Severe Intrahepatic Cholestasis Of Pregnancy Group Research Articles

Role of Systemic Immune Inflammatory Index to Predict Intrahepatic Cholestasis of Pregnancy.

The goal was to investigate the change of systemic immune inflammation index (SII) in high-risk pregnant women diagnosed with intrahepatic cholestasis of pregnancy (ICP). Between May 2018 and April 2020, we retrospectively enrolled 218 pregnant women who were followed in our hospital from the first trimester to delivery. We looked at the sociodemographics, laboratory data, SII values, Apgar ratings, and newborn birth weights of pregnant women with ICP. We also compared SII values in the first (SII 1), second (SII 2), and third trimesters (SII 3) between ICP and the control group. In the ICP group, the neutrophil level increased in the second trimester and decreased in the third trimester. The SII 2 was significantly higher in the severe ICP group, and when the SII values of the subgroups were examined, the SII 2 was significantly higher in the severe ICP group. The SII 2 showed a significant cutoff value for ICP with 92% sensitivity and 96% specificity. Again, a positive but weak correlation was found between SII 2 and SII 3 and FBA. When the neonatal outcomes were evaluated between the groups, gestational age at birth, birth weight and Apgar scores at 1 and 5 minutes were significantly lower in the ICP group. The relationship between SII and ICP was investigated for the first time in the literature and a significant cutoff value was found with the SII of the 2nd day. This showed that inflammation occupies an important place in the pathophysiology of cholestasis.

Profiles and integration of the gut microbiome and fecal metabolites in severe intrahepatic cholestasis of pregnancy

BackgroundThe pathogenesis of intrahepatic cholestasis of pregnancy (ICP) remains unknown. The gut microbiome and its metabolites play important roles in bile acid metabolism, and previous studies have indicated the association of the gut microbiome with ICP.MethodsWe recruited a cohort of 5100 participants, and 20 participants were enrolled in the severe ICP group, matched with 20 participants in the mild ICP group and 20 controls. 16S rRNA sequencing and nontargeting metabolomics were adapted to explore the gut microbiome and fecal metabolites.ResultsAn increase in richness and a dramatic deviation in composition were found in the gut microbiome in ICP. Decreased Firmicutes and Bacteroidetes abundances and increased Proteobacteria abundances were found in women with severe but not mild ICP compared to healthy pregnant women. Escherichia-Shigella and Lachnoclostridium abundances increased, whereas Ruminococcaceae abundance decreased in ICP group, especially in severe ICP group. The fecal metabolite composition and diversity presented typical variation in severe ICP. A significant increase in bile acid, formate and succinate levels and a decrease in butyrate and hypoxanthine levels were found in women with severe ICP. The MIMOSA model indicated that genera Ruminococcus gnavus group, Lachnospiraceae FCS020 group, and Lachnospiraceae NK4A136 group contributed significantly to the metabolism of hypoxanthine, which was significantly depleted in subjects with severe ICP. Genus Acinetobacter contributed significantly to formate metabolism, which was significantly enriched in subjects with severe ICP.ConclusionsWomen with severe but not mild ICP harbored a unique gut microbiome and fecal metabolites compared to healthy controls. Based on these profiles, we hypothesized that the gut microbiome was involved in bile acid metabolism through metabolites, affecting ICP pathogenesis and development, especially severe ICP.

The spatial expression of mTORC2-AKT-IP3R signal pathway in mitochondrial combination of endoplasmic reticulum of maternal fetal interface trophoblast in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is complicated by adverse fetal outcomes and even fetal death, the mechanism remains unclear. This study aims at evaluating the differential expression of mTORC2-AKT-IP3R signaling pathway, which accurately regulate Ca2+ transfer across mitochondria-associated membranes (MAMs) and determine the stress intensity experienced by endoplasmic reticulum (ER) and mitochondria, in patients diagnosed withICP. We combined western blot analysis and placental immunofluorescence co-localization detection to assess the expression and co-localization of the mTORC2-AKT-IP3R signaling pathway in severe (maternal total bile acid (TBA) levels≥40 μmol/L) and mild (maternal TBA 10-40 μmol/L) ICP. Compared with the control and mild ICP groups, phosphorylated protein kinase B (p-AKT) levels were significantly upregulated in the severe ICP group. Placental Rictor levels were lower in the mild ICP group than in the control group and were further downregulated in the severe ICP group. IP3R3 and p-IP3R3 levels were lower in placentas in the severe ICP group than in those in the mild ICP and control groups. Moreover, the co-localization of IP3R3 and p-AKT in patients in the mild and severe ICP groups was significantly elevated compared with that in patients in the control group. In patients with severe ICP, limited expression of Rictor and elevated p-AKT levels would suppress IP3R3/p-IP3R3 levels in MAMs. This inhibition might influence the transportation of Ca2+ from the ER to the mitochondria, thus weaken the stress adaptation associated with MAMs. Our results reveal the possible pathophysiological mechanism of adverse fetal outcomes in ICP.

Elevated GABRP expression is correlated to the excessive autophagy in intrahepatic cholestasis of pregnancy

In intrahepatic cholestasis of pregnancy (ICP) patients, high concentrations of bile acids altered the normal maternal-fetal-unit physiological condition and could bring negative influence on placenta functionality. GABRP is the pi subunit of the gamma-aminobutyric acid type A receptor (GABAA) and plays pivotal role in regulating GABAA receptor's physiological function. Here we presented evidence that increased expression of GABRP in parallel with autophagic biomarkers, LC3 and ATG14, in patients with ICP. Methods: A total of 27 participants, including 18 ICP patients and 9 healthy pregnancies were recruited according to strict inclusion criteria. Placentas of ICP patients and controls were collected immediately after cesarean section before labor onset. GABRP and autophagic markers expression in placenta were investigated by immunohistochemistry (IHC), RT-qPCR, and Western blot. Results: The neonatal birthweight and gestational weeks were significantly lower in severe ICP group, while the hepatic enzymes were elevated in ICP group. Semiquantitative analysis of IHC revealed the AOD of GABRP in severe ICP patients was higher than that in mild ICP patients and control pregnancies. Western blot and RT-qPCR analysis both indicated that the expression of GABRP and ATG14 were significantly elevated in severe ICP patients. Moreover, GABRP was correlated with TBA (r = 0.64, p < 0.05), ATG14 (r = 0.87, p < 0.05), direct bilirubin (r = 0.54, p < 0.05), ALT (r = 0.72, p < 0.05), and AST (r = 0.67, p < 0.05). Conclusion: There were elevated expression of GABRP, ATG14 and LC3 in ICP placentas compared with uncomplicated pregnancies. The expression of GABRP was associated with autophagy and was correlated with the TBA levels.

Severe Intrahepatic Cholestasis Pregnancy Is Associated With Maternal Endothelial Dysfunction: A Case-Control Study.

The aim of the present study was to evaluate maternal serum endocan levels, which are markers of vascular pathologies andstrongly associated with vascular inflammationand endothelial dysfunction, in pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP). The study comprised 30 pregnant women with mild ICP, 30 pregnantwomen with severe ICP, and 30 healthy pregnant women as a control group. The inclusion criteria were women with ICP, which was diagnosed based upon the presence of pruritus associated with elevated total bile acid (TBA) levels (> 10 μm/L), elevated aminotransferases, or both, and the absence of diseases that may produce similar laboratory findings and symptoms. Severe ICP was defined as TBA > 40 μmol/L. After diagnosis for ICP, blood samples were obtained before medication during hospitalization to analyze maternal serum endocan levels. Gestational age at delivery, delivery induction rates, birth weight, and newborn intensive care unit (NICU) admission rates were significantly higher in the severe ICP group than in the control group and mild ICP group. Gestational age for all groups when blood was sampled was similar. Maternal serum TBAsand aminotransferase levels were significantly higher in the severe ICP group than in the control group and mild ICP group. The mean serum endocan levels were 10.9 ± 2.6 ng/mL in the control group, 12.5 ± 2.8 ng/mL in the mild ICP group, and 24.3 ± 4.8 ng/mL in the severe ICP group (p < 0.001). Our results indicated that maternal serum endocan levels were increased in the presence of severe ICP and it can be speculated that increased bile acid levels were associated with maternal endothelial dysfunction.

Role of Vitamin B12 and Vitamin D levels in intrahepatic cholestasis of pregnancy and correlation with total bile acid

This study aimed to evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and Vitamin D and B12 levels. The study was a retrospective, cross-sectional, case–control study that evaluated 92 ICP cases and 102 pregnant women without any additional disease. ICP cases were grouped as mild and severe according to their total bile acid (TBA) levels, and their relationship with Vitamin D and B12 levels and perinatal outcomes was evaluated. Vitamin D and B12 levels of the ICP group were significantly lower than those of the control group. There was a moderate negative correlation between TBA and Vitamin D levels and a low negative correlation between TBA and Vitamin B12 levels. Adverse neonatal outcomes were significantly higher in the severe ICP group than in the mild ICP group. IMPACT STATEMENT What is already known on this subject? The pathophysiology of ICP, which can lead to adverse perinatal outcomes, is not yet fully understood, and there is no preventive treatment. What do the results of this study add? This study showed that Vitamins B12 and D levels were low in women with ICP and that TBA levels were negatively correlated with Vitamin D and B12 levels. What are the implications of these findings for clinical practice and/or further research? This study may guide future studies in terms of explaining the etiopathogenesis of ICP and developing treatment options.

Untargeted lipidomics analysis in women with intrahepatic cholestasis of pregnancy: a cross-sectional study.

To compare the plasma lipid profiles in women with normal pregnancies and those with mild or severe intrahepatic cholestasis of pregnancy (ICP). Our goal was to reveal lipidome-wide alterations in ICP and delve into the pathogenesis of ICP from a lipid metabolism perspective. Cross-sectional study, including women with normal pregnancies, women with mild ICP and women with severe ICP. Gansu Provincial Hospital. Women with ICP were recruited from October 2019 to March 2020 in Gansu, China. Untargeted lipidomics was used to analyse differentially expressed plasma lipids in controls, in women with mild ICP and in women with severe ICP (n = 30 per group). For lipidomics, liquid chromatography and Q-Exactive Plus Orbitrap mass spectrometry were performed. Differentially expressed lipids. Thirty-three lipids were differentially expressed in the severe and mild ICP groups, compared with the control group, and 20 of those were sphingolipids (ceramide, six species; sphingomyelin, 14 species). All differentially expressed sphingolipids in women with mild ICP were also differentially expressed in women with severe ICP; the fold change and significance of the differential expression were positively correlated with disease severity. We systematically characterized the lipidome-wide alterations in mild and severe ICP groups. The results indicated a link between ICP and disordered sphingolipid homeostasis. Abnormal sphingolipid metabolism is involved in the pathogenesis of ICP.

Intrahepatic cholestasis of pregnancy - prevalence and ethnic distribution in northern Israel.

Intrahepatic cholestasis of pregnancy (ICP) is charachterized by pruritis and elevated serum bile acids (BA) and is associated with adverse obstetrical outcomes. ICP etiology is poorly understood and its incidence varies with ethnicity and geographical distribution. Explore the prevalence and characteristics of ICP in the different Northern Israeli ethnic groups and compare maternal and perinatal outcomes according to disease severity. Single-center retrospective study. Women who were diagnosed with ICP based on clinical presentation and elevated fasting BA (≥ 10 μmol/L) were included. Disease incidence, maternal and neonatal complications were explored according to ethnic subgroups analysis and obstetrical complications were examined according to disease severity. The incidence of ICP in the study population was 0.58%. Higher ICP incidence was found in our cohort compared with other reports arising from Central Israel (p < 0.001). The Christian patients had a higher incidence of ICP (1.1%) and preeclampsia (23.1%). A higher rate of neonatal intensive care unit (NICU) admissions was found in the Arab Muslim and Christian groups compared with the Jewish and Druze groups (p = 0.007). A higher rate of preeclampsia was found in the severe (BA ≥ 40 μmol/L) ICP group (p < 0.001). Patients in the severe ICP group had earlier gestational age at delivery (37 versus 38.14 weeks, p < 0.001). Birth weight was significantly lower in the severe ICP group (p = 0.018). The incidence of ICP at our institution was 0.58%, which is higher compared with previous reported Israeli incidence. Higher ICP and preeclampsia incidence were found among Arab Christian patients.

Alterations of the Human Gut Microbiota in Intrahepatic Cholestasis of Pregnancy.

Background and AimsWomen with severe intrahepatic cholestasis of pregnancy (ICP) are at higher risks of fetal complications and without effective treatments. Changes in gut microbiota in pregnancy were found to be related to the altered intestinal bile acid composition, so we aimed to explore the alterations of microbiota in the gut of ICP patients.MethodsA total of 90 women were recruited, including 45 ICP patients and 45 healthy controls. The gut microbiota communities of ICP group were compared to control group through 16S ribosomal RNA gene sequencing. The results were then confirmed by real-time polymerase chain reaction (PCR) and generalized linear model (GLM). Furthermore, we analyzed the relationships between microbiota and the severity of ICP.ResultsA total of seven genera and nine taxa with differential abundances between the ICP patients and the controls were identified. All of the seven genera were verified through real-time PCR, and three key genera Parabacteroides, Flavonifractor, and Megamonas were confirmed by using the GLM model. Further analysis found that the genera Escherichia_Shigella, Olsenella, and Turicibacter were enriched in the severe ICP group, the microbial gene function related to biosynthesis of unsaturated fatty acids and propanoate metabolism were also increased in them.ConclusionsOverall, our study was the first in Asia to demonstrate an association between gut microbiota and ICP. Our findings would contribute to a better understanding of the occurrence of ICP.

Can the Severity of Intrahepatic Cholestasis of Pregnancy be Predicted by Second Trimester Screening Test Parameters?

Abstract Objective The second trimester triple test although declared inadequate for the screening of aneuploidies by the International Society for Prenatal Diagnosis remains a widely employed test. We aim to investigate the associations between the biochemical parameters of the triple test and the severity of intrahepatic cholestasis of pregnancy (ICP). Material and Methods The triple test parameters of 102 healthy pregnant women and 100 pregnant women with ICP were evaluated retrospectively. Serum bile acid level of ≥ 40 μmol/L was categorized as severe ICP. Serum α-fetoprotein (AFP), β-human chorionic gonadotropin (β-hCG), and unconjugated estriol (uE3) multiple of the median (MoM) values and the perinatal outcomes were recorded. The Student’s t-test, Mann–Whitney U test, Kruskal–Wallis test, and receiver operating characteristic curve analysis were used to compare the data. Results The AFP, β-hCG, and uE3 MoM values were higher in the severe ICP group when compared to those with mild ICP and those without ICP (p &lt; 0.01). The sensitivity and specificity values for ICP were 80.95% and 73.42%, respectively, with AFP values ≥ 1.26 MoM, 76.19% and 88.61%, respectively, with β-hCG values ≥ 1.78 MoM, and 61.90% and 94.94%, respectively, with uE3 values ≥ 1.58 MoM [95% confidence interval; area under the curve (AUC) ± standard error (SE) = 0.810 ± 0.049, AUC ± SE: 0.790 ± 0.065, and AUC ± SE: 0.797 ± 0.065, respectively]. Conclusion An increase in the AFP, β-hCG, and uE3 MoM values in the triple test can predict the risk of developing severe ICP.

The severity of intrahepatic cholestasis of pregnancy can shorten the first stage of labor in multiparous women induced by prostaglandin E2

Aim: To determine the relationship between increased serum bile acid concentrations and the first stage of labor in multiparous women induced by vaginal prostaglandin E2 (PGE2) with intrahepatic cholestasis of pregnancy (ICP). Material and Methods: In this retrospective case-control study 283 multiparous women with ICP and 283 healthy multiparous pregnant women were admitted for induction of delivery, were inserted PGE2 (10 mg dinoprostone) vaginally. The groups with mild, moderate and severe ICP were compared with control group in terms of the time from beginning of PGE2 vaginal insertion to active phase of labor, the time from beginning of PGE2 vaginal insertion to complete dilatation of cervix and fetal outcomes. Results: The time from beginning of PGE2 insertion to active phase in the mild, moderate and severe ICP groups were shorter than in the non-ICP group; 3.19±0.32, 7.26±0.34, 8.71±0.35 hours, respectively (p<0.01). The time from beginning of PGE2 insertion to complete dilatation of cervix in the groups with mild, moderate and severe ICP were shorter than in non-ICP group; 3.03 ± 0.45; 10.33 ± 0.62; 14.44 ± 0.53, respectively (p<0.01). There was no difference between the groups in terms of fetal outcomes except fetal weight and the presence of meconium (p<0.01). Conclusion: Increased bile acid concentrations in multiparous pregnant women induced by vaginal PGE2 with mild, moderate and severe ICP are associated with shorter duration of cervical ripening and labor induction time to delivery. The study concluded that multiparous women with ICP can deliver faster as the severity of cholestasis increases.

Maternal serum, placental, and umbilical venous blood irisin levels in intrahepatic cholestasis of pregnancy

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.

Women successfully treated for severe intrahepatic cholestasis of pregnancy do not have increased risks for adverse perinatal outcomes.

Intrahepatic cholestasis of pregnancy (ICP) increases adverse perinatal outcome (APO) incidence. Whether successful treatment of severe ICP reduces APO risk is unclear.This retrospective, single-center study in China enrolled consecutive women with ICP who had term delivery (≥37 weeks, singleton) between August 2013 and June 2016. Patients were divided into the mild ICP (serum bile acids (SBA) ≤40 μmol/L throughout pregnancy) and severe ICP (SBA >40 μmol/L during pregnancy but fell after ursodeoxycholate therapy) groups. Baseline characteristics, laboratory investigations, and maternal and neonatal outcomes were assessed. Logistic regression was used to identify factors associated with meconium staining of amniotic fluid (MSAF) and APOs.Seventy-three patients were included (mild ICP group, n=47; severe ICP group, n=26). Pruritus was more common in the severe ICP group (65.4% vs 40.4%; P <.05), but other baseline characteristics were similar. Compared with the mild ICP group, the severe ICP group had higher SBA at first visit and peak value, higher direct bilirubin before delivery and 4 days postpartum, and lower gamma-glutamyltransferase at peak value, before delivery and 4 days postpartum (P <.05). Other laboratory parameters, type of delivery, hemorrhage, and liver function abnormality were similar between groups, although the severe ICP group had longer duration of hepatic dysfunction (P <.05). Birth weight was lower in the mild ICP group (P <.05), but other fetal outcomes were similar between groups. Logistic regression identified no factors (including SBA group) associated with APOs or MSAF.Women successfully treated for severe ICP do not have increased risks for APOs.

Perinatal outcomes in intrahepatic cholestasis of pregnancy with monochorionic diamniotic twin pregnancy

BackgroundThe primary aim of the study is to investigate the perinatal outcomes in intrahepatic cholestasis of pregnancy (ICP) with monochorionic diamniotic (MCDA) twin pregnancy.MethodsThis study is a retrospective observational study for women with ICP and MCDA twin pregnancy. Included cases were divided into mild ICP group (10–39 mmol/L) and severe ICP group (> = 40 mmol/L), whose perinatal outcomes were compared between this two groups and whose predictors of adverse perinatal outcomes were evaluated.Results37 cases and 21 cases are in mild and severe ICP group respectively, of which, the incidence of gestational diabetes mellitus (GDM) and iatrogenic preterm delivery in severe ICP group are higher than those in mild ICP group. Gestational age (GA) at diagnosis of ICP < 32 weeks is an independent risk factor for GA at delivery < 35 weeks and for composite adverse neonatal outcome. Total bile acids (TBA) > 40 mmol/l is an independent risk factor for meconium-stained amniotic fluid.ConclusionFor women with ICP and MCDA twin pregnancy, GA at diagnosis of ICP < 32 weeks and TBA > 40umol/L are associated with adverse perinatal outcomes.

Assessment of circulating betatrophin levels in intrahepatic cholestasis of pregnancy

Objective: To investigate maternal serum levels of betatrophin and their relationship with total bile acid (TBA) levels in patients with intrahepatic cholestasis of pregnancy (ICP).Materials and methods: Fifty-nine pregnant women with ICP (31 patients with severe and 28 patients with mild disease classifications) and 23 healthy women with uncomplicated pregnancies as the control group included the study. The maternal betatrophin, fasting blood glucose, fasting insulin (FI), and homeostatic model assessment of insulin resistance (HOMA-IR) levels of the groups were compared.Results: Serum betatrophin levels were significantly higher in the ICP groups than in the control group (p = .04 and p < .001, respectively). The FI levels and HOMA-IR values were significantly higher in the severe ICP group than in the control group (p = .006 and p = .001, respectively). While a significant positive correlation was found between betatrophin levels and fasting and postprandial TBA levels, there was no significant correlation among betatrophin and HOMA-IR or FI levels.Conclusions: Betatrophin levels were shown to correlate with TBA levels, it provides a model for future studies to understand the physiopathology of ICP, a complex metabolic disease. Changes in betatrophin levels may shed light on the pathogenesis of ICP.

Predictors of adverse perinatal outcomes in intrahepatic cholestasis of pregnancy with dichorionic diamniotic twin pregnancies

Objective: The aim of our study was to investigate the predictors of adverse perinatal outcomes in intrahepatic cholestasis of pregnancy (ICP) with dichorionic diamniotic (DCDA) twin pregnancies. Methods: This study was a retrospective study of women diagnosed with ICP and DCDA twin pregnancies in Chengdu’s women and children’s central hospital. These patients were subdivided into mild and severe ICP groups according to total bile acid (TBA) level. The clinical characteristics and perinatal outcomes were collected and compared between the two groups. Logistic regression analysis was developed to evaluate predictors of adverse perinatal outcomes. Results: About 134 cases were included in the study. Eighty-four cases were in the mild ICP group, and the other 50 cases were in the severe ICP group. Level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), and direct bilirubin (DBIL) in the severe ICP group were significant higher than those in the mild ICP group. The rate of delivery before 34 gestational weeks, meconium-stained amniotic fluid, and composite adverse neonatal outcome were higher in the severe ICP group than those in the mild ICP group. After adjusting for confounders, ICP onset gestational age (GA) <30 weeks and AST >200U/l were associated with GA at delivery <34 weeks. ALP >400U/l was an independent risk factor of meconium-stained amniotic fluid. ICP onset GA <30 weeks was an independent risk factor of composite adverse neonatal outcome. Conclusion: ICP onset GA <30 weeks, TBA >40 µmol/l, AST >200U/l, and ALP >400U/l were associated with composite adverse perinatal outcomes in ICP with DCDA twin pregnancies. For those patients with these characteristics, fetal surveillance and treatment should be enhanced.

Effect of Histone Deacetylase HDAC3 on Cytokines IL-18, IL-12 and TNF-α in Patients with Intrahepatic Cholestasis of Pregnancy

Background/aims: The pathogenesis of intrahepatic cholestasis of pregnancy (ICP) is poorly understood. Objective: This study aimed to explore the possible effect of HDAC3 (histone deacetylase) on cytokines IL-18, IL-12 and TNF-α in ICP. Methods: Serum levels of cytokines IL-18, IL-12 and TNF-α, bile acids and hepatic function parameters were measured. The expression of HDAC3 in the placenta was determined by immunohistochemistry (IHC), western blotting and RT-PCR. Results: IL-18, IL-12 and TNF-α serum levels were significantly higher in the severe ICP group than in the mild ICP group and the control group, and the difference between the mild ICP group and control group was not significant. HDAC3 protein expression was identified in the nucleus of the placental trophoblast by IHC. HDAC3 mRNA and protein expression were significantly lower in the ICP groups (mild ICP and severe ICP groups) than in the control groups, and no significant difference was found between the mild ICP and severe ICP groups. Conclusions: The low expression of HDAC3 and overexpession of inflammatory cytokines (IL-18, IL-12 and TNF-α) in ICP may be involved in liver cell apoptosis. We suspect that HDAC3 may play an important role in the pathophysiology of ICP.

Intrahepatic Cholestasis of Pregnancy in Women With Twin Pregnancy.

The aim of the present work was to determine maternal and fetal outcomes of intrahepatic cholestasis of pregnancy (ICP) in twin pregnancies. All twin pregnancies delivered above 28 gestational weeks in West China Second University Hospital from January 2013 to May 2015 were included. Data on maternal demographics and obstetric complications together with fetal outcomes were collected. The risk of adverse maternal and fetal outcomes were determined in relation to ICP by crude odds ratios (OR) and adjusted ORs (aOR) with 95% confidence intervals (CI). Subgroup analysis concentrated on the effect of assisted reproductive technology (ART), ICP severity, and onset time. A total of 1,472 twin pregnancies were included, of which 362 were cholestasis patients and 677 were conceived by ART. Higher rates of preeclampsia (aOR 1.96; 95% CI 1.35, 2.85), meconium-stained amniotic fluid (aOR 3.10; 95% CI 2.10, 4.61), and preterm deliveries (aOR 3.20; 95% CI 2.35, 4.37) were observed in ICP patients. Subgroup analysis revealed higher incidences of adverse outcomes in severe and early onset ICP groups. In conclusion, adverse maternal and fetal outcomes were strongly associated with ICP in twin patients. Active management and close antenatal monitoring are needed, especially in the early onset and severe groups.

Role of inflammation in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP), the most common liver disease in pregnancy, is characterized by elevated serum total bile acid and/or transaminase concentration, and pruritus. Interleukin-6 (IL-6) is a key regulator of the immune response, hematopoiesis and inflammation. We examined both IL-6 and the frequently used inflammatory marker high-sensitivity C-reactive protein (hs-CRP) at baseline in the same study population as for the primary endpoint, in order to provide a new perspective on the pathogenesis of ICP. In this controlled cross-sectional study 65 consecutive pregnant women with ICP (34 with mild and 31 with severe disease) and 40 healthy women with uncomplicated pregnancies (control group) were examined. IL-6 and hs-CRP were compared between the groups. While serum IL-6 was significantly higher in the mild ICP (P = 0.01) and severe ICP (P = 0.001) groups than in the control group, hs-CRP was similar between the groups. Interleukin-6 may have an essential role, apart from CRP, in the pathogenesis of ICP and, also, is a more sensitive marker of inflammation.

Maternal circulating levels of irisin in intrahepatic cholestasis of pregnancy

Objective: Intrahepatic cholestasis of pregnancy (ICP), the most common liver disease in pregnancy, is characterized by elevated serum total bile acid levels and pruritus. It has become clear that bile acids are no longer labeled as simple detergent-like molecules, but also represent complex hormonal metabolic regulators. ICP has also been associated with increased incidence rates of gestational diabetes mellitus. Irisin is a newly discovered myokine that is able to regulate glucose and lipid levels, thus improving insulin sensitivity. In this study, maternal serum irisin levels were analyzed in order to provide a new perspective on the pathogenesis of ICP.Materials and methods: In this controlled cross-sectional study, 58 consecutive pregnant women with ICP (30 with mild and 28 with severe disease) and 30 healthy women with uncomplicated pregnancies (as the control group) were examined. The maternal irisin, fasting blood glucose, fasting insulin and homeostatic model assessment of insulin resistance levels of the two groups were compared.Results: Serum irisin levels were significantly higher in the severe ICP group than in the mild ICP and control groups (p = 0.005 and p < 0.001, respectively). At the best cut-off level of 908.875 pg/ml, irisin accurately predicted ICP [AUC = 0.827 (95% CI: 0.745–0.909; p < 0.001)] with sensitivity and specificity rates of 72.5 and 86.8%, respectively. There was a significant negative correlation between irisin and fasting blood glucose levels (r = −0.399; p = 0.021).Conclusion: The results of this study indicate that serum irisin levels were significantly higher in women with ICP compared to healthy pregnant controls. However, it is difficult to infer whether high irisin level is a cause or effect of ICP.