Serum bile acids in cystic fibrosis patients - glycodeoxycholic acid as a potential marker of liver disease.

BACKGROUND: Cystic fibrosis (CF) and CF-related liver disease can lead to disturbances in bile acid metabolism. AIM: This study determined serum bile acid concentrations in CF to define their usefulness in liver disease assessment. METHODS: Primary, secondary and conjugated bile acid levels were measured in three CF groups (25 patients each) exhibiting: liver cirrhosis, other liver disease, no liver disease, and in 25 healthy subjects (HS). RESULTS: Bile acid levels were higher in CF patients than in HS, except for glycodeoxycholic acid (GDCA). However, bile acid concentrations did not differ between patients with cirrhosis and other liver involvement. GDCA and deoxycholic acid (DCA) differentiated CF patients with non-cirrhotic liver disease from those without liver disease (GDCA-AUC: 0.924, 95%CI 0.822-1.000, p<0.001; DCA-AUC: 0.867, 95%CI: 0.731-1.000, p<0.001). Principal component analysis revealed that in CF liver disease was related to GDCA, GGTP activity, severe genotype and pancreatic insufficiency. CONCLUSIONS: A CF-specific bile acid profile was defined and shown to relate to liver disease. GDCA differentiates patients with non-cirrhotic liver involvement from those with no detectable liver disease. Hence, GDCA is a candidate for validation as a biomarker of non-cirrhotic progression of liver disease in CF.

Reduced glycodeoxycholic acid levels are associated with negative clinical outcomes of gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is characterized by glycemia and insulin disorders. Bile acids (BAs) have emerged as vital signaling molecules in glucose metabolic regulation. BA change in GDM is still unclear, which exerts great significance to illustrate the change of BAs in GDM. GDM patients and normal pregnant women were enrolled during the oral glucose tolerance test (OGTT) screening period. Fasting serums were sampled for the measurement of BAs. BA metabolism profiles were analyzed in both pregnant women with GDM and those with normal glucose tolerance (NGT). Delivery characteristics, delivery gestational age, and infant birthweight were extracted from medical records. GDM patients presented distinctive features compared with NGT patients, including higher body mass index (BMI), elevated serum glucose concentration, raised insulin (both fasting and OGTT), and increased hemoglobin A1c (HbA1c) levels. Higher homeostasis model assessment of insulin resistance (HOMA-IR) and decreased ß-cell compensation (i.e., oral disposition index (DIo)) were also prevalent in this group. Total BAs (TBAs) remained stable, but glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) levels declined significantly in GDM. GDCA was inversely correlated with HOMA-IR and positively correlated with DIo. No obvious differences in clinical outcome between the GDM and NGT groups were observed. However, GDM patients with high HOMA-IR and low DIo tended to have a higher cesarean delivery rate and younger delivery gestational age. In conclusion, GDCA provides a valuable biomarker to evaluate HOMA-IR and DIo, and decreased GDCA levels predict poorer clinical outcomes for GDM.

Bile acid changes after metabolic surgery are linked to improvement in insulin sensitivity.

BACKGROUND: Metabolic surgery is associated with a prompt improvement in insulin resistance, although the mechanism of action remains unknown. The literature on bile acid changes after metabolic surgery is conflicting, and insulin sensitivity is generally assessed by indirect methods. The aim of this study was to investigate the relationship between improvement in insulin sensitivity and concentration of circulating bile acids after biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGB). METHODS: This was a prospective observational study of nine patients who underwent BPD and six who had RYGB. Inclusion criteria for participation were a BMI in excess of 40 kg/m2 , no previous diagnosis of type 2 diabetes and willingness to participate. Exclusion criteria were major endocrine diseases, malignancies and liver cirrhosis. Follow-up visits were carried out after a mean(s.d.) of 185·3(72·9) days. Fasting plasma bile acids were assessed by ultra-high-performance liquid chromatography coupled with a triple quadrupole mass spectrometer, and insulin sensitivity was measured by means of a hyperinsulinaemic-euglycaemic clamp. RESULTS: A significant increase in all bile acids, as well as an amelioration of insulin sensitivity, was observed after metabolic surgery. An increase in conjugated secondary bile acids was significantly associated with an increase in insulin sensitivity. Only the increase in glycodeoxycholic acid was significantly associated with an increase in insulin sensitivity in analysis of individual conjugated secondary bile acids. CONCLUSION: Glycodeoxycholic acid might drive the improved insulin sensitivity after metabolic surgery.

A multiplex HRMS assay for quantifying selected human plasma bile acids as candidate OATP biomarkers.

AIM: Selected bile acids (BAs) in plasma have been proposed as endogenous probes for assessing drug-drug interactions involving hepatic drug transporters such as the organic anion-transporting polypeptides (OATP1B1 and OATP1B3). MATERIALS & METHODS: Plasma extracts were analyzed for selected BAs using a triple TOF API6600 high-resolution mass spectrometer. RESULTS: Glycodeoxycholic acid 3-sulfate, glycochenodeoxycholic acid 3-sulfate, glycodeoxycholic acid 3-O-ß-glucuronide and glycochenodeoxycholic acid 3-O-ß-glucuronide are presented as potential OATP1B1/3 biomarkers. CONCLUSION: Six BAs are quantified in human plasma using a multiplexed high-resolution mass spectrometry method. Glycodeoxycholic acid 3-sulfate and glycodeoxycholic acid 3-O-ß-glucuronide are proposed as potential biomarkers based on observed four- to fivefold increase in plasma AUC (vs placebo), following administration of a compound known to present as an OATP1B1/3 inhibitor in vitro.

Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.

Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.

Metabolomic Endotype of Asthma.

Metabolomics, the quantification of small biochemicals in plasma and tissues, can provide insight into complex biochemical processes and enable the identification of biomarkers that may serve as therapeutic targets. We hypothesized that the plasma metabolome of asthma would reveal metabolic consequences of the specific immune and inflammatory responses unique to endotypes of asthma. The plasma metabolomic profiles of 20 asthmatic subjects and 10 healthy controls were examined using an untargeted global and focused metabolomic analysis. Individuals were classified based on clinical definitions of asthma severity or by levels of fraction of exhaled NO (FENO), a biomarker of airway inflammation. Of the 293 biochemicals identified in the plasma, 25 were significantly different among asthma and healthy controls (p < 0.05). Plasma levels of taurine, lathosterol, bile acids (taurocholate and glycodeoxycholate), nicotinamide, and adenosine-5-phosphate were significantly higher in asthmatics compared with healthy controls. Severe asthmatics had biochemical changes related to steroid and amino acid/protein metabolism. Asthmatics with high FENO, compared with those with low FENO, had higher levels of plasma branched-chain amino acids and bile acids. Asthmatics have a unique plasma metabolome that distinguishes them from healthy controls and points to activation of inflammatory and immune pathways. The severe asthmatic and high FENO asthmatic have unique endotypes that suggest changes in NO-associated taurine transport and bile acid metabolism.

Bile acids cycle disruption in patients with nasopharyngeal carcinoma promotes the elevation of interleukin-10 secretion.

BACKGROUND: Unclear pathogenesis existed for nasopharyngeal carcinoma. AIMS: to analyze the role of bile acids in the pathogenesis of nasopharyngeal carcinoma. METHODS: 20 healthy volunteers and 20 patients with nasopharyngeal carcinoma were enrolled between January 1(st), 2013 and December 31(st), 2014. ESI-QTOF-MS analysis of serum was performed to find altered bile acids components. The biological function of changed bile acids was investigated using in vitro experiment. RESULTS: Compared with healthy volunteers, the level of DCA and GDCA exhibited higher abundance in patients with nasopharyngeal carcinoma (p<0.01). Furthermore, the biological function was investigated for the inhibition of DCA and GDCA towards the secretion of IL-10 by CD4+CD25- T cells. Both DCA and GDCA significantly inhibited the secretion of IL-10 by CD4+CD25- T cells. Furthermore, DCA+GDCA can show stronger inhibition towards the secretion of IL-10 than DCA and GDCA. CONCLUSION: The inhibition of IL-10 secretion by elevated DCA and GDCA components in nasopharyngeal carcinoma patients is the inducer for nasopharyngeal carcinoma.

Glycodeoxycholic acid levels as prognostic biomarker in acetaminophen-induced acute liver failure patients.

Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5-80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.

[Metabonomic study on the anti-liver injury effect of Si-Ni-San on rats by using UPLC-MS/MS].

A UPLC-MS/MS method based on metabonomic skills was developed to study the serum metabolic changes of rats after acute liver injury induced by CCl4 and to evaluate the action mechanism of Si-Ni-San. The integrated data were exported for principal components analysis (PCA) by using SIMCA-P software, in order to find the potential biomarkers. It showed that clear separation of healthy control group, model group, silymarin group, Si-Ni-San group was achieved by using the PCA method. Nine significantly changed metabolites were identified as potential biomarkers of acute liver injury. Compared with the health control group, the model group rats showed higher levels of phenylalanine, tryptophan and GCDCA together with lower levels of LPC 16 : 0, LPC 18 : 0, LPC 18 : 1, LPC 16 : 1, LPC 20 : 4 and LPC 22 : 6. These changes of serum metabolites suggested that the disorders of amino acid metabolism, lipid metabolism, bile acid biosynthesis and anti-oxidative damage were related to acute liver injury induced by CCl4. Si-Ni-San might have the anti-liver injury effect on all these four metabolic pathways.

[Pre- and post-operative changes in serum levels of glycocholic acid and 3,5,3'-triiodothyronine and their clinical significance in patients with cholelithiasis].

Pre- and post-operative changes of serum glycine-conjugated cholic acid (CG) and 3,5,3'-triiodothyronine (T3) levels were observed in twenty-two patients with cholelithiasis. The increase of the levels of serum CG varied with the patients; the highest levels were seen in patients with cirrhosis. After operation, the levels of serum CG and T3 were decreased significantly in patients without cirrhosis. There was positive correlation between serum CG and T3 (r = 0.4667, P < 0.01). It is indicated that the lowering of serum CG after operation may be related to the lowering of serum T3; the significant increase of serum CG level is useful to the diagnosis of liver cirrhosis, which is more sensitive than Type B ultrasonography or routine examination of liver function.

Serum concentration of bile acids in guinea pigs as an indicator of liver damage caused by aflatoxins.

Serum concentrations of glycocholic acid (GA) and glycodeoxycholic acid (GDA) and serum activity of aspartate aminotransferase (AST) were determined after guinea pigs had been fed 0, 0.005, 0.010, 0.015, 0.020, or 0.030 mg of aflatoxin B1 equivalents daily for 21 days. Mean serum concentrations for the 20 control guinea pigs were GA, 3.70 mumole/L; GDA, 0.12 mumole/L; and AST, 59.7 IU. Concentrations of GA and GDA in treated guinea pigs were significantly higher than those in controls (P less than 0.05) at doses of aflatoxin greater than or equal to 0.010 mg/day. The highest serum concentrations of bile acids were in guinea pigs given the higher doses of aflatoxin. Activities of AST in treated guinea pigs were significantly higher than those in controls for only 2 dosage levels (0.010 and 0.030 mg/day). Bile acids in the serum of guinea pigs was a more sensitive indicator of liver damage caused by aflatoxin than was AST.

Studies on steroids. CLXXXVII. Determination of serum bile acids by high-performance liquid chromatography with fluorescence labeling.

A method for the simultaneous determination of bile acids in serum by high-performance liquid chromatography (HPLC) with fluorescence labeling is described. The bile acid fraction was obtained from a serum specimen by passing it through a BondElut cartridge. Bile acids were derivatized quantitatively into the fluorescent compounds through the hydroxyl group at C-3 by treatment with 1-anthroyl nitrile in the presence of quinuclidine in acetonitrile. These derivatives were separated into the free, glycine- and taurine-conjugate fractions by ion-exchange chromatography on a lipophilic gel, piperidinohydroxypropyl Sephadex LH-20. Subsequent resolution of each fraction into cholate, ursodeoxycholate, chenodeoxycholate, deoxycholate and lithocholate was attained by HPLC on a Cosmosil 5C18 column using 0.3% potassium phosphate buffer (pH 6.0)--methanol (1:5) and 0.1% potassium phosphate buffer (pH 6.0)--methanol (1:8) as mobile phases. The anthroyl bile acids were monitored by fluorescence detection (excitation wavelength 370 nm; emission wavelength 470 nm), the limit of detection being 20 fmol. The proposed method proved to be applicable to the quantitation of bile acids in serum with satisfactory reliability and sensitivity.

Serum glycine-conjugated bile acids in pediatric hepatobiliary disorders.

Measurements of serum bile acids (glycine conjugates of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids) by radioimmunoassay in a variety of pediatric hepatobiliary disorders showed elevations in neonatal hepatitis syndromes, cholestasis, and hepatitis of extrahepatic or intrahepatic origin. Measurements of individual serum bile acids failed to differentiate between the various neonatal hepatitis syndromes. In one patient with cholestasis, the increased levels of bile acids observed returned to normal following therapy with cholestyramine and phenobarbital. In chronic active hepatitis the serum bile acid values correlated well with the bilirubin and SGOT in response to therapy with corticosteroids. These data confirm suggestions that serum cholylglycine and chenodeoxycholylglycine levels are a sensitive indicator of disturbed hepatic function and can be used in monitoring the course, activity, and therapeutic response in various hepatitis syndromes. In Reye's syndrome and protracted diarrhea of infancy, elevations in serum bile acids were detected without associated hyperbilirubinemia and provided additional evidence of disturbed hepatic function.

Serum bile acid levels in protracted diarrhea of infancy.

Significant elevations in two glycine-conjugated serum bile acid levels (cholic and chenodeoxycholic) were detected in a majority of infants with intractable diarrhea of infancy. In contrast, children with chronic inflammatory bowel disease had values of serum bile acids within the normal range. Although intravenous alimentation and constant-infusion elemental diet may alter hepatic function, serum bile acid levels were also elevated in other infants with intractable diarrhea not treated by these methods. We hypothesize that endotoxemia or other unknown mechanisms together with therapy are exerting a detrimental effect on hepatic function.