Serum Total Bile Acid Research Articles

Perinatal Outcomes of Using Ursodeoxycholic Acid to Treat Monochorionic and Dichorionic Twin Pregnancy Complicated by Intrahepatic Cholestasis of Pregnancy

To study the effect of using ursodeoxycholic acid (UDCA) to treat monochorionic and dichorionic twin pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP) and to examine the differences in perinatal outcomes. A total of 406 twin-carrying pregnant women who had ICP and received care at West China Second Hospital, Sichuan University between January 1, 2015 and November 1, 2018 were included in the study. The clinical data of monochorionic diamniotic (MCDA) and dichorionic diamniotic (DCDA) twins with ICP were analyzed. Analysis was done to compare the treatment effect for lowering serum total bile acid (TBA) and the perinatal outcomes with simple UDCA medication or combination medication. There were no statistically significant differences in TBA levels, early-onset ICP, simple UDCA medication or combination medication, neonatal Apgar score, birth weight, length of hospital stay, C-section rate, and perinatal mortality between the MCDA and the DCDA twin groups with ICP. However, maternal age, BMI, scarred uterus, in vitro fertilization-embryo transfer, preeclampsia, twin comorbidity rate of the two groups showed statistical differences. Further comparison between twin pregnancies with mildly-elevated TBA and those with severely-elevated TBA showed significant difference in preterm birth rate ( P<0.05). Simple UDCA medication or combination medication may have the same therapeutic effect on MCDA and DCDA twin pregnancies with ICP. Monochorionic twin pregnancy, twin comorbidities and pregnancy complications were still important factors affecting pregnancy outcomes of twin pregnancies with ICP. Twin pregnancies with slightly elevated TBA have been managed as severe ICP, which may be associated with increased iatrogenic preterm births.

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.

T329S Mutation in the FMO3 Gene Alleviates Lipid Metabolic Diseases in Chickens in the Late Laying Period.

Simple SummaryThe lipid deposition and health status of egg-laying hens is crucial to the development of the poultry industry. This study aimed to evaluate the effects of genetic variations in the flavin-containing monooxygenase 3 (FMO3) on the lipid metabolic diseases of laying hens during the late laying period. The results showed that the T329S mutation in FMO3 moderated the lipid parameters and decreased the atherosclerotic lesions and hepatic steatosis in laying hens with homozygous T329S mutation. In conclusion, the T329S mutation in FMO3 is closely associated with the improvement of lipid metabolic diseases in laying hens during the late laying period. The results of this study may contribute to overcoming the challenge of lipid metabolic diseases in laying hens during the late laying period.The T329S mutation in flavin-containing monooxygenase 3 (FMO3) impairs the trimethylamine (TMA) metabolism in laying hens. The TMA metabolic pathway is closely linked to lipid metabolic diseases, such as atherosclerosis and fatty liver disease. We aimed to evaluate the effects of the T329S mutation in FMO3 on lipid metabolism in chickens during the late laying period. We selected 18 FMO3 genotyped individuals (consisting of six AA, six AT, and six TT hens) with similar body weight and production performance. The lipid metabolism and deposition characteristics of the laying hens with different genotypes were compared. The T329S mutation moderated the serum-lipid parameters in TT hens compared to those in AA and AT hens from 49 to 62 weeks. Furthermore, it reduced the serum trimethylamine N-oxide concentrations and increased the serum total bile acid (p < 0.05) and related lipid transporter levels in TT hens. Moreover, it significantly (p < 0.01) decreased atherosclerotic lesions and hepatic steatosis in TT hens compared to those in the AA and AT hens. Our findings may help improve the health status in laying hens during the late laying period.

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.

Analysis of CYP27A1 mutations in Han Chinese women with intrahepatic cholestasis of pregnancy

Objective To explore the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene mutations in Chinese women with intrahepatic cholestasis of pregnancy (ICP) and the correlation between CYP27A gene mutations and BA (bile acid) level changes. Methods In this study, the entire coding region of the CYP27A1 gene was sequenced in 151 Han Chinese women with ICP and 1029 matched samples, and the pathogenicity of identified CYP27A1 gene mutations was judged through evolutionary conservation analysis, computational analysis and protein structure modeling. Finally, we verified the relationship between gene mutations and total serum bile acid (TBA) and cholesterol (CHOL) levels through experiments in cell culture. Results We identified five heterozygous CYP27A1 missense mutations in five ICP samples. Three online tools, Polyphen-2, MutationTaster and SIFT, predicted that the five CYP27A1 mutations were pathogenic. Furthermore, all five mutations caused marked protein structural changes. Experiments in cells showed that the intracellular and medium levels of TBA in the mutant groups were lower than those in the wild-type group, while the CHOL levels were higher in all mutants except for the R158H mutant. Conclusions CYP27A1 mutations are associated with the levels of TBA and CHOL, suggesting that CYP27A1 mutations contribute to abnormal total cholesterol and BA levels, which leads to ICP.

Hypercortisolism in patients with cholestasis is associated with disease severity

BackgroundCholestasis might lead to an impairment of adrenal function as suggested by in vitro and in vivo data as well as by clinical findings. Bile acid and adrenal steroid metabolism not only share the receptors farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5), but supraphysiological bile acid levels were found to stimulate steroidogenesis independent of FXR and TGR5. Our previous experimental findings revealed that mice fed bile acids or subjected to common bile duct ligation develop hypercortisolemia. We thus aimed to assess adrenal gland function in patients with cholestasis.MethodsAdrenal gland function was assessed in 36 patients with cholestasis and in 32 patients without cholestasis by measuring total serum cortisol, adrenocorticotropic hormone (ACTH), as well as the increase of cortisol 20 and 30 min after administration of 1 µg of ACTH. Bile acid levels and bile acid pool composition were determined by high-resolution mass spectrometry.ResultsPatients with cholestasis per definition had markedly elevated levels of alkaline phosphatase (AP), bilirubin and serum bile acids. Baseline cortisol and maximum cortisol after ACTH stimulation were significantly higher in patients with cholestasis compared to controls. Increase of cortisol after ACTH stimulation and ACTH did not differ. In the cholestasis group, baseline cortisol correlated with bilirubin but not with AP, total serum bile acids and levels of conjugated and unconjugated bile acid species. Patients with duration of cholestasis < 6 months (n = 30) had significantly higher baseline cortisol levels than those with long standing cholestasis (> 6 months), together with higher bilirubin levels.ConclusionsWe find no evidence of adrenal insufficiency in non-cirrhotic patients with cholestasis. In contrast, patients with cholestasis show hypercortisolism associated with disease severity as mirrored by levels of bilirubin. Lack of ACTH increase in cholestasis suggests a direct effect of cholestasis on adrenals and not on the pituitary gland. Further studies are needed to elucidate the mechanism of cortisol elevation in patients with cholestasis and its clinical significance.

Clinical features of sporadic hepatitis E virus infection in pregnant women in Shanghai, China

Hepatitis E virus (HEV) infection causes high mortality in pregnant women of developing regions during large outbreaks. The aim of this study was to investigate the clinical features of HEV-infected pregnant women in Shanghai, China where the epidemiology of HEV has shifted from large outbreaks to the sporadic form. Clinical data of 516 pregnant and nonpregnant child-bearing age women diagnosed with HEV infection during 2009-2020 was collected at the Shanghai Public Health Clinical center. Patients' data were analysed for clinical features and laboratory parameters accordingly. Most of the hospitalized HEV-infected pregnant women (85.23%, 127/149) showed no obvious clinical symptoms and the disease outcome was generally benign with no liver failure or maternal mortality observed in the patients. By comparison, fewer (37.21%, 32/86) of the HEV-infected nonpregnant women were asymptomatic, and five cases (5.81%, 5/86) of liver failure were observed among them. The levels of serum alanine aminotransferase, aspartate aminotransferase, total bilirubin (TBiL), direct bilirubin (DBiL) and total bile acids (TBA) were significantly higher (P < 0.05) in nonpregnant women than those of the pregnant women. We found 42.99% (46/107) births had adverse foetal/neonatal outcome. Mothers who presented with adverse foetal/neonatal outcome showed higher (P < 0.05) serum TBiL, DBiL and TBA levels than those without. We found that the clinical features of sporadic HEV infection in pregnant women in Shanghai, China are generally mild and no maternal mortality occurred. However foetal/neonatal adverse outcomes including preterm births and stillbirths were observed in HEV-infected pregnant women.

Myocardial Infarction and Coronary Artery Disease in Menopausal Women With Type 2 Diabetes Mellitus Negatively Correlate With Total Serum Bile Acids.

BackgroundAs metabolic molecules, bile acids (BAs) not only promote the absorption of fat-soluble nutrients, but they also regulate many metabolic processes, including the homeostasis of glucose and lipids. Although total serum BA (TBA) measurement is a readily available clinical test related to coronary artery disease (CAD), myocardial infarction (MI), and type 2 diabetes mellitus (T2DM), the relationship between TBA and these pathological conditions remain unclear, and research on this topic is inconclusive.MethodsThis study enrolled 20,255 menopausal women aged over 50 years, including 6,421 T2DM patients. The study population was divided into different groups according to the median TBA level in order to explore the clinical characteristics of menopausal women with different TBA levels. Spline analyses, generalized additive model (GAM) model and regression analyses based on TBA level were used to explore the relationship between TBA and different diseases independently, including CAD and MI, or in combination with T2DM.ResultsBoth in the general population and in the T2DM subgroup, the TBA level was significantly lower in CAD patients than in non-CAD patients. Spline analyses indicated that within normal clinical range of TBA concentration (0–10 µmol/L), the presence of CAD and MI showed similar trends in total and T2DM population. Similarly, the GAM model indicated that within the 0–10 μmol/L clinical range, the predicted probability for CAD and MI alone and in combination with T2DM was negatively correlated with TBA concentration. Multivariate regression analysis suggested that low TBA level was positively associated with the occurrence of CAD combined with T2DM (OR: 1.451; 95%CI: 1.141–1.847).ConclusionsIn menopausal women, TBA may represent a valuable clinical serum marker with negative correlation for CAD and MI in patients with T2DM.

Cholesterol-lowering effects of taurine through the reduction of ileal FXR signaling due to the alteration of ileal bile acid composition.

Studies using animal models of hypercholesterolemia have established that taurine reduces cholesterol levels; however, the precise mechanism underlying this cholesterol-lowering effect is unclear. This study addressed this issue by investigating whether bile acid/farnesoid X receptor (FXR) signaling is involved in taurine-mediated cholesterol-lowering effect. Fxr-null and wild-type mice were administered 2% (w/v) taurine in their drinking water and fed a control diet or control diet supplemented with 1% (w/w) cholesterol (cholesterol diet) for 10 days. Taurine intake did not significantly alter hepatic and serum total cholesterol (TC) levels and bile acid compositions of the liver and intestinal lumen in Fxr-null and wild-type mice fed the control diet. By changing to a cholesterol diet, taurine intake significantly decreased hepatic and serum cholesterol levels in wild-type mice. In contrast, it significantly decreased hepatic, not serum, cholesterol levels in Fxr-null mice. Taurine intake significantly altered the bile acid composition of the intestinal lumen in wild-type mice fed a cholesterol diet, but not in Fxr-null mice. An increase in FXR antagonistic bile acids was detected in the intestinal lumen of taurine-treated wild-type mice fed a cholesterol diet. Taurine intake reduced the ileal expression of FXR target genes fibroblast growth factor 15 (Fgf15) and small heterodimer partner (Shp). In contrast, it enhanced the hepatic expression of cholesterol 7α-hydroxylase (Cyp7a1) in wild-type mice fed a cholesterol diet, but not in Fxr-null mice. These results suggest that taurine is partially involved in cholesterol lowering by reducing the ileal FXR signaling due to the alteration of ileal bile acid composition.

Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways.

Objective To investigate the effect of electroacupuncture (EA) on cognitive dysfunction in rats with hepatic encephalopathy and its underlying mechanism. Methods Fifty Wistar rats were randomly divided into a normal group (n = 10) and model group (n = 40). Rat models of hepatic encephalopathy were established by administration of carbon tetrachloride and thioacetamide for a total of 12 weeks. At the 9th week after modeling, rats with cognitive impairment in the model group were identified by conducting the Morris water maze test, which were then randomly divided into a control group (CCl4) and treatment groups including EA group (CCl4 + EA), lactulose group (CCl4 + Lac), and EA plus lactulose group (CCl4 + CM), with 9 rats in each group. At the end of the 9th week, rats in CCl4 + Lac and CCl4 + CM groups had lactulose gavage at a dose of 10 mL/kg body weight, while normal control and CCl4 groups had gavage with the same volume of normal saline once a day for 21 days until the end of the experiment. Rats in CCl4 + EA and CCl4 + CM groups underwent acupuncture at Baihui (GV[DU]20), Shenting (GV[DU]24), and Zusanli (ST36) acupoints, among which EA at Baihui and Shenting acupoints were given once daily for 30 min lasting for 21 consecutive days. The effect of the treatment was measured by the Morris water maze test for learning and memory ability and magnetic resonance spectroscopy (MRS) for neuronal metabolism in the hippocampus of rats with hepatic encephalopathy. Pathological change in the rat hippocampus was observed by HE staining, while serum ammonia and liver function markers were detected. Western blot and real-time fluorescent quantitative PCR were used to detect the expressions of specific genes and proteins in the brain tissue. Results Compared with those in the control group, rats undergoing EA had significantly shortened escape latency and increased number of platform crossing. H&E staining confirmed that EA improved brain tissue necrosis and ameliorated nuclear pyknosis in rats with hepatic encephalopathy. Significantly decreased levels of serum ammonia, alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), and total bile acid (TBA) were observed in rats undergoing EA, as well as improved levels of total protein (TP) and albumin (ALB). In addition, EA inhibited the brain expressions of TNF-α, IL-1β, IL-6, iNOS, TLR4, MyD88, NF-κB, p38MAPK, phosphorylated (p)-p38MAPK, STAT3, and p-STAT3 genes, as well as protein expressions of TNF-α, IL-6, TLR4, MyD88, NF-κB, p38MAPK, p-p38MAPK, STAT3, and p-STAT3. MRS showed increased Glx/Cr and decreased NAA/Cr, Cho/Cr and mI/Cr in the control group, and EA significantly reversed such changes in Glx/Cr and mI/Cr values. Conclusion EA ameliorated the production of excessive proinflammatory cytokines in the hippocampus of rats with cognitive dysfunction secondary to hepatic encephalopathy, which also gave rise to subsequent changes such as reduced blood ammonia level, brain-protective activated astrocytes, and lower degree of brain tissue injury. The p38MAPK/STAT3 and TLR4/MyD88/NF-κB signaling pathways may be involved. EA can also improve the metabolism of NAA and Cho in the rat hippocampus and thereby improve learning and memory abilities.

A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis

Semaphorin 7A (SEMA7A) is a membrane‐bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC‐MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance‐associated protein‐2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.

Antipsychotic-induced gastrointestinal hypomotility and the alteration in gut microbiota in patients with schizophrenia

AimGut microbiota play an important role in the pathogenesis of gut hypomotility and are critical for the production of the intestinal immune system and the maintenance of the intestinal homeostasis. Patients with psychotic disorders are at a high risk of antipsychotic-induced constipation. However, the mechanisms might be more than neurotransmission properties of antipsychotics. MethodsWe recruited a total of 45 patients with constipation according to Rome IV criteria and objective test for colonic motility and the other 45 gender- and age-matching patients without constipation and investigated their differences in composition of gut microbiota. The demographic and serum metabolic indices were collected. The subjective constipation assessment scale (CAS) and the Bristol stool classification (BSS) were also used to evaluate the degree of constipation in both groups. The fecal samples were analysed using the 16S rRNA gene sequencing. ResultsThe constipation group had a significantly increased alpha diversity in Observed species, Chao 1, and ACE as compared to the non-constipation group. At the phylum levels, the relative abundances of Bacteroidetes and Fusobacteria decreased significantly, while those of Firmicutes, Verrucomicrobia, and Synergistetes increased significantly in the constipation group. At the genus level, the relative abundances of Christensenella and Desulfovibrio were higher in the constipation group. The α-diversity indices of gut microbiota were correlated positively with the levels of serum total bile acid and correlated negatively with BSS scores. The BSS scores were positively correlated with the relative abundance of Bacteroidetes but negatively correlated with the relative abundance of Firmicutes. PICRUSt analysis revealed the potential metabolic pathways of lipopolysaccharide, vitamin B6, riboflavin, pyruvate, and propionate functions. ConclusionsThe alternation of the gut microbiota in schizophrenia patients with antipsychotic-induced constipation indicates antipsychotic agents might affect gastrointestinal motility via varying microbiome-related metabolites, and the specific bacteria, such as Synergistetes which might act as an anti-inflammatory factor in the healthy human gut, related to colonic transit motility seem inconsistent to the findings from previous literature in gastroenterology. However, the causal effects are still unknown. Our study provides a new possibility to understand the mechanisms of antipsychotic-induced constipation.

Value of Serum Glycocholic Acid and Total Bile Acids in Predicting Maternal and Perinatal Outcomes in Intrahepatic Cholestasis of Pregnancy.

Objective To see whether serum glycocholic acid (CG) and total bile acids (TBA) can predict maternal and perinatal outcomes in pregnant women with intrahepatic cholestasis (ICP). Method The observation group consisted of 80 women with ICP who were treated in our hospital, whereas the control group consisted of 50 ordinary women who were also treated at our hospital at the same time. The levels of CG and TBA in the two groups were determined independently, and the differences in poor perinatal outcomes were compared. Finally, the predictive diagnostic value of CG and TBA for poor perinatal outcomes in ICP mothers was displayed using the Spearman correlation between CG and TBA and Apgar. The maternal CG and TBA levels in the observation group were substantially higher than in the control group (P0.05). The observation group had more significant maternal-fetal discomfort, neonatal asphyxia, preterm birth, and perinatal death than the control group (P0.05). The risk of poor perinatal outcomes in ICP mothers rose when TBA and CG levels increased (P0.05). Apgar ratings were inversely associated with CG and TBA (r = −0.8251 and r = −0.5969, respectively, P0.05). The CG and TBA diagnostic AUCs for unfavorable perinatal outcomes in ICP mothers were (P0.05). Conclusion CG and TBA have a high diagnostic value for ICP and may better predict and identify poor prenatal outcomes. It is suitable for clinical use.

Rate of Chicken Eggs Consumption Does not Affect Blood Pressure and Serum Lipogram, Glucose, Proteins, IGF-1 or Total Bile Acids Levels in Healthy Young Male Adult Farm Workers : A Cross-Sectional Study

Rate of Chicken Eggs Consumption Does not Affect Blood Pressure and Serum Lipogram, Glucose, Proteins, IGF-1 or Total Bile Acids Levels in Healthy Young Male Adult Farm Workers : A Cross-Sectional Study

Adjunct Fenofibrate Up-regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis.

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up‐regulate BA‐glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13‐15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145‐160 mg/day) as standard of care. Serum BA and BA‐glucuronide concentrations were measured by liquid chromatography–mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (−76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (−54%), and increased serum BA‐glucuronides (+2.1‐fold, P < 0.01) versus ursodiol monotherapy. The major serum BA‐glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid–6G (+3.7‐fold, P < 0.01), hyocholic acid–6G (+2.6‐fold, P < 0.05), chenodeoxycholic acid (CDCA)–3G (−36%), and lithocholic acid (LCA)–3G (−42%) versus ursodiol monotherapy. Fenofibrate also up‐regulated the expression of uridine 5′‐diphospho‐glucuronosyltransferases and multidrug resistance–associated protein 3 messenger RNA in primary human hepatocytes. Pearson’s correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA‐3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)‐3G (r2 = 0.48, P < 0.0001), and LCA‐3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA‐glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA‐glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα‐mediated anti‐cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA‐glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.

Probiotics Alleviated Nonalcoholic Fatty Liver Disease in High-Fat Diet-Fed Rats via Gut Microbiota/FXR/FGF15 Signaling Pathway

Gut microbiota (GM) dysbiosis and bile acid (BA) metabolism disorder play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Probiotics had a beneficial effect on NAFLD, but further study is needed to explore probiotics as a potential therapeutic agent to NAFLD. The aim of this study was to investigate the regulatory effect of probiotics on gut microbiota in NAFLD rats and to explore the possible mechanism of probiotics regulating the bile acid receptor farnesoid X receptor/growth factor 15 (FXR/FGF15) signaling pathway in rats. We established a rat model of NAFLD fed with a high-fat diet (HFD) for 14 weeks, which was given different interventions (312 mg/kg/day probiotics or 10 mg/kg/day atorvastatin) from the 7th week. Serum lipids and total bile acids (TBA) were biochemically determined; hepatic steatosis and lipid accumulation were evaluated with HE staining. The expression levels of FXR, FGF15 mRNA, and protein in rat liver were detected. 16S rDNA was used to detect the changes of gut microbiota in rats. Compared with the HFD group, probiotics and atorvastatin significantly reduced serum lipids and TBA levels. And probiotics increased dramatically the expression of FXR, FGF15 mRNA, and protein in the liver. But there were no significant changes in the atorvastatin group. Probiotics and atorvastatin can upregulate the diversity of gut microbiota and downregulate the abundance of pathogenic bacteria in NAFLD model rats. In summary, probiotics alleviated NAFLD in HFD rats via the gut microbiota/FXR/FGF15 signaling pathway.

Association of Elevated Maternal Serum Total Bile Acids With Low Birth Weight and Intrauterine Fetal Growth Restriction

Bile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear. To investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR. This retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020. Maternal sTBA concentration during pregnancy. Fetal birth weight and probability of low birth weight (LBW) and IUGR. This study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 μg/mL, 3290 [3.9] g; and for 4.1 μg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA ≥4.08 μg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 μg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.08 μg/mL (LBW: aOR, 9.13; 95% CI, 6.88-12.12; IUGR: aOR, 19.14; 95% CI, 12.09-30.28). This study found that gestational hypercholanemia was associated with an increased risk of LBW and IUGR, especially in pregnant individuals with HDP. Therefore, it would be meaningful to monitor sTBA concentration during the follow-up of pregnancies with potential IUGR.

New insights in diagnostic thresholds for total serum bile acid in intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disorder known to be associated with fetal adverse events, in particular stillbirth. At present, an effective treatment to reduce the risk of stillbirth, does not exist. Ursodeoxycholic acid (UDCA) is often given in clinical practice to reduce maternal symptom of pruritus but without strong evidence (Walker KF et al. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020 Jul 27;7(7):CD000493), and iatrogenic preterm birth is induced when the risk of stillbirth is thought to be higher (Ovadia C et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet. 2019 Mar 2;393(10174):899-909).

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.