Drugs 14: 116-119 (1977) CADIS Press 1977
Chenodeoxycholic Acid in the Management of Gall Stones R.G.Batey Department of Medicine. Royal Free Hospital. London
The introduction of a drug to treat any condition previously correctable only by surgery represents a major step forward in therapeutics. Chenodeoxycholic acid was fIrst introduced in 1971 as such an agent and its advent was heralded with much enthusiasm. Now, after 6 years of trials, it is possible to review its mechanisms of action, efficacy, toxicity and indications for use more clearly. Gall stone disease, or cholelithiasis, is a common problem in many parts of the world, causing considerable suffering and certainly costing many National Health Schemes much in the way of hospitalisations and surgery expenses. Gall stones may be composed largely of cholesterol, bile pigments. or a combination of both, and it is in the therapy of cholesterol stones that chenodeoxycholic acid (COCA) has a part to play.
1. Pathophysioiogy of Cholesterol Gall Stones Bile is composed of several substances, the two most important with respect to the formation of gall stones being cholesterol and bile acids. In health, the ratio of cholesterol and bile acids in bile is such that during the major part of the day, cholesterol remains in solution and stones do not form. In patients with
cholesterol cholelithiasis, the ratio is altered and bile becomes ~upersaturated with cholesterol, leading eventually to precipitation and the formation of stones. Possible mechanisms responsible for this abnormality are shown in table I. The discovery of this defect in bile metabolism led to the postulate that administration of a bile acid may alter the composition of bile in such a way as to return the cholesterol/bile acid ratio towards normal. Early experimental evidence appeared to indicate that COCA was effective and it was therefore .introduced for clinical trials.
Teble I. Possible mechanisms in the lithogenic bile
production of
1. Excessive bile salt loss Ileal disease Ileal resection 7 Ileal bile salt receptor deficiency 2. Oversensitive bile acid feedback (leads to decreased bile acid synthesis) 3. Excessive cholesterol secretion 4. Combination of defects 2 and 3 5. Primary disorders of the gall bladder. bile ducts. sphincter mechanisms
Chenodeoxycholic Acid in Gall Stones
117
2. Experience with Chenodeoxycholic Acid COCA is a naturally occurring primary bile acid, synthesised in the liver from cholesterol. Its metabolic pathway is illustrated in ftg. 1. The choice of this agent rather than one of the other bile acids rests largely on the relatively low incidence of side-effects associated with its use. 2.1 Mechanisms of Action COCA has been shown conclusively to decrease biliary cholesterol secretion (Northfteld et al., 1975). The possible ways in which this effect is produced include:
Cholesterol inhibits ~ synthesis , •
I
Liver
Chenodeoxycholic acid
~
COniUj;:-S
sulphat;o"
Biliary excretion into duodenum
I
•
Terminal ileal reabsorption
Enters colon
r
~
Converted to lithocholate
Lost in faeces
Fig. 1. Metabolic pathway of chenodeoxycholic acid.
• A drug-induced increase in the bile acid pool which in some way decreases cholesterol secretion. • An impairment of cholesterol synthesis. • A reduction in intestinal cholesterol absorption which thus lowers the quantity of cholesterol to be excreted. • An alteration in the cholesterol/bile acid ratio secondary to the elevation of the bile acid pool. Much experimental work has been undertaken to clarify the biochemical actions of CDCA and it is now apparent that the drug: 1) Impairs the activity of two enzymes within the cholesterol/bile acid pathway. Both HMG-CoA reductase and cholesterol 7a-hydroxylase activity are lowered by COCA and although this was postulated as the major mechanism of action of the drug, it is now less certain that this is so. Phenobarbitone increases the activity of these enzymes in patients receiving COCA but does not abolish the ability of COCA to dissolve cholesterol stones. 2) CDCA increases the bile acid pool in most patients and the increase is due purely to the administered drug. Its presence then leads to a reduction in the synthesis of other primary bile acids within the liver. 3) It now also appears that COCA impairs cholesterol absorption by the small intestine. Although much has been learned about the metabolic effects of CDCA administration, its exact chemical mechanism of action remains uncertain.
2.2 Efficacy of COCA Therapy Several trials have now conftrmed the original rmding that CDCA, administered in sufficient dosage, leads to the dissolution of cholesterol gall stones in more than 50 % of patients. The duration of therapy required varies from patient to patient and may extend from several weeks to 24 months or more, depending on the stone size. It is important to stress that COCA does nothing to correct the basic biochemical defect in the patient who produCes litho-
Chenodeoxycholic Acid in Gall Stones
genic bile and it is not surprising that when therapy is stopped there is a relatively high recurrence rate of stones in patients followed for 2 to 5 years.
2.3 Factors Influencing the Response The effectiveness of COCA therapy depends on the dose used, the duration of therapy, and the timing of administration. 2.3.1 Dosage The usual dosage is 13 to 15mg/kg body weight daily. However, in obese patients it is now evident that this dose is insufficient and should be increased to 18 to 20mg/kg. The daily dose is best given in divided amounts with the major fraction being given at night (see section 2.3.3). 2.3.2 Duration of Therapy Therapy is continued until stones dissolve or decrease in size and pass into the duodenum. In the case of single large stones this usually takes between 6 and 24 months, although multiple small stones may respond more rapidly. Following successful dissolution, maintenance therapy may well be indicated to prevent recurrences, but trials to determine the dose and frequency of administration required are still in progress. 2.3.3 Timing of Administration In man, bile is most lithogenic during the fasting hours at night and it has been shown that COCA given in the evening has a more significant effect on daily biliary cholesterol/bile acid ratios than a similar dose given in the morning.
2.4 Toxicity of COCA Studies in some animals, particularly the rhesus monkey, have demonstrated significant hepatotoxicity following continued administration of the drug. Early clinical studies reported transient eleva-
118
tions of serum transaminases, but now after 6 years of use it appears from clinical, biochemical and histological evidence that humans are not susceptible to this problem. The explanation for this interspecies difference lies in the capacity of the human liver to adequately sulphate the increase quantities of lithocholic acid absorbed from the colon during COCA therapy, thereby avoiding the hepatotoxic effects of non-sulphated lithocholate. The rhesus monkey does not possess this capacity. The only significant side-effect of CDCA therapy to date has been mild diarrhoea which usually responds to the administration of small doses of cholestyramine. The fear that alteration of cholesterol secretion into bile may predispose patients to premature coronary artery disease has not been realised. Recent evidence that cholesterol absorption is impaired may be the explanation.
Table II. Summary of the use of chenodeoxycholic acid in gall stone disease
1. Selection of patients Treatment should be confined to patients with radiolucent stones and functioning gall bladders. Groups suitable for treatment are: a) Old or sick patients considered unfit for surgery b) Patients with anatomical abnormalities of biliary tree c) Other patients refusing surgery 2. Dosege regimen Usually 13 to 15mg/kg daily; in obese patients increase to 18 to 20mg/kg daily. The daily dose is best given in divided amounts with the major fraction being given at night. 3. Duration of therepy Depends on stone size. Therapy is continued until stones dissolve or decrease in size and pass into duodenum (usually between 6 and 24 months for single large stones). Continued maintenance treatment may well prevent recurrences. 4. Side-effects Only significant side-effect to date is mild diarrhoea (usually responds to small doses of cholestyramine).
Chenodeoxycholic Acid in Gall Stones
3. Selection of Patients for Treatment When CDCA was first introduced its use was confined to the following groups of patients: 1) Old or sick patients considered unfit for surgery. 2) Patients with anatomical abnormalities of the biliary tree associated with cholelithiasis. 3) Other patients refusing surgery on medical or personal grounds. Recent work suggests that therapy may be of value in a wider group of patients. In anyone in whom therapy is considered, evidence of gall bladder function must be obtained as dissolution depends on the stone being bathed in bile. Treatment should be confined to patients with radiolucent stones since radio-opaque calcium-containing stones do not respond to therapy. Unfortunately, some radiolucent stones may be non-cholesterol in type and this has led to a suggestion that bile composition should be analysed to determine who will respond to COCA therapy. Further, it has been suggested that conversion of bile from cholesterol saturation to unsaturaHon 1 to 3 months after the start of CDCA therapy may be a useful way of predicting the chances of successful gall stone dissolution Oser et al., 1975). The rapidly accumulating evidence for both the efficacy and safety of CDCA has altered the views of many on the place of this agent in the management of cholesterol stones. It is possible that CDCA will become the first line of therapy in many patients shown to have cholesterol cholelithiasis. Surgery may be reserved for those patients with severe symptoms or non-functioning gall bladders, or those in whom CDCA therapy has failed or has produced intolerable
119
side-effects. At present, however, the majority of patients given the drug are still those listed above. Apparent drug failure should lead to the following steps before the drug is abandoned: 1) An increase in the dosage. 2) A change from morning to nocturnal dosage schedule. Persistence of stones should then be an indication for surgery.
4. Conclusion COCA appears to have established itself in the armamentarium of the doctor treating patients with cholelithiasis. Used in appropriate patients in adequate doses, it offers the possibility of dissolving cholesterol stones already present in a significant percentage of patients. Continued dosage at a maintenance level may well prevent the recurrence of the problem, thereby significantly reducing morbidity and the demand for hospital beds for patients requiring surgery for the complications of cholelithiasis.
References lser. 1.H.; Dowling, R.H.; Mok, H.Y.1. and Bell, G.D.: Chenodeoxycholic acid treatment of gallsones. New England lournal of Medicine 293: 378-383 (J 975). Northfield, T.c.; La Russo, N.F.; Hoffman, A.F. and Thistle. 1.L.: Biliary lipid output during three meals and an overnight fast. Gut 16: 12-17 (1975)
Author s address: Dr R.G. Batey. Medical Unit, The Royal Free Hospital, Pond Street. Hampstead, London NW3 lQG (England).
Chenodeoxycholic Acid in the Management of Gall Stones R.G.Batey Department of Medicine. Royal Free Hospital. London
The introduction of a drug to treat any condition previously correctable only by surgery represents a major step forward in therapeutics. Chenodeoxycholic acid was fIrst introduced in 1971 as such an agent and its advent was heralded with much enthusiasm. Now, after 6 years of trials, it is possible to review its mechanisms of action, efficacy, toxicity and indications for use more clearly. Gall stone disease, or cholelithiasis, is a common problem in many parts of the world, causing considerable suffering and certainly costing many National Health Schemes much in the way of hospitalisations and surgery expenses. Gall stones may be composed largely of cholesterol, bile pigments. or a combination of both, and it is in the therapy of cholesterol stones that chenodeoxycholic acid (COCA) has a part to play.
1. Pathophysioiogy of Cholesterol Gall Stones Bile is composed of several substances, the two most important with respect to the formation of gall stones being cholesterol and bile acids. In health, the ratio of cholesterol and bile acids in bile is such that during the major part of the day, cholesterol remains in solution and stones do not form. In patients with
cholesterol cholelithiasis, the ratio is altered and bile becomes ~upersaturated with cholesterol, leading eventually to precipitation and the formation of stones. Possible mechanisms responsible for this abnormality are shown in table I. The discovery of this defect in bile metabolism led to the postulate that administration of a bile acid may alter the composition of bile in such a way as to return the cholesterol/bile acid ratio towards normal. Early experimental evidence appeared to indicate that COCA was effective and it was therefore .introduced for clinical trials.
Teble I. Possible mechanisms in the lithogenic bile
production of
1. Excessive bile salt loss Ileal disease Ileal resection 7 Ileal bile salt receptor deficiency 2. Oversensitive bile acid feedback (leads to decreased bile acid synthesis) 3. Excessive cholesterol secretion 4. Combination of defects 2 and 3 5. Primary disorders of the gall bladder. bile ducts. sphincter mechanisms
Chenodeoxycholic Acid in Gall Stones
117
2. Experience with Chenodeoxycholic Acid COCA is a naturally occurring primary bile acid, synthesised in the liver from cholesterol. Its metabolic pathway is illustrated in ftg. 1. The choice of this agent rather than one of the other bile acids rests largely on the relatively low incidence of side-effects associated with its use. 2.1 Mechanisms of Action COCA has been shown conclusively to decrease biliary cholesterol secretion (Northfteld et al., 1975). The possible ways in which this effect is produced include:
Cholesterol inhibits ~ synthesis , •
I
Liver
Chenodeoxycholic acid
~
COniUj;:-S
sulphat;o"
Biliary excretion into duodenum
I
•
Terminal ileal reabsorption
Enters colon
r
~
Converted to lithocholate
Lost in faeces
Fig. 1. Metabolic pathway of chenodeoxycholic acid.
• A drug-induced increase in the bile acid pool which in some way decreases cholesterol secretion. • An impairment of cholesterol synthesis. • A reduction in intestinal cholesterol absorption which thus lowers the quantity of cholesterol to be excreted. • An alteration in the cholesterol/bile acid ratio secondary to the elevation of the bile acid pool. Much experimental work has been undertaken to clarify the biochemical actions of CDCA and it is now apparent that the drug: 1) Impairs the activity of two enzymes within the cholesterol/bile acid pathway. Both HMG-CoA reductase and cholesterol 7a-hydroxylase activity are lowered by COCA and although this was postulated as the major mechanism of action of the drug, it is now less certain that this is so. Phenobarbitone increases the activity of these enzymes in patients receiving COCA but does not abolish the ability of COCA to dissolve cholesterol stones. 2) CDCA increases the bile acid pool in most patients and the increase is due purely to the administered drug. Its presence then leads to a reduction in the synthesis of other primary bile acids within the liver. 3) It now also appears that COCA impairs cholesterol absorption by the small intestine. Although much has been learned about the metabolic effects of CDCA administration, its exact chemical mechanism of action remains uncertain.
2.2 Efficacy of COCA Therapy Several trials have now conftrmed the original rmding that CDCA, administered in sufficient dosage, leads to the dissolution of cholesterol gall stones in more than 50 % of patients. The duration of therapy required varies from patient to patient and may extend from several weeks to 24 months or more, depending on the stone size. It is important to stress that COCA does nothing to correct the basic biochemical defect in the patient who produCes litho-
Chenodeoxycholic Acid in Gall Stones
genic bile and it is not surprising that when therapy is stopped there is a relatively high recurrence rate of stones in patients followed for 2 to 5 years.
2.3 Factors Influencing the Response The effectiveness of COCA therapy depends on the dose used, the duration of therapy, and the timing of administration. 2.3.1 Dosage The usual dosage is 13 to 15mg/kg body weight daily. However, in obese patients it is now evident that this dose is insufficient and should be increased to 18 to 20mg/kg. The daily dose is best given in divided amounts with the major fraction being given at night (see section 2.3.3). 2.3.2 Duration of Therapy Therapy is continued until stones dissolve or decrease in size and pass into the duodenum. In the case of single large stones this usually takes between 6 and 24 months, although multiple small stones may respond more rapidly. Following successful dissolution, maintenance therapy may well be indicated to prevent recurrences, but trials to determine the dose and frequency of administration required are still in progress. 2.3.3 Timing of Administration In man, bile is most lithogenic during the fasting hours at night and it has been shown that COCA given in the evening has a more significant effect on daily biliary cholesterol/bile acid ratios than a similar dose given in the morning.
2.4 Toxicity of COCA Studies in some animals, particularly the rhesus monkey, have demonstrated significant hepatotoxicity following continued administration of the drug. Early clinical studies reported transient eleva-
118
tions of serum transaminases, but now after 6 years of use it appears from clinical, biochemical and histological evidence that humans are not susceptible to this problem. The explanation for this interspecies difference lies in the capacity of the human liver to adequately sulphate the increase quantities of lithocholic acid absorbed from the colon during COCA therapy, thereby avoiding the hepatotoxic effects of non-sulphated lithocholate. The rhesus monkey does not possess this capacity. The only significant side-effect of CDCA therapy to date has been mild diarrhoea which usually responds to the administration of small doses of cholestyramine. The fear that alteration of cholesterol secretion into bile may predispose patients to premature coronary artery disease has not been realised. Recent evidence that cholesterol absorption is impaired may be the explanation.
Table II. Summary of the use of chenodeoxycholic acid in gall stone disease
1. Selection of patients Treatment should be confined to patients with radiolucent stones and functioning gall bladders. Groups suitable for treatment are: a) Old or sick patients considered unfit for surgery b) Patients with anatomical abnormalities of biliary tree c) Other patients refusing surgery 2. Dosege regimen Usually 13 to 15mg/kg daily; in obese patients increase to 18 to 20mg/kg daily. The daily dose is best given in divided amounts with the major fraction being given at night. 3. Duration of therepy Depends on stone size. Therapy is continued until stones dissolve or decrease in size and pass into duodenum (usually between 6 and 24 months for single large stones). Continued maintenance treatment may well prevent recurrences. 4. Side-effects Only significant side-effect to date is mild diarrhoea (usually responds to small doses of cholestyramine).
Chenodeoxycholic Acid in Gall Stones
3. Selection of Patients for Treatment When CDCA was first introduced its use was confined to the following groups of patients: 1) Old or sick patients considered unfit for surgery. 2) Patients with anatomical abnormalities of the biliary tree associated with cholelithiasis. 3) Other patients refusing surgery on medical or personal grounds. Recent work suggests that therapy may be of value in a wider group of patients. In anyone in whom therapy is considered, evidence of gall bladder function must be obtained as dissolution depends on the stone being bathed in bile. Treatment should be confined to patients with radiolucent stones since radio-opaque calcium-containing stones do not respond to therapy. Unfortunately, some radiolucent stones may be non-cholesterol in type and this has led to a suggestion that bile composition should be analysed to determine who will respond to COCA therapy. Further, it has been suggested that conversion of bile from cholesterol saturation to unsaturaHon 1 to 3 months after the start of CDCA therapy may be a useful way of predicting the chances of successful gall stone dissolution Oser et al., 1975). The rapidly accumulating evidence for both the efficacy and safety of CDCA has altered the views of many on the place of this agent in the management of cholesterol stones. It is possible that CDCA will become the first line of therapy in many patients shown to have cholesterol cholelithiasis. Surgery may be reserved for those patients with severe symptoms or non-functioning gall bladders, or those in whom CDCA therapy has failed or has produced intolerable
119
side-effects. At present, however, the majority of patients given the drug are still those listed above. Apparent drug failure should lead to the following steps before the drug is abandoned: 1) An increase in the dosage. 2) A change from morning to nocturnal dosage schedule. Persistence of stones should then be an indication for surgery.
4. Conclusion COCA appears to have established itself in the armamentarium of the doctor treating patients with cholelithiasis. Used in appropriate patients in adequate doses, it offers the possibility of dissolving cholesterol stones already present in a significant percentage of patients. Continued dosage at a maintenance level may well prevent the recurrence of the problem, thereby significantly reducing morbidity and the demand for hospital beds for patients requiring surgery for the complications of cholelithiasis.
References lser. 1.H.; Dowling, R.H.; Mok, H.Y.1. and Bell, G.D.: Chenodeoxycholic acid treatment of gallsones. New England lournal of Medicine 293: 378-383 (J 975). Northfield, T.c.; La Russo, N.F.; Hoffman, A.F. and Thistle. 1.L.: Biliary lipid output during three meals and an overnight fast. Gut 16: 12-17 (1975)
Author s address: Dr R.G. Batey. Medical Unit, The Royal Free Hospital, Pond Street. Hampstead, London NW3 lQG (England).
![[In vivo dissolving of gall-stones: the effect of chenodeoxycholic acid. (author's transl)].](/assets/img/hold.png)
