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R H Dowling

Publications and source records attributed to R H Dowling.

At least 37 records · Page 2Linked to original sources

Gallbladder stone recurrence after medical treatment. Do gallstones recur true to type?

Medical treatments that dissolve or remove gallbladder stones but leave the gallbladder in situ have the disadvantage of gallstone recurrence. Little is known about the composition of recurrent stones or whether they recur true to type. In 21 patients with recurrent stones detected 5-74 months (mean +/- SEM, 26 +/- 4 months) after being rendered stone-free with dissolution therapy (N = 15) or percutaneous cholecystolithotomy (N = 6), we compared pretreatment and postrecurrence gallstone number, maximum gallstone attenuation scores measured by computed tomography (CT) and, in 13, the dissolvability of the recurrent stones with oral bile acids +/- extracorporeal shock-wave lithotripsy. Before treatment, five patients had solitary and 16 had multiple stones but on recurrence, the gallstones differed in number from the primary stones in 10 of the 21 patients. As a result of patient selection, before dissolution, the primary stones were all radiolucent with maximum CT scores of < 100 Hounsfield units (HU) (mean 45, range 10-84 HU). On recurrence, the stones were again CT-lucent in 13 of the 15 patients but were CT-dense in the remaining two (118 and 176 HU). Initially, all six patients treated by percutaneous cholecystolithotomy had radio-opaque stones, with a mean CT score of 459 (range 100-969) HU. However, on recurrence, only one had calcified stones (HU 140); the remaining five had CT-lucent stones (16-98 HU, P < 0.05). Of the 13 patients whose recurrent, plain x-ray-lucent and CT-lucent stones were treated with oral bile acids +/- lithotripsy, 12 (92%) showed evidence of gallstone dissolution. We conclude that gallbladder stones do not recur true to type in up to two thirds of patients. However, irrespective of original gallstone composition, recurrent stones are usually radio- and CT-lucent, presumed cholesterol-rich, and therefore potentially dissolvable with oral bile acids.

Bile Acids and Salts↗

Effect of acute bile acid pool depletion on total and ionized calcium concentrations in human bile.

Although calcium salts are important components of gallstones, there are few data on the total and ionized calcium content of human bile. Therefore, in 14 fasting T-tube patients studied 7-11 days after cholecystectomy, we measured bile flow, bile acid [BA], total [CaTOT] and free ionized [Ca++] calcium concentrations, in 20-30 min bile collections during acute BA pool depletion induced by 6-8 h of continuous bile drainage. During washout of the BA pool there were parallel falls in bile flow, BA output and total calcium output (correlation coefficients ranging from 0.59 to 0.99; P < 0.02-0.001). In 12 of the 14 patients, [CaTOT] also fell (from 1.84 +/- 0.29 to 1.32 +/- 0.34 mmol L-1) in parallel with [BA] (from 34.0 +/- 14.0 to 8.2 +/- 8.0 mmol L-1; r = 0.75-0.98; P < 0.005). In contrast, biliary [Ca++] remained virtually unchanged. These data suggest that the BAs are linked to the bound, rather than to the free, ionized, fraction of biliary calcium, which is consistent with in vivo calcium binding by BAs. A model is proposed in which BA-induced biliary calcium secretion results from (i) bile acid-induced water flow via solvent drag; and (ii) calcium binding in the bile canaliculus by bile acids, which induces paracellular diffusion of Ca++, thereby maintaining [Ca++] independent of [BA].

Adult↗

Composition of gall bladder stones associated with octreotide: response to oral ursodeoxycholic acid.

Octreotide, an effective treatment for acromegaly, induces gall bladder stones in 13-60% of patients. Because knowledge of stone composition is essential for studies of their pathogenesis, treatment, and prevention, this was investigated by direct and indirect methods in 14 octreotide treated acromegalic patients with gall stones. Chemical analysis of gall stones retrieved at cholecystectomy from two patients, showed that they contained 71% and 87% cholesterol by weight. In the remaining 12 patients, localised computed tomography of the gall bladder showed that eight had stones with maximum attenuation scores of < 100 Hounsfield units (values of < 100 HU predict cholesterol rich, dissolvable stones). Gall bladder bile was obtained by ultrasound guided, fine needle puncture from six patients. All six patients had supersaturated bile (mean (SEM) cholesterol saturation index of 1.19 (0.08) (range 1.01-1.53)) and all had abnormally rapid cholesterol microcrystal nucleation times (< 4 days (range 1-4)), whilst in four, the bile contained cholesterol microcrystals immediately after sampling. Of the 12 patients considered for oral ursodeoxycholic acid (UDCA) treatment, two had a blocked cystic duct and were not started on UDCA while one was lost to follow up. After one year of treatment, five of the remaining nine patients showed either partial (n = 3) or complete (n = 2) gall stone dissolution, suggesting that their stones were cholesterol rich. This corresponds, by actuarial (life table) analysis, to a combined gall stone dissolution rate of 58.3 (15.9%). In conclusion, octreotide induced gall stones are generally small, multiple, and cholesterol rich although, in common with spontaneous gall stone disease, at presentation some patients will have a blocked cystic duct and some gall stones containing calcium.

Acromegaly↗

Ultrasound-guided percutaneous fine needle puncture of the gallbladder for studies of bile composition.

Ultrasound-guided percutaneous fine needle puncture of the gallbladder (PFNP-GB) is invaluable for diagnostic and research purposes, but there are few reports about its safety. We therefore describe the efficacy and side-effects of 43 consecutive gallbladder punctures in 39 patients. PFNP-GB was successful in 40/43 (93%), but failed in three. Bile was completely aspirated in 28 of the 40 (70%) successful procedures. After 36 of the 43 punctures (84%), the patients remained asymptomatic, although on seven occasions (16%) the patients complained of right upper quadrant pain 0.5-12 h after the procedure. In six of these, the pain resolved in 2-24 h, although one developed a leucocytosis (22 x 10(9) 1(-1)). The seventh patient developed pyrexia and signs of generalized peritonism, which settled with conservative therapy. Ultrasonographic abnormalities of the gallbladder wall were seen in five of the seven symptomatic patients, consisting of: (i) an increase in the thickness of the gallbladder wall (n = 5) from less than 2 mm to 4-14 mm; (ii) peri-cholecystic collections (n = 2) measuring 5 and 11 mm in diameter; (iii) an intraluminal mucosal flap (n = 1); (iv) an intraluminal echogenic layer (n = 1); and (v) a 12 cm intraabdominal haematoma in the patient with generalized peritonism. Predictors of pain were: (i) the number of needle "passes" (3.7 +/- 0.8, range 2-8, in patients with pain vs 2.0 +/- 0.2, range 1-6, in pain-free patients, p < 0.02); (ii) the absence of gallbladder stones (p < 0.03); and (iii) incomplete aspiration of bile from the gallbladder (p < 0.02). PFNP-GB is an effective way of sampling fresh gallbladder bile, although there is a 16% risk of inducing pain and/or ultrasonographic changes in the gallbladder.

Adult↗

Percutaneous cholecystolithotomy: risks, benefits, and long-term outcome.

BACKGROUND: For symptomatic patients with gallbladder stones and a patent cystic duct who wish to retain their 'functioning' gallbladders, percutaneous cholecystolithotomy (PCCL) offers an alternative to open or laparoscopic cholecystectomy. However, there are few data on the risks and benefits of this approach or on the long-term outcome. METHODS AND RESULTS: In 21 patients with symptomatic calcified gallstones, PCCL was successful (gallstone clearance) in 17 (81%). Four to 62 (median, 35) months after clearance 9 of the 17 remained symptom-free and stone-free, whereas 4 developed biliary sludge at 7, 30, 32, and 35 months, 2 of whom subsequently developed gallstones. In four other patients gallstones recurred without evidence of preceding biliary sludge at 9, 16, 19, and 27 months, corresponding to an actuarial gallstone recurrence rate at 36 months of 53.4 +/- SEM 15.1%, and a combined stone/sludge recurrence rate of 63.4 +/- 13.5%. CONCLUSIONS: PCCL is moderately effective but, because of the frequency of complications and sludge/stone recurrence, is likely to have only a limited residual role in the era of laparoscopic cholecystectomy.

Cholecystostomy↗

Deoxycholic acid influences cholesterol solubilization and microcrystal nucleation time in gallbladder bile.

Little is known about the effects of biliary deoxycholic acid on the partitioning of biliary cholesterol between vesicles and micelles and on the rate of nucleation of cholesterol microcrystals, key steps in gallstone formation. Therefore, 43 samples of fresh gallbladder bile were obtained from a heterogeneous group of patients with and without stones. Univariate and multivariate analyses were then applied to determine the inter-relationships between biliary cholesterol saturation, total lipid concentration, and bile acid species and (1) the distribution of biliary cholesterol between vesicles and micelles and (2) the cholesterol microcrystal nucleation time. The percentage of deoxycholic acid in bile was shown to be linearly related to the cholesterol saturation index (r = .54; P < .001), the vesicular cholesterol:phospholipid molar ratio (r = .53; P < .001), and the molar concentration of cholesterol in the vesicles (r = .59; P < .001). The mean proportion of biliary deoxycholic acid conjugates was also greater in patients with rapid nucleation times (23.4 +/- SEM 1.1%) than in those with slow nucleation times (17.3 +/- 1.9%; P < .05). As total bile lipid concentration increased, the proportion of total biliary cholesterol in vesicles decreased (r = .53; P < .001), whereas the molar concentration of vesicular cholesterol increased (r = .42, P < .01). The cholesterol saturation indices, total bile lipid concentration, and proportion of biliary deoxycholate were independent determinants of the molar concentration of cholesterol in vesicles. We conclude that relative increases in the percentage of deoxycholic acid and in bile lipid concentration, favor the partitioning of cholesterol into vesicles. In turn, this leads to an increase in the vesicular cholesterol:phospholipid molar ratio and thus to a decrease in the cholesterol microcrystal nucleation time.

Adult↗

Gastric mucosal toxicity of duodenal juice constituents in the rat. Acute studies using ex vivo rat gastric chamber model.

To determine the acute gastrotoxicity of refluxed duodenal contents, an ex vivo rat gastric chamber was used to study mucosal damage produced by conjugated and unconjugated human bile acids and lysolecithin at neutral and acidic pH; the effects of trypsin, human duodenal aspirate, and combinations of chenodeoxycholic acid, lecithin, and lysolecithin were also studied. At neutral pH, all bile acids except tauroursodeoxycholic acid, caused dose-dependent falls in mucosal potential difference and losses of mucosal nucleic acid into the chamber fluid, indicating mucosal damage. The di-alpha-hydroxy bile acids, deoxycholic and chenodeoxycholic acids, were more gastrotoxic than cholic and ursodeoxycholic acids, and all unconjugated bile acids were more toxic than their conjugated species, none of which produced damage at concentrations below 2.0 mM. For all but the taurine conjugates, bile acid-induced changes in potential difference were lower at acidic then at neutral pH. Lysolecithin gastrotoxicity, comparable at neutral pH to that of chenodeoxycholic acid, was also reduced at acidic pH. Lecithin decreased the gastrotoxicity of chenodeoxycholic acid and lysolecithin. Trypsin produced no damage, and the gastrotoxicity of human duodenal aspirate was unaffected by prior heat inactivation of pancreatic enzymes.

Analysis of Variance↗

The role of bile composition and physical chemistry in the pathogenesis of octreotide-associated gallbladder stones.

BACKGROUND/AIMS: Treatment of acromegaly with octreotide inhibits cholecystokinin release and gallbladder contraction and induces gallbladder stones. However, little is known about the effects of octreotide on bile composition. METHODS: Fresh gallbladder bile was obtained from three groups: (1) 11 nonacromegalic patients with cholesterol gallstones, (2) 6 acromegalic patients with octreotide-associated stones (treatment, 300-600 micrograms/day for 3-66 months), and (3) 8 acromogalic patients with no stones before octreotide treatment, 5 of whom were reexamined after 3-24 months of therapy. RESULTS: Compared with stone-free acromegalic patients untreated with octreotide, bile from patients with cholesterol stones and from acromegalic patients with octreotide-associated stones had greater saturation indices (mean +/- SEM) (1.52 +/- 0.17 and 1.32 +/- 0.14 vs. 0.90 +/- 0.05, respectively; P < 0.01); more cholesterol in vesicles (61.2% +/- 4.5% and 67.7% +/- 7.2% vs. 37.7% +/- 3.5%; P < 0.009); more unstable vesicles (cholesterol/phospholipid ratios, 0.97 +/- 0.12 and 0.81 +/- 0.16 vs. 0.52 +/- 0.05; P < 0.02); more rapid nucleation (< 5 and < 5 days vs. > 18 days; P < 0.003); and more deoxycholic acid (22.8% +/- 2.4% and 23.6% +/- 4.8% vs. 13.9% +/- 1.4%; P < 0.05). In the paired studies, the saturation indices increased from 0.89 +/- 0.07 before octreotide treatment to 1.12 +/- 0.03 during octreotide treatment (P < 0.02), as did the percentage of deoxycholic acid from 13.3% +/- 2.1% to 24.9% +/- 2.7% (P < 0.03). CONCLUSIONS: Acromegalic patients with octreotide-associated gallstones and stone-free acromegalic patients treated with octreotide have similar changes in bile composition to those in patients with "conventional" cholesterol gallstone disease.

Acromegaly↗

Changes in serum calcium levels influence biliary calcium levels in humans.

BACKGROUND/AIMS: There are few data on the influence of serum calcium on biliary total and ionized calcium levels in humans. The aims of the study were to increase serum calcium levels short-term by intravenous calcium infusion and study the resultant changes in total and ionized calcium concentrations ([CaTOT] and [Ca2+]) in T-tube bile. METHODS: Serum and biliary total and ionized calcium concentrations were measured over an 8-hour period in 7 postcholecystectomy patients with T tubes before, during, and after a 4-hour intravenous infusion of 10% calcium gluconate. RESULTS: During the infusion, serum [CaTOT] increased from 2.08 +/- 0.14 mmol/L (mean +/- SD) to 3.18 +/- 0.33 mmol/L, and serum [Ca2+] increased from 1.13 +/- 0.13 mmol/L to 1.68 +/- 0.13 mmol/L. After a 20-40-minute time lag, there were corresponding increases in biliary [CaTOT] from 1.90 +/- 0.45 mmol/L to 2.80 +/- 0.52 mmol/L and in biliary [Ca2+] from 0.70 +/- 0.11 mmol/L to 1.19 +/- 0.16 mmol/L. When the data were pooled, serum [Ca2+] showed significant correlations with both biliary [CaTOT] (n = 128; r = 0.56; P < 0.001) and biliary [Ca2+] (n = 128; r = 0.64; P < 0.001). CONCLUSIONS: These results support the hypothesis that the biliary tree is freely permeable to calcium ions and that serum calcium level is one determinant of biliary calcium concentration. Our data may also explain the observation that patients with hypercalcemia are reported to have a greater than normal prevalence of calcified gallstones.

Aged↗

Enhanced growth of small bowel in transgenic mice overexpressing bovine growth hormone.

BACKGROUND: Transgenic mice with a bovine growth hormone gene linked to a mouse metallothionein I promoter (growth hormone transgenics) are a model of chronic growth hormone excess. METHODS: Growth of small bowel mucosa in ad libitum-fed growth hormone transgenics and wild type littermates and in growth hormone transgenics pair fed with wild-type littermates were compared. RESULTS: In both groups, body weight and small bowel weight were greater in growth hormone transgenics. Similarly, mucosal mass was 50%-100% greater in growth hormone transgenics, and the effect was greatest in proximal bowel. Villus height, measured in jejunum, was also greater in growth hormone transgenics. Measurements of mucosal proliferation did not differ between the growth hormone transgenics and wild type. Abundance of insulin-like growth factor-I messenger RNA in bowel was greater in growth hormone transgenics. CONCLUSIONS: Chronic growth hormone excess results in increased growth of small bowel mucosa. This effect appears to be specific because it occurred in ad libitum-fed and diet-restricted growth hormone transgenics, influenced villus height, and was more pronounced in upper than lower small bowel. The effect of chronic growth hormone excess does not appear to be secondary to an increase in the rate of mucosal proliferation, suggesting an effect on lifespan of mucosal cells.

Animals↗

Gall stone recurrence and its prevention: the British/Belgian Gall Stone Study Group's post-dissolution trial.

The British/Belgian Gall Stone Study Group (BBGSG) post-dissolution trial was a prospective, multicentre, randomised, double blind trial of: (i) low dose ursodeoxycholic acid, (ii) placebo, and (iii) a high fibre, low refined carbohydrate diet in the prevention of gall stone recurrence in patients with complete gall stone dissolution. Further aims included establishing the timing and frequency of recurrence and its association with biliary symptoms, a comparison of the sensitivity of ultrasonography v oral cholecystectography in detecting recurrent stones, and a search for risk factors predicting recurrence. Ninety three patients entered the study, and 82 were followed up for up to five years (mean (SEM) 28 (1.5) months) with six monthly ultrasonography and yearly oral cholecystectography. There were 21 recurrences (26 by oral cholecystectography or ultrasonography, or both), only two of which were symptomatic, which were detected between 12 and 42 months after trial entry. This corresponded to an actuarial recurrence rate of 33.9 (7.0%) by lifetable analysis at 42 months and subsequently. There were four recurrences in the ursodeoxycholic acid, six in the placebo, and 11 in the diet groups, corresponding to 21.9 (9.9)%, 27.4 (10.1)%, and 45.8 (12.4)% respectively at 42 months by lifetable analysis (NS). Variables including age, obesity, menopausal state, pregnancy, and oestrogen containing drugs were not shown to affect recurrence rate. Men had more frequent recurrence than women (NS). Patients who had had multiple stones experienced more recurrences than did those with single stones (NS). Recurrence did not occur in patients who took non-steroidal anti-inflammatory drugs (NSAIDs) (p < 0.02). The stone free interval between stone dissolution and trial entry proved to be important--those stone free > nine months had a recurrence rate of only 12.7 (6.0)% at 42 months compared with 55.4 (12.5)% in those stone free < nine months (p < 0.01). There was imbalance between the ursodeoxycholic acid and placebo groups for this factor, and after applying a statistical correction, the adjusted recurrence rate in the ursodeoxycholic acid group was 15% compared with 30% in both placebo and diet groups (NS). These data suggest that after medical dissolution, the risk of gall stone recurrence is not reduced by a high fibre, low refined carbohydrate diet: it may be lowered, but not abolished, by low dose ursodeoxycholic acid.

Adult↗

Nuclear magnetic resonance spectroscopy to determine the micellar cholesterol in human bile.

The cholesterol of gallstones comes from the vesicular rather than the micellar phase of bile. Progress in this field has been limited because conventional analytical methods disturb the distribution of cholesterol between the two phases. The resonance of the cholesterol C6 proton occurs at a chemical shift of 5.4 ppm, to be shown by 2D NMR to be specific for biliary cholesterol, and arises only from the micellar mode. Thus integration of the C6 proton resonance peak area provides a direct non-invasive determination of the cholesterol distribution in human bile.

Bile↗

Calcium and carbonate ion concentrations in gallbladder and hepatic bile.

Calcium carbonate is a major component of gallstones, but there are few data on calcium and carbonate (CO3(2-)) concentrations in human bile. Therefore, in patients undergoing cholecystectomy for gallstones, total [CaTOT] and free ionized [Ca2+] calcium concentrations, pH, PCO2, and total [CO2] were measured and [CO3(2-)] was derived in gallbladder and hepatic bile (aspirated anaerobically at surgery or from T tubes). Gallbladder bile had lower pH (6.96 vs. 7.30) and total [CO2] (14.1 vs. 21.6 mmol/L), higher PCO2 (53.8 vs. 40.2 mm Hg), lower [CO3(2-)] (2.52 vs. 6.11 x 10(5) mol/L) and lower [Ca2+] x [CO3(2-)] ion product (1.88 vs. 4.74 x 10(-8) mol/L) than did hepatic bile. Gallbladder bile pH correlated positively with total [CO2], [CO3(2-)], and [Ca2+] x [CO3(2-)] but negatively with PCO2. Patients with surface gallstone calcification had similar gallbladder bile [CaTOT] and [Ca2+] but higher gallbladder bile pH (7.30 vs. 6.90), lower PCO2 (42.9 vs. 57.2 mm Hg), higher [CO3(2-)] (7.29 vs. 1.84 x 10(-5) mol/L), and higher [Ca2+] x [CO3(2-)] ion product [4.73 vs. 1.45 x 10(-8) (mol/L)2] than those with radiolucent gallstones. There were no differences in these parameters between patients with cholesterol stones and those with pigment stones. These data suggest that the human gallbladder acidifies bile by secreting hydrogen ion and that impairment of this secretion is one cause of calcified gallstone formation in humans.

Adult↗

Gallstones during octreotide therapy.

Gallbladder stones (GBS) are found in up to 50% of patients receiving octreotide, but the reported prevalence of cholecystolithiasis in patients treated with octreotide is variable and little is known about gallstone incidence, composition, pathogenetic mechanisms, dissolvability, and primary prevention. Octreotide treatment apart, in industrialised societies most GBS are mixed in composition, cholesterol-rich (arbitrarily greater than 70% cholesterol by weight), radiolucent (70%), and, given a patent cystic duct (70%), dissolvable in bile rendered unsaturated in cholesterol by oral ursodeoxycholic (UDCA) +/- chenodeoxycholic (CDCA) acid treatment. They form when (1) GB bile becomes supersaturated with cholesterol (as the molar ratio of cholesterol to phospholipids in biliary vesicles approaches 1:1, the vesicles become unstable); (2) there is an imbalance between pro- and anti-nucleating factors, which favors cholesterol crystal precipitation; and (3) there is stasis within the GB as a result of altered motor function and/or excess mucus that traps the crystals. These changes may be associated with altered (4) biliary bile acid composition (more DCA and less CDCA than normal), and/or (5) phospholipid fatty acid composition (arachidonyl-rich lecithin acting as a substrate for mucosal prostaglandin synthesis which, in turn, may influence both gallbladder motility, and mucus glycoprotein synthesis and secretion). During octreotide treatment, meal-stimulated cholecystokinin (CCK) release is impaired leading to GB hypomotility, but little is known about the effects of octreotide on biliary cholesterol saturation, crystal nucleation time, mucus glycoprotein concentration, bile acid or phospholipid fatty acid composition. Most, but not all, reports suggest that the prevalence of GBS in octreotide-treated patients is considerably greater than that in age-, sex-, and weight-matched controls, but proof (by pre-treatment and on-treatment ultrasound) that the GBS were absent before, but developed during, therapy is not always available. Furthermore, there are few data on analysis of GBS composition in patients developing stones during treatment, although initial reports suggest that octreotide-associated GBS are also radiolucent, cholesterol-rich, and dissolve with oral bile acid treatment. Maximum GBS attenuation values, measured in Hounsfield Units (HU) by localized computerized tomography scanning of the GB, predict stone composition and dissolvability: GBS with scores of less than 100 HU are cholesterol-rich and dissolve well with oral bile acid treatment. However, preliminary results in 11 acromegalic patients treated with 200 to 600 micrograms octreotide/d for 29 to 68 months show that the HU scores range from 23 to 490 (mean +/- SEM, 116 +/- 41), suggesting that at least four of these 11 patients have non-cholesterol stones.(ABSTRACT TRUNCATED AT 400 WORDS)

Acromegaly↗

Combination therapy with oral ursodeoxycholic and chenodeoxycholic acids: pretreatment computed tomography of the gall bladder improves gall stone dissolution efficacy.

In a five year study, 55 patients with radiolucent gall stones were treated with the combination of 7.5 mg chenodeoxycholic acid (CDCA) and 5.0 mg ursodeoxycholic acid (UDCA)/kg/day--that is, half the monotherapeutic doses. Side effects were few but four patients could not tolerate the prescribed bile acids because of diarrhoea or nausea. Analysis of fasting duodenal bile confirmed that CDCA+UDCA converted supersaturated into unsaturated bile but the saturation indices did not predict the dissolution response. By actuarial analysis, the confirmed (by ultrasound x2) complete gall stone dissolution rates in all 55 patients were mean (SEM) 29 (7)% at 12 and 44 (8)% at 24 months. The advent of routine computed tomography before treatment enabled comparison of dissolution efficacy in those screened by computed tomography (n = 24), whose maximum gall stone attenuation was less than 100 Hounsfield units, with that in those not screened (n = 29). Although stone size and number were comparable, patients screened by computed tomography had significantly better dissolution rates (p less than 0.025) than those not screened in this way. At 12 months, partial or complete gall stone dissolution rates were 93 (7)% in the screened and 55 (11)% in the non-screened patients. At 18 months, complete dissolution rates were 64 (12%) and 20 (9)% respectively. Computed tomography before treatment is cost effective in selecting those patients likely to achieve gall stone dissolution on treatment with UDCA+CDCA.

Adult↗