Muricholic acids and autotaxin in intrahepatic cholestasis of pregnancy: A case-control study.

Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022.

Intrahepatic cholestasis of pregnancy: what's new.

Serum bile acids in intrahepatic cholestasis of pregnancy: Not just a diagnostic test

To investigate the changes of umbilical cord and the vasoactive substance in umbilical vein in intrahepatic cholestasis of pregnancy. By HE staining method we analyzed the pathologic change of umbilical cord of 25 women with intrahepatic cholestasis of pregnancy (ICP) and fetal distress (ICP fetal distress group), 25 ICP women without fetal distress group (ICP control group) and 27 normal pregnancies (control group). The nitric oxide synthase (NOS) and endothelin-1 (ET-1) were detected in human umbilical vein endothelial cells (HUVEC) by immunohistochemistry method. Umbilical vein total bile acid (TBA) and NOS and ET-1 were measured. (1) A remarkable high TBA level was found in umbilical vein in ICP, and it was higher in ICP fetal distress group (19.0 +/- 2.3) micromol/L than in ICP control group (9.0 +/- 1.7) micromol/L (P < 0.05); it was higher in ICP control group than the control group (4.4 +/- 1.5) micromol/L (P < 0.05). (2) A significant difference was found in the endotheliocytes of umbilical vein in ICP fetal distress group compared with ICP control group. The ratio of cells with pathological changes in ICP fetal distress group (92%, 23/25) was higher than ICP control group (68%, 17/25; P < 0.05). The occurrence of the pathological changes was associated with TBA. (3) The expression of eNOS in ICP fetal distress group 0.09 +/- 0.06 was lower than in ICP control group 0.21 +/- 0.08 (P < 0.05), and it was lower in ICP control group than in control group 0.47 +/- 0.07 (P < 0.05). In contrast, the expression of ET-1 in ICP fetal distress group 0.49 +/- 0.08 was higher than in ICP control group 0.32 +/- 0.07 (P < 0.05), and it was higher in ICP control group than control group 0.14 +/- 0.06 (P < 0.05). The expression of inducible nitric oxide synthase (iNOS) in ICP fetal distress group 0.20 +/- 0.04 and ICP control group 0.21 +/- 0.05 was lower than in control group 0.26 +/- 0.04 (P < 0.05), but no significant difference was found in ICP fetal distress group and ICP control group (P > 0.05). (4) The expression of eNOS, iNOS and ET-1 was correlated with umbilical vein TBA in ICP (r1 = -0.88, r2 = -0.45, r3 = 0.9; P < 0.01), respectively. High level of TBA in ICP is harmful to the umbilical vein endothelium, which is correlated with the raised expression of ET-1, and the decreased expression of eNOS,and iNOS in human umbilical cord endothelium cells. All these changes of umbilical vein may be associated with the occurrence of fetal distress in ICP.

To analyze the clinical characteristics and perinatal outcome of early-onset intrahepatic cholestasis of pregnancy (ICP). A total of 305 ICP cases were collected in the First Affiliated Hospital of Chongqing Medical University between June 2006 and May 2012. According to the onset time of ICP, patients were divided into early-onset ICP group (onset time < 28 gestational weeks) and late-onset ICP group (onset time ≥ 28 gestational weeks). The late-onset ICP group was further divided into 28 - 31(+6) gestational weeks and ≥ 32 gestational weeks according to the onset time. The biochemical indices and perinatal outcome of each group were assessed. (1) When the diagnosis was made for the first time, the maternal serum concentrations of total bile acid (TBA) and total bilirubin (TBIL) in early-onset ICP group were (41 ± 9) and (32 ± 9) µmol/L, respectively; while TBA and TBIL in late-onset ICP group were (32 ± 6) and (22 ± 9) µmol/L, and the difference between the two groups was statistically significant (P < 0.05). (2) There was no significant difference in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) between early-onset ICP group and late-onset ICP group (P > 0.05). The ALT of early-onset ICP group and late-onset ICP group were (159 ± 50) and (145 ± 52) U/L, respectively; and AST were (151 ± 49) and (138 ± 44) U/L, respectively. (3) The early-onset ICP group had significant higher (P < 0.05) incidence of meconium staining (18.8% vs. 7.4%), fetal distress (22.9% vs. 8.9%), newborn asphyxia (14.6% vs. 5.4%), premature delivery (33.3% vs. 15.6%), developing into severe ICP (41.7% vs. 25.3%) and cesarean section (91.7% vs. 78.6%) when compared to the late-onset ICP group. No significant difference in the incidence of premature delivery, developing into severe ICP and cesarean section was found between the two types of late-onset ICP. (4) There was significant differences in average birth weight and gestational weeks at delivery between the two groups [early-onset ICP group: (3113 ± 443) g and (36.3 ± 2.6) weeks]; late-onset ICP group: [(3513 ± 450) g and (37.7 ± 1.6) weeks]. The early-onset ICP patients presented worse clinical manifestations than late-onset ICP patients, and early-onset ICP is more likely to lead to premature delivery and fetal distress.

Intrahepatic cholestasis of pregnancy (ICP) is one of the most common hepatic disorders during pregnancy, and the etiology is thought to be multifactorial including both environmental and hormonal contributions. In twin pregnancies, the fetal and placental mass is generally greater than in singleton pregnancies, and is, theoretically, likely to have a greater influence upon the maternal hepatic metabolism compared to singleton pregnancy. The aim of this study was to compare ICP in twin and singleton pregnancies according to ICP characteristics, time of diagnosis, serum bile acid levels, pharmacological treatment, and pregnancy outcomes. This case control study was undertaken at Aarhus University Hospital, Denmark, from 2012 to 2019. The study comprised 51 women with twin pregnancies and ICP. These women were matched with 153 women with twin pregnancies without ICP and 153 women with singleton pregnancies with ICP, respectively. Three controls were matched per case, and data obtained from medical records and Danish obstetrical databases were compared. We found a significantly lower gestational age at ICP diagnosis in twin pregnancies (227 vs. 242 days for singleton pregnancies; p = 0.002). Bile acids reached significantly higher maximum blood levels in twin pregnancies (32.9 vs. 22.2 μmol/L; p = 0.012), and at a lower gestational age (gestational age maximum bile acids: 235 vs. 250 days; p < 0.001). No difference in pharmacological treatment was observed between the groups. Twin pregnancies with and without ICP had comparable pregnancy outcomes; however, ICP pregnancies had a higher incidence of gestational diabetes mellitus (15.7% vs. 5.2%; p = 0.03). In repeat pregnancies, ICP was diagnosed earlier in the twin pregnancy (p = 0.006). Compared to singleton pregnancies, twin pregnant women with ICP have an earlier diagnosis of ICP, and levels of bile acids are higher. Compared to twin pregnancies without ICP, the pregnancy outcomes are comparable.

Objective To analyze the perinatal outcomes of patients with early-onset intrahepatic cholestasis of pregnancy (ICP). Methods A total of 100 pregnant women with ICP who were treated in Xiangxiang People’s Hospital from October 2015 to October 2017 were divided into early-onset group (39 cases, onset time<28 weeks of pregnancy) and late-onset group (61 cases, onset time≥28 weeks of pregnancy) according to onset weeks of ICP; and then, enrolled patients were divided into mild ICP group (78 cases) and severe ICP group (22 cases) according to levels of cholyglycine (CG) and total bile acid (TBA). Another 100 healthy preagnant women who underwent examination during the same period were selected as control group. Regression analysis were performed on all groups. Results In iochemical indexes, the levels of glucose challenge test (GCT), alanine aminotransferase (ALT), total bilirubin (TBiL), aspartate aminotrasferase (AST), TBA in mild ICP and severe ICP group were higher than those in control group (P<0.05); and the levels of GCT, ALT, TBiL, AST and TBA in mild ICP group were significantly lower than those in severe ICP group (P<0.05). In the aspect of onset time, the severity rate of early-onset group was significantly higher than that of late-onset group (P<0.05). In labor indexes, the Apgar score, newborn body weight and postpartum bleeding volume and gestational weeks of delivery of mild ICP group were superior to those of severe ICP group (P<0.05). Compared with those indicators in control group, gestational week in mild ICP group and severe ICP group was shorter, postpartum bleeding volume was more, and newborn body weight was lower and Apgar score was lower (all P<0.05). In perinatal outcome, the perinatal outcome of control group was better than that of mild ICP and severe ICP group (P<0.05), while the perinatal outcome of mild ICP group was better than that of severe ICP group (P<0.05). Conclusions The earlier onset of ICP disease, the worse the prognosis become in the patients with ICP. It is necessary to strengthen the detection of biochemical indexes and understand the development of the disease so as to give corresponding intervention and improve the outcome of pregnancy. Key words: Early-onset intrahepatic cholestasis of pregnancy; Perinatal outcome; Analysis

Objective To explore the changes of serum, umbilical vein, placental irisin level, and the correlation between irisin level and relevant indicators in pregnant women with intrahepatic cholestasis of pregnancy (ICP), so as to provide a new perspective for in-depth studies on the causes and treatment of ICP. Methods This cross-sectional case–control study method, the serum, umbilical venous blood irisin, liver, kidney function, lipid metabolism, and other indicators of 108 normal pregnant women, 64 patients with mild ICP, and 39 patients with severe ICP were compared, and the changes in the levels of oxidative stress and irisin were observed by dihydroethidium staining and immunohistochemistry. Results The level of placental oxidative stress in severe ICP group and mild ICP group was significantly higher than that in normal pregnant women group, and the mild ICP group was significantly higher than that in severe ICP group (p < .05); the concentration of irisin in umbilical vein was significantly lower than that in peripheral blood; the serum irisin of normal pregnant women (918.51 ± 159.90 pg/ml) was significantly lower than that of pregnant women with mild ICP (1030.05 ± 137.98 pg/ml) and pregnant women with severe ICP (1094.34 ± 154.35 pg/ml). The concentration of irisin in umbilical vein blood of pregnant women with severe ICP (858.78 ± 97.42 pg/ml) was significantly higher than that of normal pregnant women (595.33 ± 162.70 pg/ml) and those with mild ICP (648.82 ± 164.81 pg/ml) (p < .05). Irisin was expressed in placental tissues of normal pregnant women group, mild ICP group and severe ICP group, and the differences were statistically significant in expression intensity of the three groups (χ 2 = 19.959, p < .05). The irisin expression intensity in the ICP group was higher than that in the control group, and the irisin expression intensity in the ICP group was higher than that in the ICP group (β = 0.292; t = 3.063; p < .05). At the best cutoff level of 989.168 pg/ml, irisin accurately predicted ICP [AUC = 0.622 (95%CI 0.543–0.701, p < .05)] with sensitivity and specificity rates of 60.9 and 40.1%, respectively. Conclusion Irisin can reduce the level of oxidative stress and improve lipid metabolism in ICP patients during the pathophysiological process of ICP, and it is possible to become a new auxiliary factor of ICP diagnosis and indexing.

To explore the expression and clinical significance of constitutive androstane receptor (CAR) in placenta syntrophoblast from patients with intrahepatic cholestasis of pregnancy (ICP). Placenta were collected from women with ICP who delivered from April 2009 to March 2010 in First Affiliated Hospital of Chongqing Medical University. According to the severity of ICP, patients were classified into mild ICP group (n = 10) and severe ICP group (n = 10). Ten healthy pregnant women who delivered in the same period were chosen as control group. The location of CAR protein in placenta was studied by immunohistochemical streptavidin-biotin complex (SABC) method. CAR mRNA level was determined by reverse transcription (RT)-PCR technique and CAR protein expression level was determined by western blot. (1) CAR was located in the placenta syncytiotrophoblastic cells in control group and mild ICP group, showed light tan when stained, and was mainly in the cytoplasm. In severe ICP group, CAR was also located in placenta syncytiotrophoblastic cells but mainly in the nucleolus, showed dark tan when stained. (2) The mRNA expressions of CAR in control group, mild ICP group, severe ICP group were 0.06 ± 0.03, 0.07 ± 0.03 and 0.56 ± 0.03, respectively. CAR in severe ICP group was significantly higher than those in control group and mild ICP group (P < 0.05). The difference of mRNA between control group and mild ICP group was not statistically significant (P > 0.05). (3) The CAR protein levels in control group, mild ICP group, severe ICP group were 0.74 ± 0.03, 0.79 ± 0.03 and 1.02 ± 0.04, respectively. CAR protein expression in the severe ICP group was significantly higher than the other two groups (P < 0.05). And there was no statistical significance between mild group and control group (P > 0.05). In ICP women, especially severe ICP patients, the CAR expression in placenta syncytiotrophoblastic cells increased appreciably, which may be involved in the maintenance of placenta barrier function and protection in ICP pathogenesis.

Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge.

OBJECTIVES/SPECIFIC AIMS: Intrahepatic Cholestasis of Pregnancy (ICP) is the most common liver disease unique to pregnancy. Progression of non-alcoholic fatty liver disease (NAFLD) has been linked to the dysregulation of bile acid homeostasis. However, an association of NAFLD with ICP has not been previously evaluated. We evaluated the association between ICP and NAFLD and associated metabolic risk factors, including obesity, dyslipidemia, hypertension, and diabetes. METHODS/STUDY POPULATION: A single-center, retrospective case-control study was conducted between January and December 2017 in a primarily Latina population in a New York City health system with a high prevalence of ICP, 2.53% of all pregnancies (compared to 0.32% nationally). Pearson’s chi-square or Fisher’s exact test and Wilcoxon rank-sum tests were performed to evaluate association of ICP with categorical variables and continuous variables, respectively. Unadjusted odds ratios (OR) with 95% confidence intervals (95% CI) were calculated in comparison with the control group for clinically significant outcomes. RESULTS/ANTICIPATED RESULTS: 149 pregnancies complicated by ICP were identified from electronic medical records; 200 controls were matched by delivery year. Hispanic women were more likely to be diagnosed with ICP than non-Hispanic women (OR 1.90, 95% CI 1.87-3.03). ICP and control patients were similar for: median age (OR 1.02, 95% CI.99-1.06), nulliparity (OR.79, 95% CI.48-1.30) and prevalence of hepatitis C (OR 1.35, 95% CI.08-21.67). In regards to metabolic risk factors, ICP patients and control patients were similar in prevalence of obesity (body mass index&gt;30kg/m^2; OR 1.01, 95% CI.62-1.61), hemoglobin A1c&gt;5.5% (OR.80, 95% CI.34-1.9), total cholesterol &gt;200 mg/dL (OR 4.15, 95% CI.83-20.84), and prevalence of hypertension (OR.69, 95% CI.31-1.52). Median bile acid levels were 30.6 µmol/L (IQR 11.6, 32.7) in the ICP group. ICP patients had higher median alanine aminotransferase (ALT) (32 vs. 16 U/L, p&lt;.0001), alkaline phosphatase (181 vs 128 U/L, p&lt;.0001) and total bilirubin levels (0.5 vs 0.35, p&lt;.0001) compared to controls. ICP patients were more likely to have ALT levels &gt; 50 U/L (2 times the upper limit of normal; OR 3.22, 95% CI 1.48-7.03). ICP patients were significantly more likely to have a history of biliary disease (OR 3.29, 95% CI 1.39-7.80). ICP patients were more likely to have evidence of steatosis on liver imaging (OR 4.69, 95% CI 1.68-13.12) than non-ICP patients. When evaluating a diagnosis of NAFLD based on ICD-10 code or evidence of steatosis on liver imaging, ICP patients were significantly more likely to have a diagnosis of NAFLD than controls (OR 5.7, 95% CI 2.08-15.65). DISCUSSION/SIGNIFICANCE OF IMPACT: ICP appears to be associated with NAFLD independently of metabolic risk factors such as obesity, dyslipidemia, hypertension, and diabetes, suggesting a direct link between NAFLD and ICP. If findings are confirmed, ICP patients, especially those with elevated ALT, would benefit from screening for NAFLD and linkage to liver specialty care postpartum.

Systemic Inflammation Response Index as a diagnostic and prognostic predictor of intrahepatic cholestasis of pregnancy: A case-control study from a tertiary center.

Efficacy and Safety of Ursodeoxycholic Acid Versus Cholestyramine in Intrahepatic Cholestasis of Pregnancy

The urinary bile acid profiling analysis of asymptomatic hypercholanemia of pregnancy: A pseudo-targeted metabolomics study

To explore the relationship between total bile acid (TBA) concentration and fetal pulmonary surfactant in intrahepatic cholestasis of pregnancy (ICP). Fifty five patients with ICP (ICP group) who received cesarean section from April 2008 to February 2010 in Second Xiangya Hospital, Central South University, were recruited. The general conditions of the neonates within 7 days after birth in ICP group were recorded. Those with fetal distress, neonatal asphyxia, or neonatal respiratory distress syndrome were referred as pathological neonates, others were referred as normal neonates. Over the same period, 23 healthy gravidas were recruited as control group. Enzymatic method was used to detect the TBA concentrations in maternal blood, cord blood and amniotic fluid. ELISA was employed to measure the urfactant protein A (SP-A) concentration in cord blood. High performance liquid chromatography system was used to detect the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), and sphingomyelin (SM) in amniotic fluid. (1) The concentrations of TBA in maternal blood, cord blood and amniotic fluid were (30.1 ± 7.9), (9.3 ± 3.3) and (4.4 ± 1.5) mmol/L in ICP group, (4.8 ± 2.2), (4.9 ± 0.9) and (1.4 ± 1.1) mmol/L in control group, respectively. The differences between the two groups were significant (P < 0.05). (2) The SP-A concentration in cord blood in ICP group was (29.5 ± 6.4) µg/L, significantly higher than that in control group, which was (22.6 ± 7.4) µg/L (P < 0.05). (3) There were 20 pathological neonates and 35 normal neonates in ICP group. In pathological neonates, the concentrations of TBA and SP-A in cord blood were (10.9 ± 2.2) mmol/L, (37.0 ± 5.9) µg/L, respectively; and were (8.0 ± 2.8) mmol/L, (26.7 ± 4.8) µg/L in normal neonates. The differences were significant (P < 0.05). (4) There was a positive correlation between TBA concentration in cord blood and in maternal blood (r(1) = 0.706, P < 0.05). The TBA concentration in cord blood was positively correlated with SP-A concentration as well (r(3) = 0.494, P < 0.05). (5) The PC and PI concentrations in amniotic fluid were (65.4 ± 7.2) mg/L and (3.8 ± 0.6) mg/L in ICP group, (69.7 ± 3.7) mg/L and (4.3 ± 0.7) mg/L in control group, respectively. The differences were significant (P < 0.05). The concentration of LPC in amniotic fluid in ICP group was (4.8 ± 0.9) mg/L, significantly higher than that in control group (P < 0.05), which was (4.2 ± 0.6) mg/L. The concentration of SM in amniotic fluid was (3.5 ± 0.8) mg/L in ICP group, (4.0 ± 0.5) mg/L in control group, with no significant difference (P > 0.05). (6)The ratio of PC/LPC in ICP group (14.2 ± 3.2) was significantly lower than that in control group (16.9 ± 2.5) (P < 0.05). (7)The TBA concentration in cord blood was negatively correlated with PC and PI concentrations (r(1) = -0.561, r(2) = -0.407, P < 0.05), and had no correlation with LPC concentration (r(3) = 0.260, P > 0.05). (1) The fetal TBA concentrations in both cord blood and amniotic fluid of patients with ICP was higher than those of healthy gravidas, they were also positively correlated with maternal TBA concentration. (2) ICP resulted in the change of fetal pulmonary surfactant and this change was associated with TBA concentrations in both cord blood and amniotic fluid.