Oral Bile Acid Treatment Research Articles

Peroxisome Deficiency Causes a Complex Phenotype because of Hepatic SREBP/Insig Dysregulation Associated with Endoplasmic Reticulum Stress

Regulation of hepatic cholesterol biosynthesis, lipogenesis, and insulin signaling intersect at the transcriptional level by control of SREBP and Insig genes. We previously demonstrated that peroxisome-deficient PEX2-/- mice activate SREBP-2 pathways but are unable to maintain normal cholesterol homeostasis. In this study, we demonstrate that oral bile acid treatment normalized hepatic and plasma cholesterol levels and hepatic cholesterol synthesis in early postnatal PEX2 mutants, but SREBP-2 and its target gene expressions remained increased. SREBP-2 pathway induction was also observed in neonatal and longer surviving PEX2 mutants, where hepatic cholesterol levels were normal. Abnormal expression patterns for SREBP-1c and Insig-2a, and novel regulation of Insig-2b, further demonstrate that peroxisome deficiency widely affects the regulation of related metabolic pathways. We have provided the first demonstration that peroxisome deficiency activates hepatic endoplasmic reticulum (ER) stress pathways, especially the integrated stress response mediated by PERK and ATF4 signaling. Our studies suggest a mechanism whereby ER stress leads to dysregulation of the endogenous sterol response mechanism and concordantly activates oxidative stress pathways. Several metabolic derangements in peroxisome-deficient PEX2-/- liver are likely to trigger ER stress, including perturbed flux of mevalonate metabolites, altered bile acid homeostasis, changes in fatty acid levels and composition, and oxidative stress.

Oral Bile Acid Treatment in Two Japanese Patients With Zellweger Syndrome

Oral Bile Acid Treatment in Two Japanese Patients With Zellweger Syndrome

Gallstone recurrence after successful oral bile acid treatment: A 20 year follow-up evaluation

Gallstone recurrence after successful oral bile acid treatment: A 20 year follow-up evaluation

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 >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 :I, the vesicles become unstable); (2) there is an imbalance between proand 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 octreotideassociated 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 pg octreotide/d for 29 to 68 months show that the HU scores range from 23 to 490 (mean f SEM, 116 it 41). suggesting that at least four of these 11 patients have noncholesterol stones. Gallstone dissolvability is being assessed by studying the response to oral UDCA (10 mg . kg-kg-‘&‘). Liquid test meal-stimulated immunoreactive CCK release and gallbladder contraction are also being measured before and during treatment, as are biliary bile acid and lipid composition, cholesterol saturation indices, and crystal nucleation times in samples of fasting bile obtained by ultrasound-guided skinny-needle aspiration of the GB. Only after establishing the relative contributions of these different pathogenetic mechanisms will we be in a position to plan, logically, prophylactic measures to prevent octreotide-induced GBS formation. Copyright 61 1992 by W.B. Saunders Company

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 > 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 μg 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. Gallstone dissolvability is being assessed by studying the response to oral UDCA (10 mg·kg −kg −1.d −1). Liquid test meal-stimulated immunoreactive CCK release and gallbladder contraction are also being measured before and during treatment, as are biliary bile acid and lipid composition, cholesterol saturation indices, and crystal nucleation times in samples of fasting bile obtained by ultrasound-guided skinny-needle aspiration of the GB. Only after establishing the relative contributions of these different pathogenetic mechanisms will we be in a position to plan, logically, prophylactic measures to prevent octreotide-induced GBS formation.

Oral bile acid treatment and the patient with zellweger syndrome

The cerebrohepatorenal syndrome of Zellweger is a congenital syndrome of multiple manifestations, including hepatomegaly and liver dysfunction. Treatment is generally of a supportive nature, aimed at improving nutrition and growth, controlling the central nervous system symptoms and limiting progression of liver disease. Because the liver disease in Zellweger syndrome may be attributed to an overproduction and accumulation of cholestanoic acids, exacerbated by diminished primary bile acid synthesis, we hypothesized that primary bile acid administration would be beneficial in improving liver function by a mechanism involving down-regulation in the synthesis of these atypical bile acids. We report here the clinical and biochemical responses to primary bile acid administration in a 2-mo-old boy who was seen with the typical signs of Zellweger syndrome. Liver disease was evident from hepatomegaly and elevated serum liver enzymes and bilirubin. The diagnosis was supported by markedly elevated serum very long chain fatty acids and the bile acids dihydroxycholestanoic acid and trihydroxycholestanoic acid. Confirmation of the lack of peroxisomes was established by electron microscopy. When the patient was 6 mo old, the primary bile acids cholic acid and chenodeoxycholic acid, (100 mg each/day) were administered orally. A significant improvement in biochemical indices of liver function occurred with a normalization of the serum bilirubin and liver enzymes and a histological improvement in the extent of inflammation and bile duct proliferation and disappearance of cannalicular plugs. Serum and urinary cholestanoic acids showed a significant decrease within a few days. A striking and sustained increase in growth was observed after therapy, and an improvement in neurological symptoms was noted. In conclusion, this study indicates that primary bile acid therapy improves liver function and growth in the patient with peroxisomal dysfunction and should be considered in the supportive therapies for this condition.

In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids

The rate of decrease of gallstone diameter appeared to be linear with oral bile acid treatment time, as estimated by inspection of graphic data of individual patient serial oral cholecystograms. A theoretical basis for this model was derived. The hypothesis of diameter decrease proportional to treatment time was tested with data from 223 patients with radiolucent gallbladder stones up to 20 mm in diameter treated with 7–8 or 14–15 mg · kg−1 · day−1 of either ursodiol or chenodiol for 1 year, followed up after 3, 6, and 12 months of treatment. Linearity of individual sets of data points was tested by mathematical and statistical methods, including polynomial curve fitting, linear regression analysis, quadratic vs. linear analyses of covariance, and prediction of 12-month stone size by linear extrapolation from diameters at 0 and 6 months. Most patients (> 70%) had rates of gallstone diameter decrease that were almost linear with treatment time, independently of different dissolution rates on a given regimen. Additional treatment time needed may be estimated from cholecystograms or ultrasonograms performed before treatment and after several months.

Gallstone recurrence after successful oral bile acid treatment: A 12-year follow-up study and evaluation of long-term postdissolution treatment

Recurrence is a major problem in the medical treatment of gallstones but its extent is still uncertain. The aim of this study was to determine the magnitude of this event and to assess the effectiveness of a postdissolution treatment in preventing it. We evaluated the long-term recurrence rate after 96 confirmed dissolutions observed in 86 subjects (71 women, 15 men) over a 12-yr follow-up period. A low-dose postdissolution treatment (ursodeoxycholic acid, 300 mg/day) was administered to 36 subjects, whereas in the remaining 60 cases no postdissolution treatment was given. By actuarial life-table analysis, the cumulative proportion of gallstone recurrence was 12.5% at the first year, rising to 61% at the 11th year. Postdissolution treatment was effective in reducing the frequency of gallstone recurrence (p = 0.0067), but this was mainly related to its effect on younger subjects (≤50 yr old). In older subjects the recurrence rate was unaffected by treatment. The probability of gallstone recurrence was significantly higher in subjects with multiple stones before dissolution treatment than in those who had had solitary stones (p = 0.0091). No other factor predictive of gallstone recurrence could be identified.

Gallstone disappearance after extracorporeal lithotripsy and oral bile acid dissolution

Extracorporeal shock-wave cholelithotripsy was carried out in 135 symptomatic patients with radiolucent gallstones, followed by oral bile acid dissolution to assess the resultant stone disappearance rates. Fragmentation was satisfactory (all fragments <5 mm in diameter) in 34 patients (25%) after a single session of lithotripsy, and in 65 (48%) after multiple sessions. The overall satisfactory fragmentation rate was significantly higher in patients with single stones ≤20 mm in diameter when compared with those with larger solitary stones (71% vs. 38%, p < 0.05), as it also was in all subjects with solitary stones when compared with those with multiple stones (60% vs. 34%, p < 0.05). After 6, 9, and 12 mo of oral bile acid treatment, the stone-free rates were significantly higher in patients with satisfactory than in those with partial fragmentation (55% vs. 0%, 80% vs. 29%, and 90% vs. 33%, respectively; p < 0.05). Only 1 of the 7 patients who had previously undergone endoscopic sphincterotomy for concomitant choledocholithiasis was free of stones after 1 yr of dissolution. During dissolution therapy, of the 102 patients in whom fragmentation had occurred, 1 (1%) developed mild acute pancreatitis, 23 (23%) suffered attacks of biliary colic, and 6 (6%) required cholecystectomy. We conclude that the result of fragmentation appears to be a major determinant of the success and rapidity of subsequent oral bile acid dissolution, and that when satisfactory, it allows for complete stone disappearance in most patients within the following year. A comparison of the present results with those of previous original studies suggests that to achieve such satisfactory fragmentation, patients should be selected on the basis of their stone characteristics, which optimally should present as solitary gallbladder calculi <20 mm in diameter. Furthermore, real-time ultrasonographic monitoring should be used during lithotripsy with a transducer centered along the shock-wave axis. Despite the innocuousness of the shock waves, the incidence of fragment migration and its possible complications, in our experience, emphasizes the need to restrict at present this nonoperative approach to the treatment of symptomatic gallstone disease.