate, lithocholylglycine , and their sulfates . Gastroenterology 69: 59, 1975. 13. ALLAN, R. N., J. L. THISTLE AND A. F. HorMANN. Lithocholate metabolism during chenotherapy for gallstone dissolution. II Absorption and sulfation. Gut 17: 413, 1976. 14. ADMIRAND, W. H., AND D. M. SMALL. The physicochemical basis of cholesterol gallstone formation in man. J. Chin. Invest. 47: 1043, 1968. 15. GRUNDY, S. M., W. C. DUANE, R. D. ADLER, J. M. ARON AND A. L. METZGER. Biliary lipid outputs in young women with cholesterol gallstones. Metabolism 23: 67, 1974. 16. MABEE, T. M., P. MEYER, L. DENBESTEN AND E. E. MASON. The mechanism of increased gallstone formation in obese human subjects. Surgery 79: 460, 1976. 17. GRUNDY, S. M., A. F. HOFMANN, J. DAVIGNON AND E. H. AHRENS, JR. Human cholesterol synthesis











1018, 1966. (abstr.). THISTLE, J. L., AND L. J. SCHOENFIELD. Induced alterations in composition of bile of persons having cholelithiasis. Gastrcenterology 61 : 488, 1971. DANZINGER, R. G., A. F. HOFMANN, L. J.



AND J. L. Tmsma. Effect of oral chenodeoxycholic acid on bile acid kinetics and biiary lipid composition in women with cholelithiasis. J. Chin. Invest. 52: 2809, 1973. DANZINGER, R. G., A. F. HOFMANN, L. J. SCHOENFIELD AND J. L. Tmsrut. Dissolution of cholesterol gallstones by chenodeoxycholic acid. New EngI. J. Med. 286: 1 , 1972. Tmsm, J. L., AND A. F. HOFMANN. Efficacy and specificity of chenodeoxycholic acid therapy for dissolvinggallstones. New Engl. J. Med. 289: 655, 1973. ISER, J. H., R. H. DOWLING, H. Y. I. MOK AND G. D. BELL. Chenodeoxycholic acid treatment of gallstones. New Engl. J. Med. 293: 378, 1975. COYNE, M. J., G. BoNoiuus, A. CauG, L. I. GOLDSTEIN, D. LAHANA AND L. J. SCHOENFIELD. Treatment of gallstones with chenodeoxycholic acid and phenobarbital. New Engl. J. Med. 292: 604, 1975. BARBARA L., E. RODA, A. RODA, C. D. Fnsn, G. MAZZELLA AND R. ALDINI. The medical treatment of cholesterol gallstones: experience with chenodeoxycholic acid. Digestion 14: 209, 1976. FROMM, H., A. ESCHLER, D. TOLLNER, H. CANZLER AND F. W. ScHwixr. Untersuchungen zur Gallensteinauflosung in vivo. Dtsch. Med. Wochenschr. 100: 1619, 1975. GEROLAMI, A., H. SARLES, R. Ba’m, A. PARAF, J. RAUTEREAU, Cii. DEBRAY, C. BERMANN, J. P. ETIENNE, J. C. Cpi.n AND J. P. PEiim. Controlled trial of chenodeoxycholic therapy for radiolucent gallstones: a multicenter study. Digestion. In press. VAN WAES L, DE WEERT M, AND SCHURGERS M. Traitement de la Lithiase Biiare par l’Acide Chenique. Acta. Gastroenterol. Belg. 38: 24, 1975. THISTLE,J. L., A. F. HOFMANN,P. Y. S. YUAND B . J . Ou. Effect of varying doses of chenodeoxycholic acid on bile lipid and biliary bile acid composition in gallstone patients: a dose response study. Am. J. Digest. Diseases. 22: 1, 1977. WOLPERS, C. Spontanauflosung von Gallenblasensteinen. Dtsch. Med. Wochenschr. 93: 2525, 1968. NORTHFIELD, T. C., N. F. L.RUsso, A. F. HoeMANN AND J. L. Tmsmit. Biiary lipid output during three meals and an overnight fast. II. Effect of chenodeoxycholic acid treatment in gallstone subjects. Gut 16: 12, 1975. LARUSSO, N. F., N. E. HOFFMAN, A. F. HoeMANN, T. C. NORTHFIELD AND J. L. Tmsm. Effect of primary bile acid ingestion on bile acid metabolism and biiary lipid secretion in gallstone patients. Gastroenterology 69: 1301-1314, 1975. COYNE, M. J., G. G. BoNoiuus, L. I. GOLDSTEIN AND L. J. SCHOENFIELD. Effects of chenodeoxycholic acid on the rate limiting enzymes of hepatic cholesterol and bile acid synthesis in patients with gallstones. J. Lab. Clin. Med. 87: 281, 1976. SALEN, G., G. NICOLAU, S. SmuitR AND E. H. MOSBACH. Hepatic cholesterol metabolism in patiets with gallstones. Gastroenterology 69: 676, 1975.



T., M. MARSH, M. OLSZEWSKI AND K. Hoi. Cholesterol solubiity in bile: evidence that supersaturated bile is frequent in healthy man. J. Clin. Invest. 52: 1467, 1973. 5 . THOMAS, P. J. , AND A . F. HOFMANN. A simple calculation of the lithogenic index: expressing biiary lipid composition on rectangular coordinates. Gastroenterology 65: 698, 1973. 6. Scisusmri, T., S. NILSSON, E. Cahlin, M. FIUPSON AND G. BEODIN-PERSSON. Relationship between the biiary excretion of bile acids and the excretion of water, lecithin, and cholesterol in man. Eur. J. Chin. Invest. 1: 242, 1971. 7. NORTHFIELD, T. C., AND A. F. Hon.s. Biliary lipid output during three meals and an overnight fast. I. Relationship to bile acid pool size and cholesterol saturation of bile in gallstone and control subjects. Gut 16: 1, 1975. HOLZBACH,


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1000 34.








A. E., M. G. KORMAN, A. F. HOFMANN, 0. W. CASS AND S. B. Comz’. Metabolism of lithocholate in healthy man. II. Enterohepatic circulation. Gastroenterology 69: 67, 1975. MENGHINI, G . , AND B . PALLO1-rA. Marked increase in serum levels of liver enzymes in patients receiving chenic acid and phenobarbital for gallstone dissolution. Digestion 14: 163, 1976. PALMER, A. K., AND R. HEYWOOD. Pathological changes in the rhesus fetus associated with the oral administration of chenodeoxycholic acid. Toxicology 2: 239, 1974. ALLAN, R. N., J. L. Tmsmi, A. F. HOFMANN, J. A. CimR AND P. Y. S. YU. Lithocholate metabolism during chenotherapy for gallstone dissolution . I . Serum levels of sulfated and unsulfated COWEN,



















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Desaturation of bile and cholesterol gallstone dissolution with chenodeoxycholic acid.

Alan F. Hofmann, Biological of bile and cholesterol with chenodeoxycholic M.D. perspective In Western European adults, fasting-state gallbladder b...
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