单纯性肥胖者血清胆汁酸谱研究

目的探讨单纯性肥胖者血清胆汁酸谱的特征,为阐明胆汁酸引发的能量代谢相关机制和探寻新的肥胖生物治疗靶点提供研究依据。方法利用超高效液相色谱-串联质谱(UPLC-MS/MS)联用方法检测体检人群中10名表观正常对照者、10例超重者和10例单纯性肥胖者血清胆汁酸谱的特征。结果表观正常对照组、超重组和单纯性肥胖组血清中14种胆汁酸亚组分均有表达,其中的石胆酸(LCA)、牛磺胆酸(TCA)、牛磺石胆酸(TLCA)和牛磺熊脱氧胆酸(TUDCA)的表达水平最低;14种胆汁酸亚组分在各组间的差异均无统计学意义(P>0.05);单纯性肥胖组的胆汁酸谱中以甘氨鹅脱氧胆酸(GCDCA)和牛磺鹅脱氧胆酸(TCDCA)增高为主;超重组及单纯性肥胖组血清游离型胆汁酸(FBA)和结合胆汁酸(CBA)水平稍低于表观正常对照组,但差异无统计学意义(P>0.05)。结论单纯性肥胖者血清胆汁酸谱中以GCDCA和TCDCA增高为主,但各种胆汁酸亚组分的表达水平与表观正常者相同。     

胆石病患者胆汁酸代谢轮廓分析

目的探讨胆石病患者与健康人群血清胆汁酸谱差异,分析其对胆石病的辅助诊断价值及可能的成石机制。方法选取2018年1月至2019年1月到重庆医科大学附属第一医院就诊的胆石病患者(n=33)及健康志愿者(对照组,n=51)共84例为研究对象。采用超高效液相色谱-串联质谱分析法同时检测胆石病患者和健康志愿者血清中15种胆汁酸的水平,并对检测所得到的数据进行多个变量的分析,从而建立胆石病的临床诊断模型,筛选出合适的胆汁酸生物标志物,并对血清中的生物标志物的统计学意义及诊断价值进行分析。结果成功构建出胆石病的正交偏最小二乘法判别分析(OPLS-DA)模型。2组甘氨鹅脱氧胆酸、鹅脱氧胆酸、牛磺熊脱氧胆酸、甘氨胆酸、牛磺脱氧胆酸、牛磺石胆酸、牛磺鹅脱氧胆酸、牛磺胆酸水平比较,差异均有统计学意义(P<0.05)。结论胆汁酸代谢轮廓对临床诊断胆石病有较大的应用价值,有望用于胆石病的早期诊断及鉴别诊断。     

血清胆汁酸测定在肝病诊断上的价值:各种胆汁酸分析对肝胆疾病的诊断意义

为了研究各种胆汁酸分析对肝胆疾病的诊断意义,作者用高效液相层析和酶测定法,对8例正常人和76例肝胆疾病患者,进行了血清总胆汁酸(TBA)和各种胆汁酸的测定。正常人和各种病例组的血清胆汁酸分析的特征如下。正常人(8例)的血清中各种胆汁酸浓度(μmol/l)是,①游离型:熊脱氧胆酸(UDCA)0.07±0.04,胆酸(CA)0.14±0.05,鹅脱氧胆酸(CDCA)0.42±0.16,脱氧胆酸(DCA)0.30±0.05,石胆酸(LCA)检不出;②结合型中的(a)甘氨酸结合型(G):甘氨胆酸(GCA)0.16±0.07,甘氨鹅脱氧胆酸(GCDCA)0.47±0.05,甘氨脱氧胆酸(GDCA)0.46±0.26,甘氨石胆酸(GLCA)检不出;(b)牛磺酸结合型(T):牛磺胆酸(TCA)0.16     

ICP患者血清疏水性胆汁酸与miR-18a水平的相关性研究

目的探讨妊娠期肝内胆汁淤积症(ICP)患者血清miR-18a水平与血清疏水性胆汁酸的相关性。方法选取健康对照组、轻度ICP组、中度ICP组、重度ICP组孕妇各40例,分别采用实时定量RT-PCR法检测血清miR-18a水平,高效液相色谱串联质谱法检测疏水性胆汁酸脱氧胆酸、鹅脱氧胆酸、石胆酸、甘氨鹅脱氧胆酸水平;并与血清miR-18a水平进行相关性分析。结果相较于健康对照组,轻度、中度和重度ICP组患者血清miR-18a水平均明显降低,差异有统计学意义(P0.05);相较于轻度ICP组,中度和重度ICP组患者血清miR-18a水平明显降低,差异有统计学意义(P0.05);相较于中度ICP组,重度ICP组患者血清miR-18a水平明显降低,差异有统计学意义(P0.05)。对照组孕妇血清miR-18a水平与疏水性胆汁酸水平无相关性(P0.05);轻度、中度和重度ICP组患者血清miR-18a水平与疏水性胆汁酸水平呈负相关(r=-0.847～-0.531,P0.05)。结论 ICP患者血清miR-18a明显降低,随病情加重,miR-18a水平越低,miR-18a水平与血清疏水性胆汁酸水平呈负相关,可能在ICP的发生、发展中发挥重要作用。     

胆汁酸负荷试验时血清胆汁酸成分的分析

胆汁酸负荷试验对肝脏疾患的诊断有用,但对血中升高的胆汁酸成分的详细情况则不明确。作者在进行熊脱氧胆酸负荷试验后接着又进行了食物负荷试验,将奥山氏的高压液相色谱法与固相酶柱结合来进行血清胆汁酸分析,研究了15种成分在不同时间内的变化,本文报道了其中变化颇大的游离型熊脱氧胆酸(UDC)、甘氨酸熊脱氧胆酸(GUDC)和甘氨酸鹅脱氧腿酸(GCDC)三种。受试者为健康人(N组)4名、急性肝炎恢复期患者(AH组)5例、慢性肝炎(CH组)5例及肝硬化(LC组)5例。清晨空腹,口服UDC 300 mg后,分别在30、60、120、180分钟抽血,然后进食作为早餐服用试验所需的食物(牛奶200ml、蛋黄-     

肝移植术后患者血清胆汁酸代谢的检测及临床意义

目的:评价肝移植术后患者血清总胆汁酸水平、胆酸/鹅脱氧胆酸比值在肝移植术后发生排斥反应及肝功能延迟恢复时的变化规律。方法:选择2004-01/2004-12在大连医科大学器官移植中心进行肝移植手术的患者28例,同时收集大连医科大学附属二院门诊健康体检者和肝硬化患者血清学标本各12例作为对照,所有观察对象均知情同意。采用高效液相色谱检测肝移植术后患者血清中不同种类胆汁酸及总胆汁酸水平,也与常规肝功能监测指标谷草转氨酶和总胆红素加以比较,对肝移植术后患者血清指标与肝功能恢复之间的关系进行综合评价。结果:所有观察对象均进入结果分析,无脱落。①肝硬化组、肝移植组术前患者的血清总胆汁酸水平显著高于正常对照组(P<0.05)。②肝移植患者术后发生排斥反应或肝功能延迟恢复时,血清总胆汁酸水平较术前明显升高(P<0.05),胆酸/鹅脱氧胆酸比值明显降低(P<0.05),且比谷草转氨酶、总胆红素的变化提前发生,随着供肝功能的恢复它们将逐渐恢复正常。结论:总胆汁酸及胆酸/鹅脱氧胆酸比率可以作为肝移植术后发生排斥反应及肝功能延迟恢复的早期诊断指标,其对于肝移植术后急性排斥反应的早期诊断、早期治疗有重大意义。     

胆汁酸代谢及其临床应用

近年来国内已陆续开展血清结合胆酸的测定,经与常规肝功能试验比较,显示其一定的优越性,值得推广应用。 本文拟有关胆汁酸的代谢及其临床应用作一简介,以供参考。 胆汁酸的生成 正常人胆汁的胆汁酸可分为二大类:一、游离胆汁酸,占少量,主要有胆酸(CA),鹅脱氧胆酸(CDCA)、脱氧胆酸(DCA)及小量熊脱氧胆酸(UDCA)和石胆酸(LCA)。二、结合胆汁酸,由游离胆汁酸分别和甘氨酸或牛磺酸结合而成,占绝大部分。     

足跟血胆汁酸代谢谱在新生儿黄疸早期的变化及其临床意义

目的探讨不同病因早期新生儿黄疸足跟血胆汁酸谱的变化及其临床意义。方法选取2018年6月至2020年4月在我院产科正常分娩的新生儿250例,出生72 h用干血纸片法采集足跟血样标本备检。根据小时龄胆红素值将纳入新生儿分为溶血性组(20例)和观察组(118例),再按照病因将观察组分为生理性组(50例),母乳性组(42例)和感染组(26例)。采用超高效液相色谱-串联质谱法(UPLC-MS/MS)对备检标本的15种胆汁酸亚组分进行定量分析。结果各组血标本中15种胆汁酸亚组分均有表达,其中胆酸(CA)、鹅脱氧胆酸(CDCA)、熊脱氧胆酸(UDCA)、甘氨石胆酸(GLCA)和牛磺石胆酸(TLCA)水平在各组间均存在显著差异(P<0.05)。结论不同病因的新生儿黄疸早期胆汁酸代谢谱呈现出不同的变化趋势和特征,有助于新生儿可能发展为高胆红素血症的风险预测及其相关病因的分析。     

婴幼儿肝炎综合征血清总胆汁酸诊断价值

<正>总胆汁酸(total bile acids,TBA)是胆固醇在肝脏内分解以及在肠肝循环中的一组代谢产物。其中胆酸、鹅脱氧胆酸为初级胆汁酸,二次代谢产物脱氧胆酸、石胆酸、熊脱氧胆酸为二级胆汁酸,总称为总胆汁酸(TBA),其生成与代谢物浓度变化能灵敏反映肝功能变化。当肝细胞发生病变或患胆管疾     

糖尿病患者胆汁中的胆汁酸

作者研究了17例(男12、女5,年龄24-50岁)重型糖尿病患者胆汁中胆汁酸组成的质与量改变。对照组由8名健康人组成。测定了肝胆汁和胆囊胆汁中下列胆酸的含量(毫克%):牛磺胆酸(TX),牛磺鹅脱氧胆酸((?))+牛磺脱氧胆酸((?)),甘氨胆酸((?)),甘氨鹅脱氧胆酸((?)),甘氨脱氧胆酸((?)),胆酸((?)),脱氧胆酸((?))+鹅脱氧胆酸((?))。测定结果:糖尿病患者胆囊胆汁中(?)的绝对含量和百分比量均升高,分别升高至2.9倍及2倍。在游离胆汁酸中发现(?),其含量百分比平均为6.1%。正常人胆汁中(?)仅为痕迹量。与此改变平行发生的是初级(?)含量与含牛磺酸的胆汁酸     

Bile acid active and passive ileal transport in the rabbit: effect of luminal stirring

The intestinal absorption of bile acids (BA) with different chemical structure has been evaluated in the rabbit, after intestinal infusion of different concentrations (0.25-30 mM) of BA, by mesenteric blood sampling. Cholic (CA), chenodeoxycholic (CDCA), ursodeoxycholic (UDCA) acid, free and taurine (T-) conjugated, together with glycocholic (GCA) acid and deoxycholic acid (DCA) were studied. The apparent uptake parameters were calculated. All conjugated BA showed active transport (T max, nmol min-1 cm-1 int.), with Tmax values in the following order: TCA > TUDCA > TCDCA; unconjugated BA showed passive uptake, with values in the following order: DCA > CDCA > UDCA > CA. GCA and CA showed both passive uptake and active transport. For all BA studied the % uptake in the ileal segment considered was less than 10%, BA uptake being thus limited by transport and/or diffusion kinetics, rather than by flow velocity. The liquid resistance to BA radial diffusion inside the lumen was evaluated, and the infusate-to-blood uptake parameters corrected for it, in order to get the uptake parameters from the epithelium-to-liquid interface to mesenteric blood: the apparent Km decreased, passive uptake coefficient increased, while Tmax was unchanged. The passive component of the uptake, corrected for the luminal resistance, correlated with the BA hydrophobicity (r = 0.963; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute changes of bile acid pool composition on biliary lipid secretion.

To elucidate the mechanism responsible for the bile acid-induced changes of biliary lipid secretion, we evaluated bile flow and biliary output of bile acids, cholesterol, phospholipids, and alkaline phosphatase activity in seven cholecystectomized subjects with a balloon occludable T-tube during two experimental periods: (a) depletion of the endogenous bile acid pool and (b) replacement of the pool by means of duodenal infusion with individual bile acids, such as deoxycholic (DCA), chenodeoxycholic (CDCA), cholic (CA), and ursodeoxycholic (UDCA) acids. Bile flow, cholesterol, and phospholipid output were linearly related to bile acid secretion in all experimental periods. During the replacement periods, the amount of cholesterol and phospholipids coupled to bile acids was significantly different (at 1% level at least) for each individual bile acid secreted; it was the highest during DCA secretion (slope value: 0.209 for cholesterol and 0.434 for phospholipids) followed, in the order, by CDCA (0.078 and 1.794), CA (0.044 and 0.127), and UDCA (0.030 and 0.122). The phospholipid to cholesterol ratio was higher during secretion of CA and UDCA as compared with DCA and CDCA. The secretion of CA seemed to stimulate a greater bile flow than the other bile acids did. The infusion of all bile acids, except UDCA, induced an increase of biliary alkaline phosphatase activity as compared with the values of the depletion period. The mean highest increase (13-fold the pretreatment value) was observed during DCA secretion followed by CDCA (fivefold) and CA (1.5-fold). These results would suggest that the physical chemical properties, namely the lipid-solubilizing capacity, of bile acids could directly contribute to the regulation of biliary lipid secretion. The observed changes in biliary alkaline phosphatase activity lend support to the view that bile acid-induced lipid secretion may be, at least in part, contributed by membrane solubilization.     

Disorders of bile acid metabolism in cholesterol gallstone disease.

The aim of the study was to evaluate the metabolism of individual bile acids in patients with cholesterol gallstone disease. Therefore, we determined pool size and turnover of deoxycholic (DCA), cholic (CA), and chenodeoxycholic acid (CDCA) in 23 female gallstone patients classified according to their gallbladder function and in 15 healthy female controls. Gallstone patients had normal hepatic bile acid synthesis, but, depending on gallbladder function, differed with respect to turnover and size of the bile acid pools: Patients with well-emptying gallbladder (group A, n = 9) had enhanced turnover and reduced pools of CA (-46%; P less than 0.01 vs. controls) and CDCA (-24%; P less than 0.05), but normal input and size of the DCA pool. With reduced gallbladder emptying (less than 50% of volume; group B, n = 6), turnover and pools of CA, CDCA, and DCA were similar as in controls. Patients with loss of gallbladder reservoir (group C, n = 8) had increased input (+100%; P less than 0.01) and pool size of DCA (+45%; P = 0.07) caused by rapid conversion of CA to DCA, while the pools of CA (-71%; P less than 0.001 vs. controls) and CDCA (-36%; P less than 0.05) were reduced by enhanced turnover. Thus, in patients with cholesterol gallstones, the pools of primary bile acids are diminished, unless gallbladder emptying is reduced. Furthermore, in a subgroup of gallstone patients, who had completely lost gallbladder function, the CA pool is largely replaced by DCA owing to rapid transfer of CA to the DCA pool. This probably contributes to supersaturation of bile with cholesterol.     

Urinary excretion of bile acids during acute administration in man

Six healthy subjects, 45-72 years old, received a 10-day feeding of 750 mg of two of the following bile acids: deoxycholate (DCA), chenodeoxycholate (CDCA), cholate (CA), hyodeoxycholate (HDCA), ursodeoxycholate (UDCA), and ursocholate (UCA). The urinary excretion of total bile acids was low during administration of lipophilic bile acids (DCA and CDCA), when serum levels show low postabsorption peaks. Instead, hydrophilic bile acids (UDCA and above all HDCA) were heavily excreted in the urine as sulphates and glucuronides, and serum levels reach high values. Only UCA, strongly hydrophilic, was predominantly excreted as unconjugated fractions. Thus, the physicochemical properties of bile acids (as measured by both the partition between octanol and water, and the water solubility) were factors that influenced the route of bile acid elimination from the body, whereas their conjugation was not always requested for urinary excretion.     

血清游离胆汁酸 CA，LCA及胎盘 HIF-1α表达水平与 ICP患者不良妊娠结局的相关性研究

目的　探究血清游离胆汁酸胆酸（cholic acid, CA）、石胆酸 (litho cholic acid, LCA）以及胎盘组织缺氧诱导因子 -1α（hypoxia-inducible factor-1α, HIF-1α）表达水平与妊娠期肝内胆汁淤积症（intrahepatic cholestasis of pregnancy, ICP）患者不良妊娠结局间的关系。方法　选择 2020年 3月 ~2021年 4月于广东省东莞市第八人民医院就诊的妊娠期肝内胆汁淤积症患者 48例和无症状高胆汁酸血症（ asymptomatic hypercholanemia of pregnancy, AHP）70例作为研究对象,分别记为 ICP组和 AHP组。所有孕妇分娩前抽取静脉血用于检测肝功能指标 [总胆汁酸（ TBA）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（ AST）]以及胆汁酸亚型 [（胆酸 (CA)、脱氧胆酸 (DCA)、鹅脱氧胆酸 (CDCA)、熊脱氧胆酸 UDCA)、石胆酸 (LCA)）]水平。产妇分娩后,记录两组产妇的妊娠结局,留取胎盘组织检测 HIF-1α的阳性表达率。比较 ICP产妇和 AHP产妇一般临床指标间的差异并探究影响产妇不良妊娠结局的独立相关因素。结果　ICP组和 AHP组产妇 TBA（46.54±6.58 μmol/L vs 47.21±6.38 μmol/L）,ALT（38.26±5.37 U/L vs 36.58±5.72 U/L）, AST（28.48±3.54 U/L vs 28.92±3.85 U/L）组间差异无统计学意义（t=0.639~1.889, 均 P>0.05）;ICP组和 AHP组产妇 CA（3.78±0.63 μmol/L vs 1.24±0.56 μmol/L）,LCA（7.86±0.54 μmol/L vs 1.13±0.17 μmol/L）组间差异有统计学意义（ t=26.100~113.936, P<0.001）。ICP组产妇 HIF-1α阳性表达率（ 68.75%）显著高于 AHP组（41.43%）,差异有统计学意义（ χ2=12.359, P<0.05）。ICP组不良妊娠结局的发生率显著高于 AHP组（50.00% vs 28.57%）,差异有统计学意义（ χ2=5.591, P=0.018）。TBA,CA,LCA以及 HIF-1α均是影响不良妊娠结局的独立相关因素（ Waldχ2=6.516,     

Profile of serum bile acids in noncholestatic volunteers: gender-related differences in response to fenofibrate

Fenofibrate belongs to the group of hypolipidemic fibrates that act as activators of the peroxisome proliferator-activated receptor-α (PPARα), which is a regulator of bile acid synthesis, metabolism, and transport. The present study aimed at evaluating the effects of fenofibrate on the circulating bile acid profile in humans. A study population of 200 healthy individuals comprising both genders completed a 3-week intervention with fenofibrate, and 17 bile acid species were measured in serum samples drawn before and after fenofibrate treatment. Fenofibrate caused significant reductions in levels of chenodeoxycholic (CDCA) (-26.4%), ursodeoxycholic (UDCA) (-30.5%), lithocholic (LCA) (-18.4%), deoxycholic (DCA) (-22.3%), and hyodeoxycholic (HDCA) (-19.2%) acids. A gender-related difference was observed in the responses of various bile acids, and the total bile acid concentration was significantly reduced only in men (-18.6%), whereas it remained almost unchanged in women (+0.36%). This difference suggests that fenofibrate would be more efficient at reducing bile acid toxicity in men than in women in cholestatic liver diseases.     

Effects of cholecystectomy on the kinetics of primary and secondary bile acids.

Removal of the gallbladder is thought to increase formation and pool size of secondary bile acids, mainly deoxycholic acid (DCA), by increased exposure of primary bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA]) to bacterial dehydroxylation in the intestine. We have tested this hypothesis by simultaneous determination of pool size and turnover of DCA, CA, and CDCA in nine women before and at various intervals after removal of a functioning gallbladder. An isotope dilution technique using marker bile acids labeled with stable isotopes (2H4-DCA, 13C-CA, 13C-CDCA) was used. After cholecystectomy, concentration and output of bile acids relative to bilirubin increased (P less than 0.02) in fasting duodenal bile and cholesterol saturation decreased by 27% (P less than 0.05) consistent with enhanced enterohepatic cycling of bile acids. Three months after removal of the gallbladder bile acid kinetics were in a new steady state: pool size and turnover of CDCA were unchanged. Synthesis of CA, the precursor of DCA, was diminished by 37% (P = 0.05), probably resulting from feedback inhibition by continuous transhepatic flux of bile acids. The fraction of CA transferred after 7 alpha-dehydroxylation to the DCA pool increased from 46 +/- 16 to 66 +/- 32% (P less than 0.05). However, this enhanced transfer did not lead to increased input or size of the DCA pool, because synthesis of the precursor CA had decreased.     

Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy

ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 microM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC), in 30 healthy pregnant women and in 10 non-pregnant women. A highly significant correlation between CE and HPLC for total SBAs (r=0.990) and for individual SBAs was found. Normal pregnant women had higher total SBA levels than non-pregnant women (due to an increase in taurine-conjugated dihydroxy SBAs). Women with ICP had higher levels of total SBAs, the free/conjugated ratio, LCA, CA, CDCA and DCA than normal pregnant women. Newborns from women with ICP had lower birth weight and gestational age. Women with AHP had higher levels of conjugated dihydroxy SBAs than normocholanaemic patients, without any evidence of a clinical difference. In conclusion, the present study has shown a clear difference in SBA profiles between ICP and normal pregnancies (including AHP), involving a shift towards a characteristic hydrophobic composition in women with ICP.