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Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients.
Koelfat, KVK, Plummer, MP, Schaap, FG, Lenicek, M, Jansen, PLM, Deane, AM, Olde Damink, SWM
Hepatology (Baltimore, Md.). 2019;(1):308-318
Abstract
Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum-derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient-stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high-lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient-stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.
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Effect of an Olive Oil-Based Lipid Emulsion Compared With a Soybean Oil-Based Lipid Emulsion on Liver Chemistry and Bile Acid Composition in Preterm Infants Receiving Parenteral Nutrition: A Double-Blind, Randomized Trial.
Wang, Y, Zhou, KJ, Tang, QY, Hong, L, Feng, Y, Lu, LN, Wang, WP, Cai, W
JPEN. Journal of parenteral and enteral nutrition. 2016;(6):842-50
Abstract
BACKGROUND The pathogenesis of parenteral nutrition (PN)-associated liver dysfunction is multifactorial. Lipid emulsions may be one of the putative mechanisms. Our aim was to comparatively assess the effect of parenteral olive oil- and soybean oil-based lipid emulsions on liver chemistry and bile acid composition in preterm infants. METHODS We performed a double-blind, randomized clinical study in which 103 preterm infants were randomly assigned to PN using either soybean oil-based lipid emulsion (SO; n = 51) or olive oil (OO)-based lipid emulsion (OO; n = 52). The primary end point was liver chemistry. The secondary end point was the plasma bile acid composition. RESULTS One hundred infants completed this study. In the SO group, the serum direct bilirubin was significantly higher after PN for 7 days compared with the OO group. Bile acids increased over time in both treatment groups. However, specific differences in the change in bile acid composition over time were noted between groups. CONCLUSIONS Differences in direct bilirubin and bile acid composition were observed over time between the 2 groups. Considering the long-term use of lipid emulsions in higher risk babies, these findings might be useful for understanding the pathogenesis of PN-associated liver dysfunction.
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Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.
Ferslew, BC, Xie, G, Johnston, CK, Su, M, Stewart, PW, Jia, W, Brouwer, KL, Barritt, AS
Digestive diseases and sciences. 2015;(11):3318-28
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BACKGROUND AND AIMS The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. METHODS Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. RESULTS Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. CONCLUSIONS Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.
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The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study.
Locatelli, F, Spasovski, G, Dimkovic, N, Wanner, C, Dellanna, F, Pontoriero, G
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(5):1061-73
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BACKGROUND This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3% for colestilan and 54.0 and 80.6% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer.
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Total serum bilirubin predicts fat-soluble vitamin deficiency better than serum bile acids in infants with biliary atresia.
Venkat, VL, Shneider, BL, Magee, JC, Turmelle, Y, Arnon, R, Bezerra, JA, Hertel, PM, Karpen, SJ, Kerkar, N, Loomes, KM, et al
Journal of pediatric gastroenterology and nutrition. 2014;(6):702-7
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OBJECTIVE Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia. METHODS Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA. RESULTS The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998). CONCLUSIONS We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.
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Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids.
Kohli, R, Bradley, D, Setchell, KD, Eagon, JC, Abumrad, N, Klein, S
The Journal of clinical endocrinology and metabolism. 2013;(4):E708-12
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CONTEXT It has been hypothesized that increased plasma bile acids (BAs) contribute to metabolic improvements after Roux-en-Y gastric bypass (RYGB) surgery by the G protein-coupled receptor TGR5-mediated effects on glucagon-like peptide-1 secretion and thyroid hormones. OBJECTIVE The objective of this study was to evaluate the importance of bariatric surgery-induced alterations in BA physiology on factors that regulate glucose homeostasis (insulin secretion and sensitivity) and energy metabolism (resting energy expenditure and thyroid hormone axis). DESIGN, PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURE Eighteen extremely obese subjects were studied before and after 20% weight loss, induced by either laparoscopic adjustable gastric banding (LAGB) (n = 10) or RYGB surgery (n = 8). RESULTS Plasma BAs more than doubled after RYGB [fasting: 1.08 (0.26-1.42) to 2.28 (1.59-3.28) μmol/L, P = .03; postprandial: 2.46 ± 1.59 to 6.00 ± 2.75 μmol/L, P = .01] but were either lower or did not change after LAGB [fasting: 1.80 (1.49-2.19) to 0.92 (0.73-1.15) μmol/L, P = .02; postprandial: 3.71 ± 2.61 to 2.82 ± 1.75 μmol/L, P = .14]. Skeletal muscle expression of TGR5 targets, Kir6.2 and cyclooxygenase IV, increased after RYGB but not LAGB. Surgery-induced changes in BAs were associated with increased peak postprandial plasma glucagon-like peptide-1 (r(2) = 0.509, P = .001) and decreased serum TSH (r(2) = 0.562, P < .001) but did not correlate with the change in insulin response to a meal (r(2) = 0.013, P = .658), insulin sensitivity (assessed as insulin stimulated glucose disposal during a hyperinsulinemic-euglycemic clamp procedure) (r(2) = 0.001, P = .995), or resting energy expenditure (r(2) = 0.004, P = .807). CONCLUSIONS Compared with LAGB, RYGB increases circulating BAs and TGR5 signaling, but this increase in BAs is not a significant predictor of changes in glucose homeostasis or energy metabolism.
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Acute effects of dietary fat composition on postprandial plasma bile acid and cholecystokinin concentrations in healthy premenopausal women.
Costarelli, V, Sanders, TA
The British journal of nutrition. 2001;(4):471-7
Abstract
Bile acids derived from intestinal bacterial metabolism and transported to the breast in plasma may influence risk of breast cancer. The purpose of the present study was to test the hypothesis that fatty acid chain length and degree of unsaturation differ with regard to their influence on the postprandial release of cholecystokinin (CCK) and the subsequent increase in plasma bile acid concentrations that occur following a meal. A randomized crossover design was used to compare five high-fat test meals (50 g fat) with a low-fat test meal (15 g) on plasma bile acid and CCK concentrations in eighteen healthy premenopausal women. The high-fat meals were enriched in oleate or palmitate, or linoleate or medium-chain triacylglycerols (MCT) or a blend of oleate and long-chain n-3 fatty acids. The postprandial increase in plasma CCK concentration was lower on the MCT meal compared with all meals and was greater following the linoleate compared with the low-fat meal. Plasma bile acid concentrations increased 2-3-fold postprandially but the increase was lower following the MCT meal compared with the other meals and was greater on the linoleate meal compared with the low-fat meal. The postprandial increases in plasma chenodeoxycholic acid concentration showed a trend to rise with increasing unsaturation of the test meal. In conclusion, meals rich in linoleate are a potent stimulus for CCK release and lead to prolonged elevations of plasma bile acids and meals containing MCT inhibit CCK release and the subsequent increase in plasma bile acid concentrations.