Total Serum Bile Acid Concentrations Research Articles

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.

Percutaneous transvenous coil embolization (PTCE) for treatment of single extrahepatic portosystemic shunt in dogs

BackgroundThere is limited information regarding percutaneous transvenous coil embolization (PTCE) for single extrahepatic portosystemic shunt (PSS). This study aimed to describe the procedure and outcome of PTCE in dogs with a single extrahepatic PSS. Forty-two privately owned dogs were included in this study. All dogs were diagnosed with extrahepatic PSS by computed tomography (CT). Preoperative CT images were used to evaluate the diameter of the PSS for coil placement. A multipurpose balloon catheter was percutaneously inserted into the PSS via the jugular vein, and transvenous retrograde portography (TRP) and measurement of blood pressure in the PSS (pPSS) were performed during balloon inflation; one or more embolization coils were implanted via the catheter.ResultsIn most cases, preoperative median fasting and postprandial serum total bile acid (TBA) concentrations were high (fasting, 86.5 μmol/L [ 3.7–250.0 μmol/L]; postprandial, 165.5 μmol/L [ 1.5–565.0 μmol/L]). CT revealed that 30 dogs had left gastrophrenic shunt; eight had left gastroazygos shunt; and one each had left gastrocaval, splenocaval, splenophrenic, and left colocaval shunt. TRP revealed that intrahepatic portal vascularity was clearly detectable in all dogs. The median values of pPSS before and during the balloon occlusion were 4.8 mmHg [2.0–13.0 mmHg] and 8.6 mmHg [5.0–18.0 mmHg], respectively. The median number and diameter of coils used were 2 coils [1 – 5 coils] and 8.0 mm [4.0 – 12.0 mm], respectively. The median times of irradiation and PTCE were 9 min [4–26 min] and 40 min [23–75 min], respectively. The median fasting and postprandial TBAs significantly decreased to 8.2 μmol/L [0.3–45.1 μmol/L, n = 38, p = 0.0028] and 19.8 μmol/L [0.3–106.7 μmol/L, n = 38, p = 0.0018], respectively, approximately 1 month after PTCE. The clinical success rate of PTCE without requirement for a second surgery was 95.2% (40/42 dogs). During revision surgery, one dog underwent surgical ligation and, in another dog, an ameroid constrictor was placed.ConclusionsPTCE was clinically effective in treating single extrahepatic PSS in dogs. Preoperative CT and TRP prior to PTCE might be clinically valuable for choosing the size of embolization coils, deciding the appropriate location of coil implantation, and estimating the number of coils to be implanted. PTCE is a promising alternative to conventional surgical procedures for single extrahepatic PSS in dogs.

Serum Bile Acids Concentrations and Liver Enzyme Activities after Low-Dose Trilostane in Dogs with Hyperadrenocorticism.

Hyperadrenocorticism (HAC) often leads to vacuolar hepatopathy. The impact of trilostane treatment on serum total bile acids (SBAs) concentrations in dogs with HAC remains unknown. This study investigated SBAs concentrations in healthy dogs and those with HAC following trilostane therapy. Ten healthy dogs and fifteen dogs with HAC were prospectively enrolled. A biochemistry profile and pre- and post-prandial SBAs concentrations were determined in each dog. Dogs with HAC were reassessed at 1 and 3 months after the initiation of trilostane treatment. Dogs with HAC had significantly higher serum ALT, ALP, and GGT activities, and cholesterol, triglyceride, and pre-prandial SBAs concentrations compared to healthy dogs. After 3 months of trilostane treatment, polyuria/polydipsia and polyphagia were completely resolved in 42.8% and 35.7%, respectively. Significant improvements in serum ALT and ALP activities and cholesterol concentrations were observed within 1-3 months of trilostane treatment. However, pre- and post-prandial SBAs concentrations did not significantly decrease. These findings suggest that treatment with low-dose trilostane for 3 months appears to reduce serum liver enzyme activities, but not SBAs concentrations. Further investigation is warranted to explore the effects of low-dose trilostane treatment on SBAs concentrations for a longer duration or after achieving appropriate post-ACTH cortisol levels.

Intrahepatic cholestasis of pregnancy - Time to redefine the reference range of total serum bile acids: A cross-sectional study.

ObjectiveTo establish pregnancy‐specific reference ranges for fasting and postprandial total serum bile acid (TSBA) concentrations.DesignCross‐sectional study.SettingTertiary‐care university hospital.PopulationHealthy pregnant women at term admitted to the Obstetrics Department over a period of 1 year. Exclusion criteria were an established diagnosis of intrahepatic cholestasis of pregnancy (ICP) or any coexisting condition of increased risk for ICP.MethodsBoth fasting (after 8–14 h of fasting) and postprandial (2 h after meal) TSBA concentrations were measured in 612 women (with 528 fasting samples and 377 postprandial samples) by automated enzymatic spectrophotometric assay.Main outcome measuresFasting and postprandial TSBA concentrations in 612 women.ResultsReference intervals of 4.4–14.1 μmol/L for fasting TSBA and 4.7–20.2 μmol/L for postprandial TSBA were established. The postprandial values were significantly higher than the fasting values, with a median increase of 1.0 μmol/L (p < 0.0001). A correlation between fasting TSBA concentrations and postprandial concentrations was found, as well as correlations with fetal sex, parity and assisted reproductive technologies. A seasonal pattern was noticed for both fasting and postprandial TSBA, with the highest values measured in the winter season (p < 0.01 and 0.02, respectively)ConclusionsNormal pregnancy is associated with mild hypercholanaemia, and therefore a higher threshold should be considered for the diagnosis of ICP. We suggest using the upper reference limits observed in our healthy pregnant population (14 μmol/L for fasting TSBA and 20 μmol/L for postprandial TSBA). As the fasting measurement is more specific for the diagnosis, and the postprandial measurement is essential for the assessment of severity, it is recommended to measure both values rather than use random sampling.Tweetable abstractNormal pregnancy is associated with mild hypercholanaemia, a higher threshold should be considered for the diagnosis of ICP.

Intrahepatic cholestasis of pregnancy: Case series of a rare disease in an African setting

Intrahepatic cholestasis of pregnancy commonly presents in the second and third trimester with unexplained pruritus sine materia, abnormal liver function tests, and/or elevated serum total bile acid concentration. Its incidence ranges from less than 1% to 27.6%, with Araucana Indians from Chile being the highest affected. Intrahepatic cholestasis of pregnancy complicates pregnancy, hence influencing its outcomes. Our series involves three cases of pruritus in pregnancy ending with one elective cesarean delivery and two emergency cesarean deliveries without any significant complications to babies as well as immediate resolution of maternal symptoms. High index of suspicion for intrahepatic cholestasis of pregnancy is of paramount importance among clinicians even in primary care setup. Prompt treatment and intervention will prevent poor perinatal outcome.

Association of Maternal Thyroid Function with Gestational Hypercholanemia.

Background: High bile acid concentration is associated with adverse perinatal outcomes (i.e., stillbirth and preterm birth) and experimental studies indicate that thyroid hormone regulates bile acid metabolism, but this has not yet been translated to clinical data in pregnant women. We aim to explore the association of thyroid function with bile acid concentrations and the risk of gestational hypercholanemia. Methods: This study comprised 68,016 singleton pregnancies without known thyroid or hepatobiliary diseases before pregnancy and thyroid medication based on a prospective cohort. Thyroid function and serum total bile acid (TBA) were routinely screened in both early (9-13 weeks) and late pregnancy (32-36 weeks). Hypercholanemia was defined as serum TBA concentration ≥10 μmol/L. Multiple linear regression models and multiple logistic regression models were performed. Results: A higher free thyroxine (fT4) during both early or late pregnancy was associated with a higher TBA concentration and a higher risk of hypercholanemia (all p < 0.01). A higher thyrotropin (TSH) in early pregnancy was associated with a higher TBA concentration in early pregnancy (p = 0.0155), but with a lower TBA concentration during later pregnancy (p < 0.0001), and there was no association of TSH with hypercholanemia. Overt hyperthyroidism in late pregnancy was associated with a 2.12-fold higher risk of hypercholanemia ([confidence interval; CI 1.12-4.03], p = 0.021) and subclinical hyperthyroidism during later pregnancy was associated with a 1.5-fold higher risk of hypercholanemia ([CI 1.14-1.97], p = 0.0034). Sensitivity analyses indicated that a high fT4 throughout pregnancy was associated with a higher risk of hypercholanemia rather than only in early or late pregnancy. Conclusions: A higher fT4 concentration during either early or late pregnancy, but not the TSH concentration, is associated with higher TBA and a higher risk of gestational hypercholanemia. Furthermore, hyperthyroidism during pregnancy could be a novel risk factor for hypercholanemia.

Circulating bile acids concentration is predictive of coronary artery disease in human

Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human.

Changes in serum total bile acid concentrations are associated with the risk of developing adverse maternal and perinatal outcomes in pregnant Chinese women

Background and aimsWe aimed to investigate the association between total bile acid (TBA) concentrations changes during the second and third trimesters and the risk of developing adverse maternal and perinatal outcomes (AMPO). MethodsA total of 1569 pregnant Chinese women were enrolled. Serum TBA concentrations were measured during the 16–18th and 29–34th weeks of gestation. Logistic regression models were performed. ResultsAfter multivariable adjustment, each standard deviation increase in the TBA concentrations in the second trimester was associated with a 30% (odds ratio [OR] = 1.30, 95% confidence interval [CI]: 1.13, 1.50) increased risk of gestational diabetes mellitus (GDM) and a 22% (OR = 1.22, 95% CI: 1.07, 1.63) increased risk of premature rupture of membranes (PROM). When we compared the highest and lowest quartiles of changes in the TBA Z-scores across the second and third trimesters, the adjusted ORs were 1.84 (95% CI: 1.28, 2.65) for PROM and 1.47 (95% CI: 1.07, 2.28) for macrosomia. ConclusionElevated serum TBA concentrations during pregnancy were positively associated with increased risks of GDM and PROM. Women with more drastic changes in TBA concentrations across the second and third trimesters were at a higher risk of developing PROM and macrosomia.

Decreased Physiological Serum Total Bile Acid Concentrations in Patients with Type 2 Diabetic Peripheral Neuropathy.

PurposeBile acids, amphipathic cholesterol metabolites, have been reported to have cytoprotective and neuroprotective effects in humans and animal models. The relationship of physiological serum total bile acid (TBA) levels with diabetic peripheral neuropathy (DPN), however, has not been determined. The purpose of this study was to investigate the relationship between physiological serum TBA and DPN.Patients and MethodsIn total, 856 patients with type 2 diabetes mellitus (T2DM) aged 20–89 years were enrolled in this cross-sectional study. Serum TBA was measured, and its relationship with DPN and other parameters was analyzed.ResultsT2DM patients with DPN had significantly lower serum TBA compared with those without (P<0.01). Serum TBA was negatively associated with glycated hemoglobin A1C, plateletcrit, fibrinogen, urine albumin-to-creatinine ratio, vibration perception thresholds, and prevalence of DPN, peripheral arterial disease, and diabetic foot ulceration after adjustment for age, sex, and body mass index (P<0.01 or P<0.05). A graded association with prevalence of DPN and increase in serum TBA quartiles was observed (P for trend <0.01), and there was an 48.2% decreased risk of DPN in the highest quartile of serum TBA versus the lowest quartile (95% CI 0.299–0.617; P=0.000) after multivariate adjustment. Receiver-operating characteristic analysis revealed that the optimal cutoff point of serum TBA to indicate DPN was 2.85 μmol/L (sensitivity 77.6% and specificity 45.6%).ConclusionThese findings suggest that lower physiological serum TBA level may be associated with the prevalence of DPN in T2DM patients and may be a potential biomarker for DPN.

Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations

Background & AimsIntrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of stillbirth. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in patients with ICP who were or were not treated with ursodeoxycholic acid (UDCA).MethodsBile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCA-treated). Fetal electrocardiogram traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability (HRV) parameters were measured in 2 behavioral states (quiet and active sleep).ResultsIn untreated ICP, fetal total serum bile acid (TSBA) concentrations (r = 0.49, p = 0.019), hydrophobicity index (r = 0.20, p = 0.039), glycocholate concentrations (r = 0.56, p = 0.007) and taurocholate concentrations (r = 0.44, p = 0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r = 0.40, p = 0.026) and alanine aminotransferase (r = 0.40, p = 0.046) also positively correlated with fetal NT-proBNP. There were no significant correlations between maternal or fetal serum bile acid concentrations and fetal HRV parameters or NT-proBNP concentrations in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r = 0.46, p = 0.027) and UDCA-treated ICP (r = 0.54, p = 0.026). Measures of HRV in active sleep and quiet sleep were significantly higher in untreated ICP cases than controls. HRV values in UDCA-treated cases did not differ from controls.ConclusionsElevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterized by increased NT-proBNP concentration, PR interval length and HRV. UDCA treatment partially attenuates this phenotype.Lay summaryThe risk of stillbirth in intrahepatic cholestasis of pregnancy (ICP) is linked to the level of bile acids in the mother which are thought to disrupt the baby’s heart rhythm. We found that babies of women with untreated ICP have abnormally functioning hearts compared to those without ICP, and the degree of abnormality is closely linked to the level of harmful bile acids in the mother and baby’s blood. Babies of women with ICP who received treatment with the drug UDCA do not have the same level of abnormality in their hearts, suggesting that UDCA could be a beneficial treatment in some ICP cases, although further clinical trials are needed to confirm this.

Enzymatic methods may underestimate the total serum bile acid concentration.

Enzymatic assays based on bacterial 3α-hydroxysteroid dehydrogenase are the method of choice for quantification of total bile acids (BAs) in serum. Although non-specific, it is generally considered precise and robust. The aim of this study was to investigate how changes in the BA spectrum might affect the reliability of the method. We measured standard solutions of twenty-three human and murine BAs using a commercial enzymatic assay and compared the measured vs. expected concentrations. Additionally, total BA concentrations in rat and human cholestatic samples with an abnormal BA spectrum were measured using an enzymatic assay, and a more specific LC-MS/MS method. We observed a great variability in the response of individual BAs in the enzymatic assay. Relative signal intensities ranged from 100% in glycocholic acid (reference) to only 20% in α-muricholic acid. The enzymatic assay markedly underestimated the BA concentrations in both human and rat cholestatic sera when compared to the LC-MS/MS assay. Our study indicated that the performance of an enzymatic assay largely depends on the BA spectrum, and the total concentration of BAs can be markedly underestimated. Samples with an atypical BA spectrum (viz. in rodents) should preferably be measured by other methods.

Increased serum bile acid level is associated with high-risk coronary artery plaques in an asymptomatic population detected by coronary computed tomography angiography

There are limited data on the association between serum total bile acid level and coronary plaque characteristics. This study investigated the relationship between serum total bile acid level and the severity of coronary stenosis and coronary plaque features in an asymptomatic population using coronary computed tomography angiography (CTA). A total of 1,137 consecutive participants with no known coronary artery disease (CAD) undergoing CTA as part of a general routine health evaluation were recruited. Serum total bile acid level and clinical parameters were assayed. Coronary stenosis and high-risk plaques features (napkin-ring sign, low-attenuation plaque, spotty calcification, positive remodelling) were evaluated. Associations between serum total bile acid concentration and high-risk coronary plaques was tested through univariate and multivariate analyses. A total of 101 high-risk coronary plaques subjects and 93 controls were eligible for study inclusion. The severity of coronary artery stenosis and high-risk coronary plaques increased with serum total bile acid level quartiles (all P<0.001). The independent predictor of high-risk coronary plaques in multivariate analysis was serum total bile acid level (P<0.001). Receiver operating characteristic (ROC) confirmed that serum total bile acid concentration significantly differentiated high-risk coronary plaques [the area under the curve (AUC) =0.876; P<0.001, with a sensitivity of 87.13% and a specificity of 86.02%]. Higher serum total bile acid level was associated with the severity of coronary artery stenosis and high-risk coronary artery plaques detected by CTA in asymptomatic populations.

Still in Search of an Effective Treatment for Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is diagnosed based on presence of pruritus, elevated total serum bile acid concentration, and/or elevated

A phase 2 trial of N-Acetylcysteine in Biliary atresia after Kasai portoenterostomy.

BackgroundBiliary atresia (BA) is a life-threatening liver disease of infancy, characterized by extrahepatic biliary obstruction, bile retention, and progressive liver injury. The Kasai portoenterostomy (KP) is BA's only nontransplant treatment. Its success is variable and depends on restoration of hepatic bile flow. Many adjunctive therapeutics have been studied to improve outcomes after the KP, but none demonstrate effectiveness. This study tests if N-acetylcysteine (NAC), a precursor to the choleretic glutathione, improves bile flow after KP.MethodsThis report describes the design of an open-label, single center, Phase 2 study to determine the effect of NAC following KP on markers of bile flow and outcomes in BA. The intervention is intravenous NAC (150 mg/kg/day) administered continuously for seven days starting 0–24 h after KP. The primary outcome is normalization of total serum bile acid (TSBA) concentrations within 24 weeks of KP. The secondary objectives are to describe NAC therapy's effect on other clinical parameters followed in BA for 24 months and to report adverse events occurring with therapy. This study follows the “minimax” clinical trial design.DiscussionThis is the first clinical trial to test NAC's effectiveness in improving bile flow after KP in BA. It introduces three important concepts for future BA therapeutic trials: (1) the “minimax” study design, a pertinent design for rare diseases because it detects potential effects quickly with small subject size; (2) the more sensitive bile flow marker, TSBAs, which may correlate with positive long-term outcomes better than traditional bile flow markers such as serum bilirubin; and (3) liver enzyme changes immediately after KP, which can be a guideline for potential drug-induced liver injury in other BA peri-operative adjunctive therapeutic trials.

Total bile acid levels are associated with left atrial volume and cardiac output in patients with cirrhosis.

Bile acids (BAs) are potent signaling molecules involved in the regulation of several metabolic and functional aspects of cardiovascular homeostasis. BA pool alteration in cirrhosis may contribute toward the development of hemodynamic and cardiac disturbances. We aimed to investigate the association between total BA levels and echocardiographic and biochemical markers of cardiac dysfunction in cirrhotic patients. Cirrhotic patients were enrolled prospectively in this hypothesis-generating study and evaluated for cardiac and hemodynamic dysfunction through clinical, echocardiographic, and biochemical means. Associations between total serum BA concentrations and markers of systolic or diastolic dysfunction and the presence of cirrhotic cardiomyopathy were tested through univariate and multivariate analyses. Fifty-eight patients with cirrhosis were assessed in this monocentric study. 49 (85%) patients had decompensated cirrhosis according to the Child class. The median total BA level was 45 µmol/l. There was no correlation between BA levels and the etiology of cirrhosis (P=0.2), current alcohol use (P=0.8), sex (P=0.1), smoking status (P=0.2), age, or BMI. Systolic and diastolic dysfunction were rare in the cohort. Total BA levels associated with several echocardiographic parameters of the hyperdynamic syndrome in univariate analysis but only with left atrial volume in multivariate analysis (P=0.007). BA concentrations did not differ according to the presence of echocardiographically diagnosed cirrhotic cardiomyopathy in the two models tested. Total serum BA levels are associated with enlarged left atrial volume and markers of the hyperdynamic circulation in patients with cirrhosis irrespective of the etiology or the severity of liver disease.

Clinicopathological Findings and Prognosis in Canine Cases Diagnosed As Primary Hypoplasia of the Portal Vein.

Canine primary hypoplasia of the portal vein (PHPV) is a microscopic malformation of the hepatic vasculature. The prevalence, clinical signs, and clinicopathological findings of PHPV in dogs are unclear, because there are few reports concerning PHPV in the veterinary literature. This retrospective study reviewed clinical records and liver biopsy data from 48 dogs with hepatic disease that were examined at a private veterinary hospital in Japan between April 2011 and March 2014 to determine the prevalence of PHPV among dogs that underwent liver biopsy and to determine the clinical and clinicopathological findings of PHPV in dogs. Records for all 48 dogs that underwent liver biopsy were investigated. Collected data included signalment, clinical signs, physical examination findings, complete blood cell count, chemistry results, pre-and postprandial serum total bile acid concentrations, coagulation profiles (prothrombin time, activated partial thromboplastin time, fibrinogen, and antithrombin), and abdominal ultrasonography findings at the first medical examination. The diagnosis of PHPV was made on the basis of histological examination of hepatic biopsy specimens and portography or CT angiography. Among the 48 canine cases, 28 dogs (58.3%) were diagnosed with PHPV, which was the most common diagnosis. The most frequent clinical sign in dogs with PHPV was asymptomatic persistently increased liver enzymes (57.1%). Toy poodles were at a significantly higher risk of PHPV than other breeds among dogs that underwent liver biopsy (P < 0.001). The median survival time of dogs with PHPV was more than 5 years. Plasma fibrinogen concentration below the reference range was an indicator of PHPV in this study. Dogs with PHPV frequently had mild clinical signs and a favorable prognosis.

Bile Acid Synthesis Disorders in Arabs: A 10-year Screening Study.

Early diagnosis of bile acid synthesis disorders (BASDs) is important because, untreated, these conditions can be fatal. Our objectives were to screen children with cholestasis or unexplained liver disease for BASD and in those with confirmed BASD to evaluate the effectiveness of cholic acid therapy. A routine serum total bile acid measurement was performed on children with cholestasis, liver cirrhosis, and liver failure. Patients were screened for BASD by fast atom bombardment ionization-mass spectrometry (FAB-MS) analysis of urine, and molecular analysis confirmed diagnosis. Treatment response to oral cholic acid (10-15 mg/kg bw/day) was assessed from liver function tests and fat-soluble vitamin levels. FAB-MS analysis of urine was used to monitor compliance and biochemical response. Between 2007 and 2016, 626 patients were evaluated; 450 with infantile cholestasis. Fifteen cases of BASD were diagnosed: 12 presented with infantile cholestasis (2.7%, 7 boys), an 8-year-old boy presented with cirrhosis, and two 18-month-old boys presented with hepatomegaly and rickets. Eleven were caused by 3β-hydroxy-Δ-C27-steroid oxidoreductase dehydrogenase deficiency, 3 from Δ-3-oxosteroid 5β-reductase deficiency, and 1 had Zellweger spectrum disorder. In all but 1, serum total bile acids were normal or low. With cholic acid therapy, 10 are alive and healthy with their native liver. Liver failure developed in 3 infants despite therapy; 2 died and 1 underwent liver transplantation. BASDs are rare but treatable causes of metabolic liver disease in Saudi Arabia. BASD should be considered in infants with cholestasis and low or normal serum total bile acid concentrations.

Early indications of ANIT-induced cholestatic liver injury: Alteration of hepatocyte polarization and bile acid homeostasis

Hepatocyte polarization is essential for biliary secretion, and loss of polarity causes bile secretory failure and hepatotoxicity. Here, we showed that alpha-naphthyl isothiocyanate (ANIT)-induced liver injury was accompanied by the dynamic interruption of bile acid homeostasis in rat plasma, liver and bile, which was characterized by the redistribution of bile acids in plasma and bile and a small range of fluctuations in the liver. Molecular mechanism studies indicated that these factors are dynamically mediated by the disruption of bile acid transporters and hepatic tight junctions. Dynamic changes in tight junction (TJ) permeability were observed by hepatobiliary barrier function assessment. Hepatocyte polarization was disrupted by ANIT before the development of cholestatic hepatotoxicity and alteration of bile acid metabolic profiles, which were assayed by high-performance liquid chromatography-tandem mass spectrometry, further verifying TJ deficiency. S1PR1 activation with SEW2871 reduced ANIT-induced liver injury by reducing the total serum bile acid concentration, liver functional enzyme activity and inflammation. Our data suggest that hepatocyte polarization plays an important role in maintaining bile acid homeostasis before the development of cholestatic hepatotoxicity and that TJs were more prominent in the early stage of cholestasis. S1PR1 may be a potential target for the prevention of drug-induced cholestatic liver injury.

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study

Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov, number NCT01899703. Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were -57% (95% CI -73 to -42, p<0·0001) in the NRS, -31% (-42 to -20, p<0·0001) in the PBC-40 itch domain and -35% (-45 to -25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (-23%, 95% CI -45 to -1; p=0·037), PBC-40 itch domain, (-14%, -26 to -1; p=0·034), and 5-D itch scale (-20%, -34 to -7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI -37 to -61, p<0·0001) from 30 to 15 μM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. GlaxoSmithKline and National Institute for Health Research.

The Diagnostic Usefulness of Serum Total Bile Acid Concentrations in the Early Phase of Acute Pancreatitis of Varied Etiologies.

The most common causes of acute pancreatitis (AP) are biliary tract diseases with cholestasis and alcohol consumption. In 10%–15% of patients, etiology determination is difficult. Identification of the etiology allows for the implementation of adequate treatment. The aim of this study was to assess the utility of the serum concentrations of total bile acids (TBA) to diagnose AP etiology in the early phase of the disease. We included 66 patients with AP, admitted within the first 24 h from the onset of symptoms. TBA were measured in serum at 24, 48, and 72 h from the onset of AP, using an automated fifth generation assay. The bilirubin-to-TBA ratio (B/TBA) was calculated. TBA was highest on the first day of AP and decreased subsequently. In patients with biliary etiology, serum TBA was significantly higher compared to those with alcoholic and other etiologies. B/TBA was significantly higher in patients with alcoholic etiology. At admission, the cut-off values of 4.7 µmol/L for TBA and 4.22 for the B/TBA ratio allowed for a differentiation between biliary and other etiologies of AP with a diagnostic accuracy of 85 and 83%. Both TBA and B/TBA may help in the diagnosis of AP etiology in the early phase of AP.