Metabolic Profiling of Bile Acids in the Urine of Patients with Alcohol-Associated Liver Disease.
Hepatology communications
Bile acids (BAs) play important functions in the development of alcohol-associated liver disease (ALD). In the current study, urine BA concentrations in 38 patients with well-described alcohol-associated hepatitis (AH) as characterized by Model for End-Stage Liver Disease (MELD), 8 patients with alcohol-use disorder (AUD), and 19 healthy controls (HCs) were analyzed using liquid chromatography-mass spectrometry. Forty-three BAs were identified, and 22 BAs had significant changes in their abundance levels in patients with AH. The potential associations of clinical data were compared to candidate BAs in this pilot proof-of-concept study. MELD score showed positive correlations with several conjugated BAs and negative correlations with certain unconjugated BAs; taurine-conjugated chenodeoxycholic acid (CDCA) and MELD score showed the highest association. Cholic acid, CDCA, and apocholic acid had nonsignificant abundance changes in patients with nonsevere ALD compared to HCs but were significantly increased in those with severe AH. Receiver operating characteristic analysis showed that the differences in these three compounds were sufficiently large to distinguish severe AH from nonsevere ALD. Notably, the abundance levels of primary BAs were significantly increased while most of the secondary BAs were markedly decreased in AH compared to AUD. Most importantly, the amount of total BAs and the ratio of primary to secondary BAs increased while the ratio of unconjugated to conjugated BAs decreased as disease severity increased. Abundance changes of specific BAs are closely correlated with the severity of AH in this pilot study. Urine BAs (individually or as a group) could be potential noninvasive laboratory biomarkers for detecting early stage ALD and may have prognostic value in AH morbidity.
10.1002/hep4.1671
Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy.
The Cochrane database of systematic reviews
BACKGROUND:Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information. OBJECTIVES:To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity. SEARCH METHODS:We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland. SELECTION CRITERIA:Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus. DATA COLLECTION AND ANALYSIS:We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies. MAIN RESULTS:Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. AUTHORS' CONCLUSIONS:The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.
10.1002/14651858.CD012546.pub2
Utilizing Untargeted Ion Mobility-Mass Spectrometry To Profile Changes in the Gut Metabolome Following Biliary Diversion Surgery.
Poland James C,Schrimpe-Rutledge Alexandra C,Sherrod Stacy D,Flynn Charles Robb,McLean John A
Analytical chemistry
Obesity and obesity-related disorders are a global epidemic affecting over 10% of the world's population. Treatment of these diseases has become increasingly challenging and expensive. The most effective and durable treatment for Class III obesity (body mass index ≥35 kg/m) is bariatric surgery, namely, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy. These procedures are associated with increased circulating bile acids, molecules that not only facilitate intestinal fat absorption but are also potent hormones regulating numerous metabolic pathways. We recently reported on a novel surgical procedure in mice, termed distal gallbladder bile diversion to the ileum (GB-IL), that emulates the altered bile flow after RYGB without other manipulations of gastrointestinal anatomy. GB-IL improves oral glucose tolerance in mice made obese with high-fat diet. This is accompanied by fat malabsorption and weight loss, which complicates studying the role of elevated circulating bile acids in metabolic control. A less aggressive surgery in which the gallbladder bile is diverted to the proximal ileum, termed GB-IL, also improves glucose control but is not accompanied by fat malabsorption. To better understand the differential effects achieved by these bile diversion procedures, an untargeted ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) method was optimized for fecal samples derived from mice that have undergone bile diversion surgery. Utilizing the UPLC-IM-MS method, we were able to identify dysregulation of bile acids, short-chain fatty acids, and cholesterol derivatives that contribute to the differential metabolism resulting from these surgeries.
10.1021/acs.analchem.9b02924
Plasma and serum oxylipin, endocannabinoid, bile acid, steroid, fatty acid and nonsteroidal anti-inflammatory drug quantification in a 96-well plate format.
Pedersen Theresa L,Gray Ira J,Newman John W
Analytica chimica acta
The goal of this research was to develop a high-throughput, cost-effective method for metabolic profiling of lipid mediators and hormones involved in the regulation of inflammation and energy metabolism, along with polyunsaturated fatty acids and common over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs). We describe a 96-well plate protein precipitation and filtration procedure for 50 μL of plasma or serum in the presence of 37 deuterated analogs and 2 instrument internal standards. Data is acquired in two back-to-back UPLC-MS/MS analyses using electrospray ionization with positive/negative switching and scheduled multiple reaction monitoring for the determination of 145 compounds, including oxylipins, endocannabinoids and like compounds, bile acids, glucocorticoids, sex steroids, polyunsaturated fatty acids, and 3 NSAIDs. Intra- and inter-batch variability was <25% for >70% of metabolites above the LOQ in both matrices, but higher inter-batch variability was observed for serum oxylipins and some bile acids. Results for NIST Standard Reference Material 1950, compared favorably with the 20 certified metabolite values covered by this assay, and we provide new data for oxylipins, N-acylethanolamides, glucocorticoids, and 17-hydroxy-progesterone in this material. Application to two independent cohorts of elderly men and women showed the routine detection of 86 metabolites, identified fasting state influences on essential fatty acid-derived oxylipins, N-acylethanolamides and conjugated bile acids, identified rare presence of high and low testosterone levels and the presence of NSAIDs in ∼10% of these populations. The described method appears valuable for investigations in large cohort studies to provide insight into metabolic cross-talk between the array of mediators assessed here.
10.1016/j.aca.2020.11.019
Characteristics of bile acids metabolism profile in the second and third trimesters of normal pregnancy.
Zhu Bo,Yin Peiyuan,Ma Zhixin,Ma Yu,Zhang Hong,Kong Hongwei,Zhu Yuning
Metabolism: clinical and experimental
PURPOSE:Bile acids are a group of cholesterol metabolites functioning as key regulators of glucose, lipid, and energy metabolism. Their homeostatic control is essential to the physiology of the normal pregnancy. Abnormalities of bile acids regulation in pregnancy lead to intrahepatic cholestasis of pregnancy, a serious condition associated with a number of fetal and maternal morbidities. Dysregulation of glucose and lipids is also tied to perturbations in bile acid concentrations. Changes in bile acid metabolic profiles in the second and third trimesters of pregnancy have been incompletely explored. We seek to establish pregnancy-specific normative ranges for a number of bile acids in women in the second and third trimesters and explore changes in their concentrations in the period from 12 to 40 weeks gestation. PROCEDURE:In this cross-sectional study, a total of 782 normal pregnant women were enrolled including n = 290 in the second trimester (12-28 weeks) and n = 492 in the third trimester (29-40 weeks). The concentrations of 14 bile acids were measured by liquid chromatography and mass spectrometry (LC-MS) and compared at various time points. Reference intervals of these bile acids were calculated using standard statistical techniques. RESULTS:A reference interval profile of 14 bile acids from a cohort of 782 normal pregnant women was developed. Significant differences in concentration were found between the second trimester and the third trimester. Unconjugated bile acids dominate the bile acid profile in the second trimester, while conjugated bile acids, especially (taurine-conjugated) dominate in the third trimester. 28-31 weeks gestation was the notable change period of bile acid metabolism. CONCLUSION:This study establishes pregnancy-specific reference intervals for bile acids in the second and third trimesters. As bile acid composition changes with gestational age, this study establishes a foundation for trimester-specific clinical interpretation of bile acid metabolic profiles in pregnant women.
10.1016/j.metabol.2019.04.004
Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis.
Scientific reports
Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr and Tgr5 mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.
10.1038/s41598-020-67968-6
Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.
Chappell Lucy C,Bell Jennifer L,Smith Anne,Linsell Louise,Juszczak Edmund,Dixon Peter H,Chambers Jenny,Hunter Rachael,Dorling Jon,Williamson Catherine,Thornton Jim G,
Lancet (London, England)
BACKGROUND:Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS:We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. FINDINGS:Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION:Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING:National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
10.1016/S0140-6736(19)31270-X
Prevalence and risk factors of intrahepatic cholestasis of pregnancy in a Chinese population.
Gao Xing-Xing,Ye Meng-Ying,Liu Yan,Li Jin-Yan,Li Li,Chen Wei,Lu Xue,Nie Guiying,Chen Yuan-Hua
Scientific reports
Studies on the risk factors for intrahepatic cholestasis of pregnancy (ICP) in a population-based cohort are lacking. We assess the prevalence and risk factors of ICP in a Chinese population. In this study, a cohort study was conducted that included 12,200 eligible pregnant women. The overall incidence of ICP in this cohort was 6.06%. With increasing maternal age, the incidence of ICP decreased in women younger than 30 years of age but increased in those older than 30. With increasing pre-pregnancy BMI, the incidence of ICP decreased if the pre-pregnancy BMI was less than 23 kg/m but increased if it was 23 kg/m or higher. Further analysis showed that the risk of ICP increased when maternal age was < 25 years (Adjusted RR 2.01; 95% CI 1.64-2.47) or ≥ 35 years (Adjusted RR 1.34; 95% CI 1.02-1.76). Furthermore, an increased risk of ICP was associated with pre-pregnancy underweight (adjusted RR 1.27; 95% CI 1.04-1.56), inadequate gestational weight gain (GWG) (adjusted RR 1.58; 95% CI 1.28-1.96), lower maternal education (adjusted RR 2.96; 95% CI 2.35-3.74), multiparity (adjusted RR 1.54; 95% CI 1.23-1.93), and twin/multiple pregnancies (adjusted RR 2.12; 95% CI 1.25-3.58). Maternal age (< 25 or ≥ 35 years), underweight, inadequate GWG, lower maternal education, multiparity, and twin/multiple pregnancies were identified as risk factors of ICP.
10.1038/s41598-020-73378-5