bile salts and gallstone disease

The British Journal of Surgery Vol. 62 : No. 7 : July 1975

Br. J. Surg. Vol. 62 (1975) 505-512

Bile salts and gallstone disease C O L I N MACKAY*

SUMMARY Bile salts play an important role in maintaining cholesterol in aqueous solution in bile. There is evidence that in some patients at least gallstones arise as a result of bile salt deficiency. The evidence to date suggests that although oral bile salts may be of use in treating some gallstone patients they are unlikely to replace cholecystectomy in the foreseeable future. The instillation of bile salts via an indwelling T-tube may well bt. of great use in the management of stones retained in the common duct after choledocholithotomy. There is no doubt that in this branch of medicine as in all others prevention is better than cure and our aim should be to pt 'r f ect our technique so that we do not leave stones behind. How- ever, should the situation occur we may soon have safe efectiue physiological solvents to dissolve our mistakes.

GALLSTONE disease is a very common condition and there is evidence that it is becoming even commoner (Holland and Heaton, 1972). Although no accurate figures are available, probably about 10 per cent of the population of the United Kingdom aged over 40 years have gallstones most of which will be cholesterol in type (Sutor and Wooley, 1971). In this review three aspects will be considered: how bile salts maintain cholesterol in aqueous solution in bile, the part played by bile salts in the aetiology of gallstone disease and the role of bile salts in the treatment of gallstone disease.

Physiology Bile salts are synthesized in the liver from cholesterol (Bergstrom and Danielsson, 1968; Mosbach, 1972), and indeed they constitute the major pathway of cholesterol excretion by the body. In man there are two primary bile acids, cholic and chenodeoxycholic, and these are excreted in bile conjugated with glycine or taurine. After entering the small bowel they pass along its length before being actively reabsorbed in the terminal ileum. This is normally a most efficient process such that some 95 per cent of bile salts are reabsorbed to return via the portal circulation to the liver and be re-excreted in bile. The bile salts in the enterohepatic circulation constitute the bile salt pool, which in man amounts to 2 4 g and recirculates two or three times during the digestion of a single meal.

A small percentage of bile salts pass through the terminal ileum into the colon where they encounter bacterial enzymes. These enzymes produce deconjuga- tion and dehydroxylation such that the glycine and taurine moieties are split off and cholate is dehydroxy- lated to deoxycholate and chenodeoxycholate to lithocholate. Deoxycholate is reabsorbed and returns in the portal circulation to the liver where it is conjugated with glycine or taurine and excreted in bile as a secondary bile salt. Lithocholate, on the other hand, is insoluble and is excreted in the stool so that in man only trace amounts are present in bile. Thus in human bile there are normally glycine and taurine conjugates of cholic, chenodeoxycholic and deoxycholic acids.

The principal lipids in bile in addition to the bile salts are cholesterol and phospholipid which is almost entirely lecithin. Each of these three substances is amphiphilic, i.e. part of the molecule is soluble in water and part is soluble in fat solvents. The taurine and glycine moieties of bile salts, together with the hydroxyl groups, are so strongly water soluble that they bring the whole molecule into aqueous solution and so bile salts are water soluble. However, this is not so with lecithin and cholesterol. The water soluble portions of these molecules are relatively so small that they are not strong enough to bring the rest of the molecule into aqueous solution and so lecithin and cholesterol are not soluble in water. The principal function of bile salts in bile is to maintain in aqueous solution these two substances, lecithin and cholesterol. A description of the physicochemical processes involved is beyond the scope of this article but the subject has been well reviewed by Carey and Small (1970); suffice it to say that this process of solubilization is brought about by the formation of mixed micelles-structures with a water soluble coating and a water insoluble core. In bile the bile salts form the water soluble coating and lecithin and cholesterol the water insoluble core. Lecithin, although itself insoluble in water, plays an important role in enhanc- ing the solubility of cholesterol in bile salt micelles. Bile salt micelles are able to dissolve relatively small amounts of cholesterol, but in the presence of lecithin

* University Department of Surgery, Western Infirmary, Glasgow.

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Colin MacKay

Fig. 1. Triangular coordinate plot showing physicochemical characteristics of solutions containing different proportions of bile salt, cholesterol and lecithin.

100 95 90 85 80 75 70 65 60 55 50 yo Bile salt

Fig. 2. Relative composition of hepatic bile obtained at the time of cholecystectomy from 103 gallstone patients.

the micelle is expanded and the cholesterci solubility enhanced.

In the small intestine bile salts play an important role in the digestion and absorption of fat. They aid in the emulsification of fat, help activate pancreatic lipase and render water soluble the products of pancreatic lipolysis. Pancreatic lipase hydrolyses tri- glyceride into monoglyceride and fatty acid, substances which are insoluble in water but which are rendered water soluble by the formation of mixed micelles with bile salts. Bile salts are similarly involved in the absorption of the fat soluble vitamins.

Bile salts and aetiology of gallstones We have established the role of bile salts in maintaining cholesterol in aqueous solution in bile. This process

was further elucidated by Admirand and Small (1968), who constructed an in vitro model system which allowed the prediction of the maximum amount of cholesterol which could be dissolved in aqueous solutions containing varying proportions of bile salt and lecithin. They expressed their results on triangular coordinates and constructed a phase diagram as shown in Fig. 1. All mixtures whose relative composition lay within the shaded area were in micellar solution whereas all others contained crystals of cholesterol. They then studied the relative amounts of bile salt, cholesterol and phospholipid in gallbladder bile from patients with cholesterol gallstones and in bile from patients without gallstones. They showed that normal bile was less than saturated with cholesterol relative to bile salt and phospholipid whereas bile from patients with cholesterol gallstones was saturated and in some cases contained insoluble cholesterol in the form of microcrystals. As a result of these studies they suggested that the physical state of bile (i.e. the presence or absence of insoluble cholesterol) was determined by the relative concentra- tion of bile salt, lecithin and cholesterol.

There is no doubt that this was a major advance in the understanding of the aetiology of gallstones, but it is important to emphasize that they established the limits of cholesterol solubility from in vitro studies and that only one bile salt, sodium taurocholate, was studied. Whether or not their findings apply in vivo and are applicable for all bile salts remains to be shown and this should be borne in mind when their findings are applied to the clinical situation. They themselves showed that alteration of the total solids outwith the range of 5-20 per cent altered the line of maximum solubility of cholesterol in bile salt and lecithin, and it may well be that other factors, as yet unknown, also alter the limits of solubility. With these reservations, however, it would appear, from the studies of Admirand and Small, that cholesterol gallstones are associated with gallbladder bile which is saturated with cholesterol.

Is this bile secreted in a saturated form by the liver or does it become saturated in the gallbladder? Almost simultaneously Small and Rap0 (1970) and Vlahcevic et al. (1970b) reported studies in which they examined the relative composition of gallbladder bile and hepatic bile in patients undergoing cholecystectomy for cholesterol gallstones. Both groups showed that hepatic bile was supersaturated with cholesterol and the conclusion was reached that cholesterol gallstones were due to the production by the liver, and not the gallbladder, of abnormal bile. Since these two studies were reported, others studying the relative composition of bile at the time of cholecystectomy have shown that while many patients with cholesterol gallstones secrete supersaturated hepatic bile this is not always the case, as shown by MacKay et al. (1972), Smallwood et al. (1972) and Heller and Bouchier(l973). The latest data of the author are shown in Fig. 2, from which it is evident that although many patients with cholesterol gallstones do secrete hepatic bile which is supersaturated with cholesterol, a large number

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secrete bile whose relative composition lies within the micellar zone. Studies of bile composition in gallstone patients are open to the criticism that they give no indication of the composition of bile pertaining at the time of initiation of stone formation, and it is entirely possible that patients with a bile which is not supersaturated at the time of cholecystectomy could well have secreted supersaturated bile at some time in the past. The finding of undersaturated bile at the time of cholecystectomy does not therefore preclude the part played by supersaturation of bile in the initiation of gallstone formation.

Supersaturated bile came to be known as ‘lithogenic’, but care should be exercised in the use of this term. Nakayama and Van der Linden (1970) showed that many patients without gallstones secretedl supersaturated bile, and Metzger et al. (1973) showed that fasting bile was consistently more ‘lithogenic’ than gallbladder bile or hepatic bile obtained during feeding and this occurred even in patients without gallstones. Metzger’s findings were supported by Northfield and Hofmann (1973), who showed that the secretion of ‘lithogenic’ bile occurred with equal frequency in gallstone patients and controls, especially during overnight fasting, and seemed to be physiological. It may be that the production of supersaturated bile during fasting, if prolonged or combined with inadequate mixing within the gallbladder, couild be an important factor in the formation of cholesterol gallstones.

The association of cholesterol gallstones with supersaturation of bile gains support from some epidemiological and animal studies. Redinger and Small (1972) have collected data showing that there is a correlation between the prevalence of gallstone disease and the degree of saturation of gallbladder bile in different ethnic groups. From Fig. 3 it is evident that young North American Indian females who have a high prevalence of cholesterol gallstones also have a high percentage of cholesterol saturation in bile, whereas the African Masai, a population in which cholesterol gallstones do not occur, have a much lower percentage saturation. These workers also cited data from animal studies showing that animals which do not form gallstones spontaneously and only with difficulty by dietary manipulation, e.g. dog and pig, secrete bile containing little cholesterol relative to bile salt and phospholipid. Hamsters, on the other hand, secrete bile with a relatively higher proportion of cholesterol and although they do not form stones spontaneously they can be induced to do so fairly readily by dietary manipulation. Baboons secrete bile which has a relative composition approaching the limits of cholesterol solubility and they are known to form stones spontaneously without dietary manipulation. These data are illustrated in Fig. 4.

How can the current state of knowledge be sum- marized? It would appear that in many patients with cholesterol gallstones hepatic bile contains an excess of cholesterol relative to bile salt and phospholipid, and even in the others the bile may well have been supersaturated at some time in the past. In view of the

% Saturation

lsOi *-Swedes

Young North American ~i~~~ Indian women

O-Masai

Estimated prevalence (%)

Fig. 3. Percentage cholesterol saturation of gallbladder bile in different populations (from the data of Redinger and Small, 1972, as adapted by Lukie and Dietschy, 1973).

0

Bile salt

Fig. 4. Relative composition of animal gallbladder bile (adapted from Rcdinger and Small, 1972).

fact that bile is ‘normally’ supersaturated when patients are fasting it is perhaps not surprising that some patients develop gallstones but more surprising that all patients do not develop a stone. It should be emphasized that supersaturation is only one event in the formation of a gallstone; it has to be followed by the precipitation of cholesterol and the formation of microstones which enlarge to form macrostones (Small, 1970). It may well be that in patients who do not develop gallstones precipitation does not occur or should it occur the crystals are washed out in the bile into the gastro-intestinal tract.

We have established the role of supersaturation of hepatic bile in the aetiology of cholesterol gallstones.

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Theoretically, this could arise from excessive cholesterol secretion or impaired bile salt and/or phospholipid secretion. There is some evidence to suggest that cholesterol intake may influence bile composition but little evidence to incriminate phospholipid. These subjects are beyond the scope of this article which considers the evidence that cholesterol gallstones are due to a lack of bile salts. It is possible to measure the size of the bile salt pool in man by administering bile salt labelled with a radioactive isotope and aspirating specimens of bile by duodenal intubation. Vlahcevic et al. (1970a) measured the pool size by this method of isotope dilution; they gave 14C cholic acid to gallstone patients and controls and found that the pool size was significantly smaller in the gallstone patients. Arnesjo and Stahl (1973) and Danzinger et al. (1973) also reported a reduced bile acid pool size in gallstone patients. However, it could be argued that the diminished pool size was the result rather than the cause of the gallstones. The studies of Bell et al. (1973) would suggest that the diminished pool size was more likely to precede than to result from the gallstones. They studied bile salt pool size in three groups of American Indians, namely: (a) patients with gallstones and saturated bile; (b) patients without gallstones but saturated bile; (c) patients with no gallstones and normal bile. The pool size was greatly diminished in both groups of saturated bile patients. The fact that the pool was reduced even in the patients with no evidence of gallstones would suggest that the reduced pool preceded rather than resulted from the gallstones. Care must be taken in drawing too many conclusions from studies in American Indians with their remarkably high prevalence of gallstone disease (Sampliner et al., 1970), as the aetiology in such patients may be very different from the aetiology in other populations with a much lower prevalence of gallstone disease.

The hypothesis that a diminished bile acid pool size is responsible for the production of cholesterol gallstones received further support from the work of Heaton and Read (1969). They studied the prevalence of gallstones in patients who had previously undergone resection of the terminal ileum, the bile-salt-absorbing area of the gut, and found the prevalence to be significantly higher than in control groups. Abaurre et al. ( I 969) have shown that patients with ileal resection have a diminished bile salt pool.

It has been assumed that this small bile acid pool recirculates at the normal rate in the enterohepatic circulation, thus leading to a reduced secretion rate of bile acid but not cholesterol in bile. Northfield and Hofmann (1973) studied biliary lipid output in patients with radiolucent gallstones and in matched controls. They found that there was an inverse relationship between the size and the recycling rate of the bile salt pool so that the bile salt secretion rate remained constant over a wide range of pool sizes. They found that the total daily output of all three biliary lipids was similar in gallstone patients and controls. This is in contrast to the findings of Grundy et al. (1972), who showed that obese American Indian

women with gallstones had a higher cholesterol output and a lower bile salt output than thin Caucasian controls, the diminished bile salt output probably arising from impaired hepaticsynthesis. This difference may well be racial, the American Indians having a much higher prevalence of gallstone disease. Low- Beer and Pomare (1973) also showed that the size of the bile salt pool was largely determined by the frequency of its enterohepatic circulation. Therefore the exact role of a small bile acid pool in the patho- genesis of cholesterol gallstones remains to be determined.

The part played by a reduced bile salt pool in the production of cholesterol gallstones has been considered, but is there any evidence that an alteration in its component bile salts is responsible for gallstone formation? Van der Linden (1971) has reviewed the available literature and shown that there is a tendency for patients with gallstones to have an increase in dihydroxy bile salts relative to trihydroxy salts. He pointed out that while the difference did not reach the level of statistical significance in many of the studies reported the regular trend could not be ignored. The ratio of trihydroxy to dihydroxy bile salts in gallstone and duodenal ulcer patients studied by the author was found to be 0.44 and 0.67 respectively, the difference being statistically significant. Similar findings have been reported by Arnesjo and Stahl(l973) and Heller and Bouchier (1973). There would seem, therefore, to be good evidence that gallstones are associated with a relative increase in dihydroxy or a relative decrease in trihydroxy bile salts. Dihydroxy bile acids have been claimed to form larger micelles with less surface charge and consequently less stability (Bouchier and Freston, 1968), and a shift towards these acids may therefore favour gallstone formation. Haslewood (1967) has suggested that man’s liability to gallstones may be connected with the fact that while having a herbivore’s bile acid pattern, i.e. mainly dihydroxy- cholanic acids, he eats to a great extent a carvinore’s diet and carnivores have predominantly cholic acid. The ratio of glycine-conjugated to taurine-conjugated bile salts in gallstone and duodenal ulcer patients studied by the author was found to be 2.4 and 2.1 respectively, the difference not reaching a level of statistical significance. Similar findings were reported by Arnesjo and Stahl(l973). Alterations in the patterns of conjugation cannot therefore be incriminated.

A few years ago it seemed as if the gallstone problem had been solved, the cause being a hepatic abnormality resulting in the production of bile supersaturated with cholesterol. Since then further data have complicated rather than simplified the problem, and recently the gallbladder has again been implicated. In the past stasis and infection in the gallbladder were blamed with little good scientific evidence. Dilatation of the gallbladder occurs in the later stages of pregnancy (Gerdes and Boyden, 1938), in the progesterone phase of the menstrual cycle (Nilsson and Stattin, 1967) and after truncal vagotomy (Rudick and Hutchison, 1964; Parkin et al., 1973). Gallstones are commoner in females than in males,

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certainly in the childbearing age groups, and may be commoner in patients after vagotomy, although this is a matter for debate (Fletcher and Clark, 1968). Impaired gallbladder emptying with stasis of bile and particularly bile salts may lead to a functional diversion of bile salts from the enterohepatic circulation and a tendency, therefore, for hepatic bile to become temporarily supersaturated, with the risk of cholesterol precipitation. The whole question of the role of the gallbladder in the aetiology of ga.llstones requires further investigation, especially since it has been shown that hepatic bile which was supersaturated prior to cholecystectomy tends to become normal after removal of the gallbladder (Shaffer et al., 1972; Simmons et al., 1972; Smith et al., 1973).

Bile salts and the treatment of gallstone disease Thistle and Schoenfield (1971) at the Mayo Clinic were the first to show that the oral adminstration of chenodeoxycholic acid to women with gallstones produced a significant increase in the ratio of cholesterol-solubilizing agents in bile to cholesterol, i.e. the ‘lithogenic’ potential of bile was decreased. This group then went on to show (Danzinger et al., 1972) that chenodeoxycholic acid not only improved the relative composition of bile by expanding the diminished bile salt pool but caused stones to decrease in size and even disappear in some patients. These results were confirmed in this country by Bell, Whitney and Dowling (1972). The next step was to establish a trial, and the initial results of a single blind controlled therapeutic trial have been reported from the Mayo Clinic by Thistle and Hofmann (1973). They studied 53 patients with asymptomatic radiiolucent gallstones in functioning gallbladders. The patients received chenodeoxycholic acid, cholic acid or a placebo. After 6 months 11 of 18 patients receiving chenodeoxycholic acid showed a decrease in gallstone size or number, but no response was observed in the 17 treated with cholic acid or in the 18 receiving a placebo. Since then a multicentre investigation into the efficacy and safety of chenodeoxycholic acid has been initiated in the United States of America supported by the National Institutes of Health (Schoenfield, 1974).

There is therefore no doubt that chenodeoxycholic acid is effective in treating some patients with gallstones but many questions remain to be answered:

1. What is the optimum dose? 2. What are the side effects of treatment? 3. Is long term treatment safe? 4. Why is chenodeoxycholic acid effective and

5 . Is chenodeoxycholic acid the best bile acid? 6. Has treatment to continue for life? 7. Does the calcium content clf the stone affect its

8. What are the contraindications to treatment ?

cholic acid ineffective?

rate of dissolution?

1. Dosage The dosage of chenodeoxycholic acid used in the early studies ranged from 1-5 to 4.5 g/day but this has been

reduced in later studies. In the Mayo Clinic trial the dose varied from 10 to 26mg/kg body weight. The lowest therapeutic dose remains to be determined.

2. Side effects One of the potentially most troublesome side effects is diarrhoea due to the secretion of water and electrolytes by the colonic mucosa. This is dose related, and in the controlled trial reported by Thistle and Hofmann (1973) patients adjusted the dose so that the stools were usually partially or completely formed. Symptoms of gastric irritation have not occurred to any great extent in the studies reported.

3 . Sajety of long term treatment The main worries over long term treatment are liver damage and the development of atheroma. Chenode- oxycholic acid may induce liver damage directly or via its bacterial metabolite lithocholic acid. Transient elevation of the serum transaminases during treatment has been reported (Thistle and Hofmann, 1973). Bell et al. (1974) studied liver biopsies from patients receiving chenodeoxycholic acid (0.5-1.5 g/day) and from patients with untreated cholelithiasis and found no appreciable difference; they considered that in this dosage chenodeoxycholic acid was not hepatotoxic.

There are several reasons, albeit theoretical, why the long term administration of bile salt might lead to cholesterol retention by the body and the risk of atheroma. First, the administration of exogenous bile salt will inhibit endogenous bile salt synthesis, thus abolishing one of the major excretory routes for cholesterol. Secondly, exogenous bile salt may well enhance the intestinal absorption of dietary and endogenous cholesterol. Thirdly, since bile salts aller the relative composition of bile in such a way that there is a smaller percentage of cholesterol, unless a marked increase in bile secretion occurred the total secretion of cholesterol into the intestine would be depressed (Small, 1971). These theoretical considera- tions were put to the test by Hoffman et al. (1974). They measured the cholesterol pool and the cholesterol input to the pool in 23 patients with gallstones; 8 receiving chenodeoxycholic acid, 7 receiving cholic acid and 8 receiving a placebo. The values were similar in all three groups and were almost the same as those reported for patients without gallstones. They concluded that chenodeoxycholic acid did not cause any major change in the body’s cholesterol metabolism and that the likelihood of detectable acceleration of atheroma was quite small. They admitted, however, that any increase in cholesterol pool size may have been too small to be detectable by presently available methods. In addition, bile salts were given for a period of 6 months and the effect of more prolonged administration is unknown. It may well be that patients with hyperlipidaemia, atheroma or a tendency to develop atheroma behave in a different way; these patients may have difficulty in excreting cholesterol and the additional strain imposed by bile salt adminstration may further exacerbate cholesterol handling. Further work is required before chenodeoxycholic acid can be

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Colin MacKay

completely cleared of the charge of being potentially at herogenic.

4. Mechanism of action The precise mechanism by which chenodeoxycholic acid alters the composition of bile and produces gallstone dissolution is not clear. It cannot simply be due to an increase in the size of the bile salt pool because cholic acid also increases the bile salt pool size and yet does not alter the relative composition of bile or dissolve gallstones. Recent measurements of biliary lipid secretion before and after ingestion of chenodeoxycholic acid suggest that its major effect is to cause a relative or absolute reduction in cholesterol secretion (Northfield et al., 1973). Salen et al. (1973) have reported data suggesting that chenodeoxycholic acid reduced the activity of HMG-CoA reductase, an enzyme which regulates cholesterol synthesis by the liver. Confirmation of these findings is awaited.

5. Best bile acid To date chenodeoxycholic acid is the best available. Farrell et al. (1973) have shown by in vitro studies of gallstone dissolution that dihydroxy bile salts are more efficient than trihydroxy bile salts and glycine conjugates more efficient than taurine conjugates. It may well be that further work will produce a more effective bile salt or even a better synthetic detergent.

6. Length of treatment The natural history of patients whose gallstones have been dissolved medically is unknown, but it would seem that the relative composition of bile returns to pre-treatment values within 1 month of stopping treatment. Gallstones recurred in 2 of the first 5 patients in whom therapy was discontinued for 1 year. It may well be that even after successful stone dissolution continuous or intermittent prophylactic therapy will be necessary (Schoenfield, 1974).

7. Effect of calcium content of stone Bell, Sutor et al. (1972) showed from in vitro studies that an outer ring of calcification delayed gallstone dissolution. In Thistle and Hofmann’s (1973) trial of 13 patients with radio-opaque gallstones, 11 showed no change in stone size or number in response to chenodeoxycholic acid, presumably because the calcium prevented the bile salt from gaining access to the cholesterol.

8. Contraindications There would seem to be no point in treating patients with blockage of the cystic duct as the bile salt would not enter the gallbladder to dissolve the stones. Similarly, treatment is contraindicated in patients with a high calcium content of the stones, as bile salt, although entering the gallbladder, would be unable to dissolve the stones. However, it remains to be shown how accurate an estimate of stone calcium can be made from inspection of a radiograph.

The safety of treatment in pregnancy and inflam- matory bowel disease is quite unknown.

How can we summarize the current position of chenodeoxycholic acid in the treatment of cholesterol gallstones? There is no doubt that stones can be dissolved, but the place of this therapy in the management of the condition as a whole requires much more investigation and should at the moment be considered to be at the research and development stage. The words of Kurt Isselbacher (1972) are still true: ‘In the meantime our surgical colleagues can relax, their treatment of gallstones, although threatened, is not yet out-moded.’

Does this mean that bile salts have no place in the surgeon’s armamentarium? There may well be an important use for bile salts in the management of the stone retained in the common bile duct following choledocholithotomy. While no surgeon will admit to seeing this condition frequently, it is surprising how often such cases are referred from that mythical ‘other hospital’. These patients are often frail and poor surgical risks and the retained stone is frequently small, otherwise it would not have been missed in the first place. Most of us have at some time or another spent time and sweat looking for a stone which was blatantly obvious in the T-tube cholangiogram but not nearly so obvious at the second operation. For these reasons it would be useful to have a safe effective gallstone solvent which could be introduced via the indwelling T-tube. Do bile salts come into this category?

Way et al. (1972) reported results from 22 patients with residual stones in the common bile duct who had a sodium cholate solution infused via an indwelling T-tube. Stones were eliminated in 12 patients while the treatment was unsuccessful in the remaining 10. Lansford et al. (1974) reported success in 5 of 6 patients treated in a similar fashion. The solution is sterilized by Millipore filtration and is given by gravity drip in such a way that excessive pressure rises within the common duct are avoided. Diarrhoea almost always arises owing to the cathartic action of the bile salt, but this can usually be controlled with chole- styramine.

Although preliminary experience with this method of treatment is promising it must be stated that it has not been subjected to a controlled trial. In addition, postoperative cholangiograms can be difficult to interpret and all filling defects are not stones. For this reason more than one cholangiogram should be performed before using bile salt infusion. It is difficult to be sure how sodium cholate exerts its beneficial effect-how much is due to cholesterol solubilization and how much to mechanical flushing. Catt et al. (1974) have shown that simply infusing saline was successful in 6 out of 10 patients. Farrell et al. (1973) have found from in vitro studies that trihydroxy bile salts such as sodium cholate are less effective than dihydroxy bile salts at dissolving gallstones. However, it may be unnecessary to dissolve the stone completely; simply reducing it to a size at which it starts to disintegrate or is small enough to negotiate the ampulla of Vater may be sufficient.

Gardner (1973) has reported stone disappearance following the infusion of heparinized saline, and the

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combined use of heparin and bile salts merits further investigation.

References ABAURRE R., GORDON s. G., MANN J. G. and KERN F.

(1969) Fasting bile salt pool size and composition after ileal resection. Gastroenterology 57,1579-688.

ADMIRAND w. H. and SMALL D. M. (1968) The physicochemical basis of cholesterol gallstone formation in man. J. Clin. Invest. 47, 1043-1052.

ARNESJO B. and STAHL E. (1973) Taurocholate metabolism in patients with cholesterol gallstones. Scand J . Gastroenterol. 8, 369-375.

BELL c. c. jun., VLAHCEVIC L. R., PRAZICH J. and SWELL L. (1973) Evidence that a diminished bile acid pool precedes the formation of cholesterol gallstones in man. Surg. Gynecol. Obstet. 136, 961- 965.

HENRY K. B. and DOWLING R. H. (1974) Liver structure and function in cholelithiasis: effect of chenodeoxycholic acid. Gut 15, 165-172.

BELL G. D., SUTOR D. J. WHITNEY B. and DOWL'LNG R. H. (1 972) Factors influencing human :gallstone dissolution in monkey, dog and human bile. Gut 13, 836.

BELL G. D., WHITNEY B. and DOWLING R. kr. (1972) Gallstone dissolution in man using chenode- oxychoiic acid. Lancet 2, 1213-1216.

BERGSTROM s. and DANIELSSON H. (1968) The formation and metabolism of bile acids. In: CODE c. F. and HEIDEL B. (ed.) Handbook of Physiology, Section 6, Vol. V. Washington DC, American Physio- logical Society, pp. 2391-2408.

BOUCHIER I. A. D. and FRESTON J. w. (1968) The aetiology of gallstones. Lancet 1, 340-34.9.

CAREY M. c. and SMALL D. M. (1970) The characteristics of mixed micellar solutions with particular reference to bile. Am. J. Med. 49, 590-6808.

CATT P., HOGG F., CLUNIE G. and HARDIE I. (1974) Retained biliary calculi : removal by a simple non-operative technique. Ann. Surg. 180,247-251.

and THISTLE J. L. (1972) Dissolution of cholesterol gallstones by chenodeoxycholic acid. New Engl. J . Med. 286, 1-8.

DANZINGER R. G., HOFMANN A. F., THISTLE .I. L. and

oxycholic acid on bile acid kinetics and biliary lipid composition in women with cholelithiasis. J . Clin. Invest. 52, 2809-2821.

FARRELL K. E., SMITH D. c. and MACKAY c. ( I 973) Gall- stone dissolution in vitro. Br. J. Surg. 60, 900.

FLETCHER D. M. and CLARK c. G. (1968) Gallstones and gastric surgery. Br. J . Surg. 55, 895-899.

GARDNER B. (1973) Experiments with the use of intra- choledochal heparinised saline for the treatment of retained common duct stones. Ann. Surg. 177,

GERDES M. M. and BOYDEN E. A. (1938) Thlc rate of emptying of the human gallbladder in pregnancy. Surg. Gynecol. Ohstet. 66, 145-156.

BELL G. D., MOK H. V. I., THWE M., MURPHY G. M.,

DANZINGER R. G., HOFMANN A. F., SCHOENFIELD L. J.

SCHOENFIELD L. J. (1973) Effect Of Oral chenode-

240-244.

GRUNDY s. M., METZGER A. L. and ADLER R. (1972) Defective bile salt synthesis as cause of cholesterol gallstones. J. Clin. Invest. 51, 3026-3043.

HASLEWOOD G. A. D. (1967) Bile Salts. London, Methuen, p. 69.

HEATON K. w. and READ A. E. (1969) Gallstones in patients with disorders of the terminal ileum and disturbed bile salt metabolism. Br. Med. J . 3, 494496.

HELLER F. and BOUCHIER I. A. D. (1973) Cholesterol and bile salt studies on the bile of patients with cholesterol gallstones. Gut 14 83-88.

HOFFMAN N. E. HOFMANN A. F. and THISTLE J. L. (1974) Effect of bile acid feeding on cholesterol metabolism in gallstone patients. Mayo Clin. Proc. 49, 236239.

HOLLAND c. and HEATON K. w. (1972) Increasing frequency of gallbladder operations in the Bristol clinical area. Br. Med. J . 3, 672-675.

ISSELBACHER K. J. (1972) A medical treatment for gallstones? New Engl. J. Med. 286, 4042.

LANSFORD c., MEHTA s. and KERN F. (1974) The treatment of retained stones in the common bile duct with sodium cholate infusion. Gut 15, 48-51.

LOW-BEER T. S. and POMARE E. w. (1973) Regulation of bile salt pool size in man. Br. Med. J . 1, 338- 340.

LUKIE B. E. and DIETSCHY J. M. (1973) Cholesterol gallstone formation: recent advances in patho- physiology. Tex. Med. 69, 90-100.

MACKAY c., CROOK J. N., SMITH D. c. and MCALLISTER R. A. (1972) The composition of hepatic and gallbladder bile in patients with gallstones. Gut 13,

METZGER A. L., ADLER R., HEYMSFIELD s. and GRUNDY s. M. (1973) Diurnal variation in biliary lipid composition. Possible role in cholesterol gallstone formation. New Engl. J . Med, 288, 333- 336.

MOSBACH E. H. (1972) Hepatic synthesis of bile acids. Biochemical steps and mechanisms of rate control. Arch. Intern. Med. 130, 478487.

NAKAYAMA F. and VAN DER LINDEN w. (1970) Bile from gallbladder harbouring gallstone: can it indicate stone formation? Acta Chir. Scand. 136,605-610.

NILSSON s. and STATTIN s. (1967) Gallbladder emptying during the normal menstrual cycle. Acta Chir. Scand. 133, 648-652.

NORTHFIELD T. c. and HOFMANN A. F. (1973) Biliary lipid secretion in gallstone patients. Lancet. 1, 747-748.

NORTHFIELD T. c., LA RUSSO N. F., THISTLE J. L. and HOFMANN A. F. (1973) Effect of chenodeoxycholic acid therapy on biliary lipid secretion in gallstone patients. Gastroenterology 64, 780.

PARKIN G. J. s., SMITH R. B. and JOHNSTON D. (1973) Gallbladder volume and contractility after truncal, selective and highly selective (parietal-cell) vagotomy in man. Ann. Surg. 178, 581-586.

REDINGER R. N. and SMALL D. M. (1972) Bile composition, bile salt metabolism and gallstones. Arch. Intern. Med. 130, 618-630.

759-762.

51 1

Colin MacKay

RUDICK J. and HUTCHISON J. s. F. (1964) Effects of vagal-nerve section on the biliary system. Lancet 1, 579-581.

SALEN G., NICOLAU G. and SHEFER S. (1973) Chenode- oxycholic acid (CDCA) inhibits elevated hepatic HMG-CoA reductase activity in subjects with gallstones. Clin. Res. 21, 523.

and BURCH T. A. (1970) Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. New Engl. J . Med. 283, 1358-1364.

stones. Gastroenterology 67, 725-729. SHAFFER E. A., BRAASCH J. w. and SMALL D. M. ( 1 9 7 2 )

Bile composition at and after surgery in normal persons and patients with gallstones. Influence of cholecystectomy. New Engl. J. Med. 287, 1 3 1 7 - 1322.

SIMMONS F., ROSS A. P. J. and BOUCHIER I. A. D. ( 1 9 7 2 ) Alterations in hepatic bile composition after cholecystectomy. Gastroenterology 63, 466-470.

SMALL D. M. (1970) The formation of gallstones. Adu. Intern. Med. 16, 243-264.

SMALL D. M. (1971) Prestone gallstone disease-is therapy safe? New Engl. J. Med. 284, 214-216.

SMALL D. M. and RAPO s. (1970) Source of abnormal bile in patients with cholesterol gallstones. New Engl. J . Med. 283, 53-57.

SMALLWOOD R . A., JABLONSKI P. and WATTS J. MCK. (1972) Intermittent secretion of abnormal bile in patients with cholesterol gallstones. Br. Med, J . 4, 263-266.

SAMPLINER R. E., BENNETT P. M., COMESS L. J., ROSE F. A.

SCHOENFlELD L. J. (1974) Medical therapy for gall-

SMITH D. c., MCALLISTER R. A. and MACKAY c. (1973) The effect of cholecystectomy on the composition of bile in gallstone patients. Br. J. Surg. 60, 899.

SUTOR D. J. and WOOLEY s. E. (1971) A statistical survey of the composition of gallstones in eight countries. Gut 12, 55-64.

THISTLE J. L. and HOFMANN A. F. (1973) Efficacy and specificity of chenodeoxycholic acid therapy for dissolving gallstones. New Engl. J . Med. 289, 655-659.

THISTLE J. L. and SCHOENFIELD L. J. (1971) Induced alterations in composition of bile of persons having cholelithiasis. Gastroenterology 61, 488- 496.

VAN DER LINDEN w. (1971) Bile acid pattern of patients with and without gallstones. Gastroenterology 60, 1144-1 145.

VLAHCEVIC Z. R., COOPER-BELL C., BUHAC I., FARRAR J. T. and SWELL L. (1970a) Diminished bile acid pool size in patients with gallstones. Gastroenterology

VLAHCEVIC z. R., COOPER-BELL c. and SWELL L. (1970b) Significance of the liver in the production of lithogenic bile in man. Gastruenterofogy 59,

WAY L. w., ARMIRAND W. H. and DUNPHY J. E. (1972) Management of choledocholithiasis. Ann. Surg. 176. 347-359.

59, 165-173.

62-69.

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