Resistance to chenodeoxycholic acid (CDCA) treatment in obese patients with gall stones

In most patients with radiolucent gall stones who were given chenodeoxycholic acid (CDCA) in doses of 13-15 mg/kg body weight/day the bile became unsaturated in cholesterol, and their gall stones dissolved. The patients whose stones did not dissolve were significantly heavier and fatter than the responders, which suggested that obese patients might be “resistant” to the effects of CDCA. To test this hypothesis, 32 consecutive patients presenting for medical treatment of gall stones had their ideal body weight (IBW) and estimated body fat mass calculated. The eight most obese and the eight least obese patients were then selected, and their fasting bile lipid responses to CDCA 13-15 mg/kg/day were measured. The very obese patients were also given larger doses, and any changes in bile lipid composition were studied in relation to subsequent gall-stone dissolution.Before treatment the obese patients had a higher mean biliary cholesterol saturation index than the non-obese patients, and this difference was maintained during treatment with the normal dose of CDCA: the bile in the obese patients remained supersaturated while that in the non-obese became unsaturated with cholesterol. When the obese patients were given larger doses of CDCA their bile ultimately became unsaturated in cholesterol. Gall stones dissolved partially or completely in five of the eight non-obese patients after 6-18 months of 13-15 mg CDCA/kg/day, but none of the obese patients showed any response after comparable periods of treatment with this standard dose. With increased doses and unsaturated bile, however, three of the obese patients showed partial gall-stone dissolution after 3-12 months'' treatment and one showed complete gall-stone dissolution after three years'' treatment.These results suggest that when giving CDCA to patients with gall stones, larger than normal doses (some 18-20 mg/kg/day) should be prescribed. Alternatively the lipid composition of the patients'' bile should be monitored by duodenal intubation and the CDCA dose increased until the bile becomes unsaturated in cholesterol.     

Gall stone dissolving agents.

During the decade in which the medical dissolution of gall stones has become feasible several drugs have been introduced but only the two listed in the British National Formulary have been intensively evaluated and shown to be effective--chenodeoxycholic acid and the closely allied ursodeoxycholic acid. The dissolution of gall stones was last reviewed in the "BMF" in 1976, at which stage experience with chenodeoxycholic acid was limited. Since then the indications and potential for this bile acid in treating gall stones have become better understood, and data on the newly introduced ursodeoxycholic acid are being evaluated. Cholesterol, but not pigment, gall stones are amenable to oral dissolution treatment. This review will cover firstly, chenodeoxycholic acid, secondly, ursodeoxycholic acid, then a comparison of the two drugs, an assessment of the place of medical dissolution in the management of gall stones, and, finally, the dissolution of stones in the common bile duct.     

Serum Lipids in Cholelithiasis: Effect of Chenodeoxycholic Acid Therapy

Hypercholesterolaemia has been predicted as a possible complication of chenodeoxycholic acid treatment for gall stones. To exclude this, fasting serum lipids were measured in patients with stones before and at monthly intervals for six months after starting chenodeoxycholic acid. Before treatment half of a group of 36 patients with presumed cholesterol gall stones had serum cholesterol levels exceeding 260 mg/100 ml or serum triglyceride values greater than 160 mg/100 ml or both; these lipid levels were significantly greater than those in control subjects matched for age and sex. Treatment with chenodeoxycholic acid (0·5-1·5 g/day by mouth) did not change serum cholesterol levels but did significantly reduce serum triglyceride concentrations from a pretreatment level of 118 (± S.E. of mean 11·7) mg/100 ml to 95 (± 7·2) mg/100 ml after six months of therapy. The mechanism of this triglyceride-lowering action of chenodeoxycholic acid is not known, but it may have therapeutic value in patients with hypertriglyceridaemia.     

Gall stones in sickle cell disease in the United Kingdom.

The prevalence of gall stones was studied prospectively by abdominal ultrasound examination in 131 patients with sickle cell disease aged 10-65 years. Of 95 patients with homozygous sickle cell disease, 55 (58%) had gall stones or had had a cholecystectomy. Gall stones were present in four out of 24 (17%) patients with haemoglobin S + C disease and two out of 12 (17%) with haemoglobin S beta thalassaemia. The presence of gall stones was not related to sex, geographical origin, or haematological variables and was not associated with abnormal results of liver function tests. Symptoms typical of biliary colic were reported by 32 out of 47 adult patients with gall stones, and cholecystitis or cholestasis was diagnosed in 18. Cholecystectomy was performed in 29 patients with good relief of symptoms in most cases. Postoperative complications were common, occurring in 10 of the 28 patients who could be evaluated, but not generally serious; they were considerably lessened by a preoperative exchange transfusion that reduced the haemoglobin S concentration to below 40%. It is suggested that all patients with sickle cell disease should be screened for gall stones and that elective cholecystectomy should be performed in those with symptoms or complications.     

Postprandial gall-bladder emptying in patients with gall stones.

Gall-bladder emptying in response to a standard meal was assessed in 34 patients with radiolucent gall stones and 34 matched controls. Percentage gall-bladder emptying, derived from volume measurements made on standardised oral cholecystography, was significantly higher at 15 minutes in the patients than the controls (mean +/- SE of mean 38.0 +/- 3.7% v 28.0 +/- 3.8%). This difference was maintained at 30 and 60 minutes. It is concluded that postprandial gall-bladder emptying is increased in patients with cholesterol gall stones, and that this may be the cause of the small bile-acid pool found in these patients.     

Gall-bladder sensitivity to cholecystokinin in patients with gall stones.

Gall-bladder sensitivity to cholecystokinin (CCK) was determined by dynamic cholescintigraphy in 18 patients with radiolucent gall stones and 18 matched controls during an infusion of CCK in which the rate of infusion was increased. In 10 of the matched pairs the patient was more sensitive than the control, in one the control was more sensitive, and in seven no difference was detected (p = 0.012). It is concluded that patients with cholesterol gall stones have increased gall-bladder sensitivity to CCK, and that this may be important in the pathogenesis of this disease.     

Low-cholesterol diet: enhancement of effect of CDCA in patients with gall stones.

Fifteen patients with gall stones who were taking chenodeoxycholic acid(CDCA) 15 mg/kg at bedtime participated in two separate experiments to investigate the effects of altering sterol intake on the cholesterol saturation index (SI) of fasting gall-bladder bile. In experiment I the 15 patients on an unrestricted diet had a SI of 0.87 +/- 0.04 (mean +/- SE of mean), which fell to 0.75 +/- 0.04 after one week in hospital on a diet of 100 mg cholesterol daily. In experiment II seven of the patients were given four different dietary regimens lasting one month each in random order as outpatients. On a diet of 600 mg of cholesterol daily the mean SI was 0.72 +/- 0.05, which fell to 0.67 +/- 0.05 when the patients were put on a 100 mg cholesterol diet. The addition of plant sterols (3 g daily) to both diets raised the mean SIs to 0.80 +/- 0.05 and 0.77 +/- 0.05 respectively. The percentage CDCA in bile was unaffected by alterations in the cholesterol and plant sterol intakes. We conclude that a low-cholesterol diet but not a high intake of plant sterols enhances the effect of CDCA in patients with gall stones.     

Gall-stone dissolution and recurrence: are we being misled?

Oral cholecystography repeated at six-months intervals is the standard method for determining reduction in size of gall stones (partial success) and complete dissolution of stones (complete success). In a comparative study of oral cholecystography and cholecystosonography six out of 14 patients with gall stones achieving complete success by oral cholecystographic criteria had stones still detectable by ultrasonography. Repeat oral cholecystography in a further 11 patients receiving post-dissolution maintenance treatment detected stones in two, whereas ultrasonography detected stones in seven. In future complete dissolution of gall stones should be reported only if both oral cholecystography and ultrasonographic studies give negative results and the progress of patients receiving post-dissolution maintenance treatment is monitored by ultrasonography rather than serial oral cholecystography.     

Prediction of gall-stone pancreatitis by computer.

The clinical features at presentation of 53 patients admitted with primary acute pancreatitis due to gall stones were compared with those of 31 patients in whom the disease was due to other causes. Between these two groups 10 significant differences existed. By listing the frequency of symptoms and signs for each group a computer data base was prepared and incorporated into a program used in the differential diagnosis of acute abdominal pain. A program written to predict the presence of gall stones in patients with acute pancreatitis was accurate in 92% of the patients studied. A predictive index devised from the presence of three of the significantly differing clinical features correctly identified 82% of patients with gall-stone pancreatitis. Predicting the presence of gall stones on admission by analysing the presenting symptoms and signs with a computer had an accuracy comparable to that of ultrasonography or radiology and may be of value in the management of patients with acute pancreatitis.     

Non-operative removal of bile duct stones by duodenoscopic sphincterotomy in the elderly.

Between January 1975 and December 1979, 71 patients over the age of 70 underwent attempted duodenoscopic sphincterotomy for stones in the common bile duct. Fifteen patients still had gall bladders in situ. Sphincterotomy was possible in 69 of the patients and in 65 of these duct clearance was achieved, giving an overall success rate of 92%. Failure to achieve sphincterotomy in two cases was due to substantial peripapillary diverticula. Duct clearance failed in four patients, mostly due to the size of the retained stones. The largest stone extracted was 24 mm diameter. There were no deaths but complications occurred in nine patients (13%); these were haemorrhage in four (requiring surgery in one), cholangitis in four (two of whom required surgical extraction of stones), and pancreatitis in one. The average duration of hospital stay in successful cases was 11 days (range three to 30). Clinical follow-up of 55 patients one to five years after sphincterotomy showed no evidence of stones or of stenosis of the sphincter. Duodenoscopic sphincterotomy is a major advance in the management of elderly patients with stones in the common bile duct.     

Effect of vegetarianism on development of gall stones in women.

Real time ultrasonography was used to compare the prevalence of gall stones in two groups of women aged 40-69: 632 women recruited from general practice registers and 130 vegetarians. One hundred and fifty-six (25%) of the 632 women who ate meat and 15 (12%) of the 130 vegetarian women either had gall stones visible on ultrasonography or had previously undergone cholecystectomy (p less than 0.01). The prevalence of gall stones was found to increase with age and body mass index. The 2.5 fold increase in risk of developing gall stones in non-vegetarians compared with vegetarians was reduced to 1.9 when controlling for these two potentially confounding factors, but remained significant. A family history of gall stones was reported more often by women with gall stones, but no association was found with parity or use of exogenous oestrogens. Thus the importance of age and obesity to determine the prevalence of gall stone was confirmed, and a dietary factor associated with vegetarianism may prevent this common condition.     

Can colonic bacterial metabolites predispose to cholesterol gall stones?

The cholesterol content of biliary lipids increased significantly when 16 healthy volunteers ingested deoxycholic acid (DC) for two weeks in a daily dose of 100-150 mg. Serum cholesterol also fell significantly to 88% of the baseline levels. Since DC is formed in the colon we suggest that populations in whom there is a high colonic absorption of bacterially metabolized cholate--that is, DC--have an increased predisposition to cholesterol gall stones.     

Migration of gall stones.

The factors influencing the migration of gall stones are ill understood. Altogether 331 patients undergoing cholecystectomy were studied prospectively. The diameters of the cystic and common bile ducts and of stones in the gall bladder and bile ducts were measured. Increasing pressure was applied to the freshly excised gall bladder in an attempt to evacuate stones through the cystic duct. Stones passed in 33 (60.0%) of patients with choledocholithiasis, 45 (67.2%) of patients with pancreatitis, and 7 (3.2%) of patients without either pancreatitis or choledocholithiasis. Stones migrated in 6 (3.0%) who had a normal cystic duct diameter (less than or equal to 4 mm) and in 46 (32.5%) with a duct over 4 mm diameter. Common bile duct stones were often larger than the diameter of the cystic duct and when reintroduced into the gall bladder would not migrate. The passage of debris (less than or equal to 1 mm) through the cystic duct bore no relation to the presence or absence of choledocholithiasis or a dilated cystic duct. Small stones (1-4 mm diameter) must migrate to initiate and facilitate further migration; some must increase in size in the common bile duct. Increased biliary pressure consequently dilates the duct system retrogradely, allowing larger stones to follow. Patients at risk of stone migration and thereby pancreatitis and jaundice have large ducts that can be detected by ultrasound assessment.     

Bile acids of a 3200-year-old Egyptian mummy.

The bile acids of the gall bladder and hepatic tissue of a 3200-year-old Egyptian mummy were isolated by thin-layer chromatography and identified by combined gas-liquid chromatrography and mass spectrometry. Except for complete deconjugation and extensive dehydration, the bile acids were found to correspond in their qualitative and quantitative composition to the gall bladder bile acids of modern man. The secondary bile acids constituted about 50% of the total and were identified as the normal bacterial oxidoreduction products of the primary bile acids and their dehydration products. In addition a series of unsaturated bile acids were identified, which corresponded to the dehydration products of cholic and chenodeoxycholic acids. It is suggested that both bile acid deconjugation and the limited oxidoreduction were probably brought about by the Clostridium organisms identified in the tissue. On the basis of the bile acid composition it is concluded that the ancient man metabolized cholesterol along the same pathways as modern man.     

Efficacy and safety of allopurinol in patients with the Lesch-Nyhan syndrome and partial hypoxanthine- phosphoribosyltransferase deficiency: a follow-up study of 18 Spanish patients

Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.     

Intermittent Secretion of Abnormal Bile in Patients with Cholesterol Gall Stones

Gall bladder and hepatic bile was sampled from 66 patients undergoing elective operations on the biliary tract. Fifty-one patients had cholesterol gall stones but only 59% of these were found to have bile which was supersaturated with cholesterol. Repeated sampling of hepatic bile from patients with T-tubes showed that the secretion of supersaturated bile was intermittent.These results indicate that it is impossible to separate patients with cholesterol stones from controls simply by examination of the lipid composition of their bile, since an appreciable number of bile samples from patients with cholesterol stones were unsaturated.The fact that cholesterol gall stones form when the bile is supersaturated with cholesterol only intermittently suggests that the gall bladder may also have a part in their formation.     

Efficacy and Safety of Allopurinol in Patients with the Lesch-Nyhan Syndrome and Partial Hypoxanthine- Phosphoribosyltransferase Deficiency: a Follow-up Study of 18 Spanish Patients

Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.     

Gallstones

Cholesterol saturation of bile has a primary role in the pathogenesis of gallstone formation. Predisposing factors should be considered. The characteristic features of biliary colic are important to keep in mind, as well as the fact that a history of fatty food intolerance is not of value in the diagnosis of gallstones. The technique of endoscopic retrograde cholangiography is useful for the diagnosis of bile duct stones in jaundiced patients and in patients with a strong clinical history, but in whom findings on oral and intravenous cholangiograms are within normal limits. Improved techniques of operative cholangiography to diminish the incidence of retained gallstones have been developed. Also, choledochoscopy provides a remarkable technique for diagnosis and choledocholithotomy. The dissolution of gallstones with chenodeoxycholic acid is an experimental procedure. This bile acid is thought to act by increasing the chenodeoxycholic acid pool size and decreasing cholesterol synthesis and secretion, thereby reversing the defects responsible for gallstone formation.     

Increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, resulting in (23R)-hydroxylation of bile acids

Patients suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis, excrete excessive amounts of 23-hydroxylated bile alcohols, 23-norcholic acid and 23-hydroxycholic acid into urine. In this study the configuration of this excreted 23-hydroxycholic acid was established as (23R)-hydroxycholic acid. Urine samples of two treated patients, receiving chenodeoxycholic acid, were investigated to see whether this administered bile acid was partly converted into 23-hydroxychenodeoxycholic acid. One patient was treated with ursodeoxycholic acid for 1 month and subsequently with chenodeoxycholic acid, and the urinary excretion of both (23R)-hydroxychenodeoxycholic acid and (23R)-hydroxyursodeoxycholic acid were followed. Indeed, all three patients excreted (23R)-hydroxylated chenodeoxycholic acid during oral treatment with chenodeoxycholic acid, and the patient treated with ursodeoxycholic acid excreted (23R)-hydroxylated ursodeoxycholic acid. During treatment with chenodeoxycholic acid the excretion of (23R)-hydroxychenodeoxycholic acid increases at first and later on decreases markedly. These findings suggest increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, acting both on endogenously synthesized bile alcohols and on exogenously administered bile acids; during continuation of chenodeoxycholic acid treatment in an effective dose (750 mg/day) this enzyme activity gradually disappears.     

Prevalence of gall stones in Dundee: a necropsy study.

Necropsy records from two large general hospitals in Dundee showed short-term fluctuations in the prevalence of gall stones that had not previously been described. There was no evidence of a rise in the standardised prevalence rate between 1902-9 and 1953-73. A spurious increase was apparent from the crude prevalence rates for these periods, which resulted simply from the increased age of the patients in the later period. Since there was no real increase in prevalence no conclusions can be drawn about dietary or other changes. Patients with stones in the common bile duct were likely to die from an associated cause. This related mainly to a high mortality rate in women. In patients with established epilepsy the prevalence of gall stones was greater than expected, which suggests that phenobarbitone does not diminish the likelihood of gall stones.