Pregnancy-specific Liver Disease Research Articles

The maternal hair metabolome is capable of discriminating intrahepatic cholestasis of pregnancy from uncomplicated pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with elevated bile acids in the blood. Diagnosis typically only occurs after the manifestation of clinical symptoms and the metabolic mechanisms underlying its development remain unclear. The aim of this study was to investigate potential specific metabolites and the underlying metabolic changes occurring during the development of ICP in the maternal plasma and hair metabolomes of women diagnosed with either ICP or having a healthy pregnancy. A total of 35 Chinese women with ICP and 42 healthy pregnancies were enrolled in our study. Plasma and hair samples, total bile acid levels (TBA), alanine transaminase levels (ALT), aspartate aminotransferase levels (AST), and additional clinical information were collected during the third trimester. Metabolites from maternal plasma and hair segments collected pre-conception and analyzed using gas chromatography-mass spectrometry (GC-MS). Three plasma metabolites (p < 0.05, q < 0.38) and 21 hair metabolites (p < 0.05, q < 0.05) were significantly different between ICP and healthy pregnancies. A combination of the eight most significant hair metabolites in a multivariate receiver operating characteristic curve model showed the best area under the curve (AUC) was 0.885, whereas the highest AUC using metabolites from plasma samples was only 0.74. Metabolic pathway analysis revealed 32 pathways were significantly (p and q values < 0.05) affected in the hair samples of patients with ICP. Pathways associated with glutathione metabolism and ABC transporters were affected. No metabolic pathways were significantly affected in plasma. Overall, this study showed that the hair metabolome could be more useful than the plasma metabolome for distinguishing ICP from normal pregnancy.

Factors and a model to predict three-month mortality in patients with acute fatty liver of pregnancy from two medical centers

BackgroundAcute fatty liver of pregnancy (AFLP) is an uncommon but potentially life-threatening complication. Lacking of prognostic factors and models renders prediction of outcomes difficult. This study aims to explore factors and develop a prognostic model to predict three-month mortality of AFLP.MethodsThis retrospective study included 78 consecutive patients fulfilling both clinical and laboratory criteria and Swansea criteria for diagnosis of AFLP. Univariate and multivariate cox regression analyses were used to identify predictive factors of mortality. Predictive efficacy of prognostic index for AFLP (PI-AFLP) was compared with the other four liver disease models using receiver operating characteristic (ROC) curve.ResultsAFLP-related three-month mortality of two medical centers was 14.10% (11/78). International normalised ratio (INR, hazard ratio [HR] = 3.446; 95% confidence interval [CI], 1.324–8.970), total bilirubin (TBIL, HR = 1.005; 95% CI, 1.000-1.010), creatine (Scr, HR = 1.007; 95% CI, 1.001–1.013), low platelet (PLT, HR = 0.964; 95% CI, 0.931–0.997) at 72 h postpartum were confirmed as significant predictors of mortality. Artificial liver support (ALS, HR = 0.123; 95% CI, 0.012–1.254) was confirmed as an effective measure to improve severe patients’ prognosis. Predictive accuracy of PI-AFLP was 0.874. Area under the receiver operating characteristic curves (AUCs) of liver disease models for end-stage liver disease (MELD), MELD-Na, integrated MELD (iMELD) and pregnancy-specific liver disease (PSLD) were 0.781, 0.774, 0.744 and 0.643, respectively.ConclusionTBIL, INR, Scr and PLT at 72 h postpartum are significant predictors of three-month mortality in AFLP patients. ALS is an effective measure to improve severe patients’ prognosis. PI-AFLP calculated by TBIL, INR, Scr, PLT and ALS was a sensitive and specific model to predict mortality of AFLP.

Proteomic Biomarkers of Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine death. The pathogenesis of ICP is still unclear. We hypothesized that pathological index leads to abnormal placenta changes in ICP. Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying ICP. The present study screened differentially expressed proteins (DEPs) as novel diagnostic markers for ICP. Proteomic profiles of placental tissues from 32 ICP patients and 24 healthy volunteers (controls) were analyzed. Our founding was valid by following western blotting and immunohistochemistry staining, respectively. The association of the key protein expression with clinicopathological features of ICP was further analyzed. A total of 178 DEPs were identified between the ICP and control groups. Functional enrichment analysis showed these proteins were significantly enriched in the PPAR singling pathway by KEGG and PPARα/RXRα activation by IPA. Apolipoprotein A2 (APOA2) was the only upregulated protein, which uniquely identified in ICP groups and related to both pathways. Validation of western blotting and immunohistochemical staining analysis showed significantly higher APOA2 expression in the ICP group than in the control group. Furthermore, the expression of APOA2 is associated with clinicopathological features in ICP groups. Receiver operating characteristic (ROC) curve analyses showed that the AUC of APOA2 was 0.8984 (95% confidence interval (CI): 0.772–1.000). This study has identified up-regulated APOA2 associated with PPAR singling pathway and PPARα/RXRα activation in ICP. Thus, APOA2 may be involved in ICP pathogenesis, serving as a novel biomarker for its diagnosis.

Diagnostic Approach to Elevated Liver Function Tests during Pregnancy: A Pragmatic Narrative Review.

Liver disease is not uncommon during pregnancy and is associated with increased maternal and fetal/neonatal morbidity and mortality. Physiological changes during pregnancy, including a hyperestrogenic state, increase in circulating plasma volume and/or reduction in splanchnic vascular resistance, and hemostatic imbalance, may mimic or worsen liver disease. For the clinician, it is important to distinguish among the first presentation or exacerbation of chronic liver disease, acute liver disease non-specific to pregnancy, and pregnancy-specific liver disease. This last group classically includes conditions such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, liver disorders associated with the pre-eclampsia spectrum, and an acute fatty liver of pregnancy. All of these disorders often share pathophysiological mechanisms, symptoms, and laboratory findings (such as elevated liver enzymes), but a prompt and correct diagnosis is fundamental to guide obstetric conduct, reduce morbidity and mortality, and inform upon the risk of recurrence or development of other chronic diseases later on in life. Finally, the cause of elevated liver enzymes during pregnancy is unclear in up to 30-40% of the cases, and yet, little is known on the causes and mechanisms underlying these alterations, or whether these findings are associated with worse maternal/fetal outcomes. In this narrative review, we aimed to summarize pragmatically the diagnostic work-up and the management of subjects with elevated liver enzymes during pregnancy.

Expression and Significance of Galectin-1 and Galectin-3 in the Serum and Placental Tissues of Patients with Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, usually occurring in the third trimester of pregnancy. Its typical clinical manifestations are itching and elevated serum total bile acid levels, which are more harmful to the fetus, and can lead to a variety of adverse pregnancy outcomes. This paper discusses the expressions of galectin -1 and 3 in the serum and placenta of ICP patients and their relationship with the effect of the incidence of ICP. Galectin-1 and 3 in serum and placenta were detected in 22 pregnant women with ICP and 20 healthy pregnant women admitted to the obstetrics Department of Northern Jiangsu People's Hospital from May 2021 to February 2022. Serum levels of galectin-1 and galectin-3 in ICP pregnant women were significantly higher than those in controls, with significant differences (P<0.05). Placental galectin-1 and 3 were higher in normal pregnant women, and there were statistical differences between groups (P<0.05). In ICP, the maternal serum and placental galectin-1 and 3 levels were significantly increased, both of which may play an important role in the development of ICP, which may be the initiation factor of ICP pathophysiology, a marker of ICP prediction, and a target of ICP prevention strategies.

Distribution of endotoxin in maternal and fetal body with intrahepatic cholestasis of pregnancy and its association with adverse fetal outcome

Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disease. In this study, we sought to explore the distribution of lipopolysaccharide in the maternal body, and its effect on the fetal body in the intrahepatic cholestasis of pregnancy mice. It provides a new sight for the clinical treatment of women with intrahepatic cholestasis of pregnancy. The serum levels of lipopolysaccharide and lipopolysaccharide binding protein in women with intrahepatic cholestasis of pregnancy were analyzed. To assess the association between lipopolysaccharide levels and adverse fetal outcomes, ursodeoxycholic acid, resveratrol, and phosphatidylinositol-3-kinase inhibitor were employed in intrahepatic cholestasis of pregnancy mice, and we studied the fluorescence intensity and distribution of lipopolysaccharide in mice with intrahepatic cholestasis of pregnancy. Our data indicated significantly elevated levels of lipopolysaccharide and lipopolysaccharide binding protein in women with intrahepatic cholestasis of pregnancy. In vivo fluorescence imaging revealed that the intensity of lipopolysaccharide in mice with intrahepatic cholestasis of pregnancy was higher than that in the control group, and decreased after ursodeoxycholic and resveratrol treatment. The fluorescence intensity analysis indicated that lipopolysaccharide levels in maternal liver, placenta, fetal brain and fetal liver were significantly higher in the intrahepatic cholestasis pregnancy mice group than in the control group. This study provided evidence of endotoxin distribution in maternal liver, placenta, fetal liver and fetal brain in mice with intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid and resveratrol treatment effectively reduced lipopolysaccharide levels in pregnant mice with intrahepatic cholestasis of pregnancy.

Specific fluorescence release based on synergistic activation of enzymes and position-dependent of electrophilic groups to diagnose intrahepatic cholestasis of pregnancy

The early diagnosis and effective treatment of disease have presented new challenges to today's researchers. Recently, an important direction of the development of the fluorescent probes field is to provide convenient detection tools for clinical diagnosis. Intrahepatic cholestasis of pregnancy (ICP), a pregnancy-specific liver disease associated with poor maternal and fetal outcome, lack biochemical diagnosis indicator with relatively high specificity. Glutathione S-transferases may be a potential candidate for ICP diagnosis owing to their high concentrations in the liver, however, fluorescent detection tool for GSTs with high selectivity is scarce, owing to the interference of high non-enzymatic reaction with GSH. In this work, a probe (MB5) through fine structure regulation for specific fluorescence response GSTs was obtained with synergistic activation of enzymes and position-dependent of electrophilic groups. Furthermore, overexpressed GSTs were visualized directly in cholestatic mice models through in vivo imaging, isolated organ imaging, and tissue slice analysis. More importantly, the serum samples of the ICP patients hold significantly high levels of GSTs concentrations, compared with healthy pregnant women. Therefore, a novel diagnostic tool and excellent detection method for ICP were provided, which will promote to the establishment of new biochemical markers of liver function in pregnancy.

Predictors of adverse maternal outcome in jaundiced pregnant women identified as having pregnancy-specific liver disease (P-sLD)

We aimed to study the factors including model for end stage liver disease (MELD) score in predicting mortality in women with pregnancy-specific liver diseases (P-sLD). A total of 154 women with clinical jaundice were studied of which 138 women were diagnosed with P-sLD. The most common P-sLD was HELLP syndrome (51.9%) followed by acute fatty liver of pregnancy (AFLP) (17.5%). The mean age was 26.3 ± 4.7 years and the mean gestational age was 35.1 ± 4.2 weeks. The maternal death rate was 26.8% and the most common cause was coagulopathy followed by sepsis. The mean MELD score among non survivors was 25.98 ± 8.17 compared to 17.29 ± 8.12 among survivors (p value .00). On univariate analysis, gestational age at admission, presence of hypertension, the platelet count, serum creatinine, INR and MELD score were found to significant. The AUC for INR (0.82) and MELD score (0.77) was better than platelet count (0.72) and serum creatinine (0.67). On multivariate analysis, only the INR and presence of AKI were found to be significantly associated with maternal mortality. The performance of INR was better than MELD score in predicting mortality in women with P-sLD. Additional factors like platelet count may be incorporated in to MELD score for the prediction of mortality in pregnant women. IMPACT STATEMENT What is already known on this subject? Pregnancy-specific liver disorders (P-sLD) have significant effect on maternal and foetal outcome, often considered as a spectrum of disease with significant overlap of clinical and laboratory parameters. MELD score is used reliably outside the pregnancy to predict mortality may not be good in pregnant women. There are only few studies that looked at the factors predictive of adverse maternal outcome. What do the results of this study add? Though we have demonstrated that MELD score was significantly high among non-survivors, serum bilirubin an important component of MELD score was not found to be significant. The other factors which were found to be significant on univariate analysis include gestational age at admission, hypertension and platelet count. However, international normalised ratio (INR) and acute kidney injury (AKI) were the factors independently associated with mortality. What are the implications for clinical practice and/or further research? The utility of MELD score in P-sLD should be studied prospectively in different populations. Moreover, the feasibility of developing a simple model which incorporates platelet count in addition to other components of MELD score should also be explored in future studies.

Intrahepatic cholestasis of pregnancy can increase the risk of metabolic disorders: A meta-analysis.

Gestational diabetes mellitus (GDM) and preeclampsia (PE) are common complications during pregnancy. Studies indicated that abnormal bile acid metabolism is related to its pathogenesis. Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease, which classic symptoms include generalized pruritus that commonly and biochemical evidence of elevated bile acids. Our study aimed to explore the correlation between the ICP presence and risk of GDM, PE incident in pregnant women. A meta-analysis, which included 10 eligible studies including 17,688 ICP cases and 1,386,771 controls, was performed to assess the correlation of ICP with preeclampsia (PE) and gestational diabetes mellitus (GDM). There were 7 studies investigating the relationship between ICP and PE, and 9 studies that evaluated the relationship between ICP and GDM. All eligible studies were screened from Pubmed, Web of Science and EBSCO databases. The results of this meta-analysis indicate that ICP significantly increase the risk for both PE (pooled odds ratio OR: 2.56 95%CI: 2.27 2.88, I2 heterogeneity = 35%, p heterogeneity = 0.16) and GDM (pooled OR: 2.28 95%CI: 1.69 3.07, I2 heterogeneity = 81%, p heterogeneity < 0.001). In the sensitivity analysis of GDM, excluding the largest heterogeneity study cannot change the result (pooled OR: 2.86 95%CI: 2.59 3.16, I2 heterogeneity = 0%, p heterogeneity = 0.56). This meta-analysis shows that ICP is closely associated with ICP increased risk of PE and GDM) during pregnancy.

Prevalence and Pregnancy Outcomes of Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy is a common pregnancy-specific liver disease associated with increased risk of adverse fetal and maternal outcomes. We sought to determine its prevalence, risk factors and feto-maternal outcomes. A retrospective review of data of 164 pregnant women diagnosed with intrahepatic cholestasis of pregnancy at Chitwan Medical College, Nepal from August 2018 to September 2020 was done. Socio-demographic data, clinic-laboratory profile and feto-maternal outcomes were obtained from clinical audit books and electronic records. A multivariate logistic regression analysis was used to evaluate the predictors of adverse neonatal outcome. The prevalence of intrahepatic cholestasis of pregnancy was 2.5% (164 out of 6539 deliveries). The mean age was 27.5 ± 4.4 years and 51.2% were multigravida. The preterm delivery rate was 15.2% and Caesarean delivery rate was 69.5%. 22% of the neonates needed intensive care admission out of which Respiratory Distress Syndrome or Transient Tachypnea of Newborn was seen in half of them. There were 2 cases of Intrauterine Fetal Death. In multivariate analysis, delivery <34 weeks of gestation was only found to be a significant independent predictor of adverse neonatal outcome Conclusion: The prevalence of intrahepatic cholestasis of pregnancy among pregnant women is significant in our setting which is associated with adverse fetal outcome. Early diagnosis and timely intervention is necessary in order to reduce associated perinatal morbidity.

Prediction of intrahepatic cholestasis of pregnancy in the first 20 weeks of pregnancy

Aim Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with a significant risk of fetal complications including pre-term delivery and fetal death. Typically, it was diagnosed in the third trimester of pregnancy. This study utilized characteristics from routine maternal examinations in the first 20 weeks’ gestation to predict ICP in pregnant women. Methods This is a retrospective case-control study. 13,329 medical records were collected on pregnant women presenting to the West China Second University Hospital between December 2017 and December 2018. After screening according to strict criteria, a total of 487 patients, 250 intrahepatic cholestasis of pregnancy cases, and 237 controls were selected for this study. We collected seven maternal characteristics indices for analysis and forty-three routine blood examination indices were obtained from routine hepatic, renal, and coagulation function examinations. The least absolute shrinkage and selection operator regression was applied for variable selection. Classification and regression trees, logistic regression, random forests, and light gradient boosting machines were fit for predictive modeling. We randomly divided 25% of the original data as testing set to conduct internal validation of the performance of the prediction model. The area under the receiver operating characteristic curves (AUC) was used to compare methods. Results Eight variables were selected out as potentially significant predictors that could reliably predict ICP. The sensitivity, specificity, accuracy, and AUC of the final prediction model obtained by light gradient boosting machines were 72.41, 79.69, 76.23, and 79.77%, respectively. Significantly higher platelet large cell ratio, alanine aminotransferase, glutamyl transpeptidase, and fibrinogen levels were found in cases as compared to healthy controls, while activated partial thromboplastin time and mean corpuscular hemoglobin concentration levels were significantly lower (p < .001). Conclusions The combination of alanine aminotransferase, glutamyl transpeptidase, fibrinogen, platelet large cell ratio, activated partial thromboplastin time, lactate dehydrogenase, creatinine, and mean corpuscular hemoglobin concentration levels can effectively predict ICP in the first 20 weeks of gestation. These could help provide direction for earlier detection and prevention of ICP.

Molecular Pathogenesis of Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids, causing several adverse outcomes for fetuses, including an increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth. Genetic, hormonal, immunological, and environmental factors contribute to the pathogenesis of ICP, and the estrogen-bile acid axis is thought to play a dominant role. The advances in the past 10 years uncover more details of this axis. Moreover, dysregulation of extracellular matrix and oxygen supply, organelle dysfunction, and epigenetic changes are also found to cause ICP, illuminating more potential drug targets for interfering with. Here, we summarize the molecular pathogenesis of ICP with an emphasis on the advancement in the past 10 years, aiming to give an updated full view of this field.

Intrahepatic cholestasis of pregnancy

Die Schwangerschaftscholestase („intrahepatic cholestasis of pregnancy“, ICP) ist die häufigste schwangerschaftsspezifische Lebererkrankung. Das Leitsymptom Juckreiz sowie eine begleitende Serumkonzentrationserhöhung von Gallensäuren und/oder der Alaninaminotransferase (ALT) sind wegweisend in der Diagnosestellung. Die mütterliche Prognose ist gut. Das fetale Outcome ist abhängig von der Gallensäurenkonzentration. Die ICP ist dabei sowohl mit Frühgeburt als auch mit intrauterinem Fruchttod (IUFT) assoziiert. Dieser ist Folge einer akuten fetalen Asphyxie, nicht einer chronischen uteroplazentaren Dysfunktion. Ein prädiktives Monitoring, z. B. durch Kardiotokographie (CTG) oder Ultraschall gibt es nicht. Eine medikamentöse Therapie mit Ursodeoxycholsäure (UDCA) bessert den Juckreiz, aber beeinflusst das fetale Outcome nicht nachweislich. Eine Entbindungsindikation ist in Abhängigkeit von Gallensäurenkonzentration und Gestationsalter gegeben. In Folgeschwangerschaften besteht ein hohes Wiederholungsrisiko.

Case report of atypical scrub typhus in pregnancy coexistent with HELLP syndrome mimicking pregnancy specific liver disease (P-sLD): A management dilemma

Introduction: Jaundice is one of the most dreaded medical disorders in pregnancy. Infective causes of jaundice are often confused with pregnancy specific liver disorders (P-sLD) like HELLP syndrome and acute fatty liver of pregnancy. Delivery may be needed in some situations irrespective of the etiology.

Pregnancy outcomes in women with liver disease: Is pregnancy safe? A cross-sectional study.

BackgroundThere is evidence suggesting that the pregnancy outcome may be affected by some medical conditions, such as liver diseases.ObjectiveThe present study aimed to investigate the prevalence of liver disease and its outcomes in pregnant women referred to antenatal clinic in the hospital.Materials and Methods In this cross-sectional study, all pregnant women with abnormal liver function test attending antenatal clinic affiliated to Shahid Beheshti University of Medical Sciences were recruited from August 2017 to July 2018. All participants were followed-up until delivery with respect to the maternal and neonatal outcome.ResultsOf a total of 7,121 pregnant women recruited in the study, 110 (1.58%) women were detected with a liver disease; of these, 105 women were diagnosed with pregnancy-specific liver diseases, including HELLP syndrome (10.9%), preeclampsia (50.98%), partial HELLP (0.9%), eclampsia (0.9%), acute fatty liver (9.1%), intra-hepatic cholestasis 25 (22.7%), and 5 women the non-pregnancy-specific liver disease, including Liver transplantation (2.7%), and Autoimmune hepatitis (1.8%). Prevalence of the premature birth was 64.5% in pregnancy-specific liver disease, but no premature birth was detected in cases with liver transplantation. We found that neonatal mortality was significantly associated with neonatal prematurity (p = 0.013), IUGR (p 0.001), placental pathology (p = 0.04), we had no maternal mortality.ConclusionLiver disease is not uncommon in pregnancy. This study demonstrated that pregnancy is safe in women with liver disease.

Coenzyme Q 10 supplementation: A potential therapeutic option for the treatment of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disease characterized by pruritus, elevated serum bile acids and abnormal liver function that may be associated with severe adverse pregnancy outcomes. We previously reported that plasma coenzyme Q10 (CoQ10) is decreased in women with ICP as it is its analogue coenzyme Q9 (CoQ9) in rats with ethinyl estradiol (EE)-induced cholestasis. The aim of the present study was to evaluate the possible therapeutic role of CoQ10 in experimental hepatocellular cholestasis and to compare it with ursodeoxycholic acid (UDCA) supplementation. Bile acids, CoQ9, CoQ10, transaminases, alkaline phosphatase, retinol, α-tocopherol, ascorbic acid, thiobarbituric acid reactive substances, carbonyls, glutathione, superoxide dismutase and catalase were assessed in plasma, liver and/or hepatic mitochondria in control and cholestatic rats supplemented with CoQ10 (250 mg/kg) administered alone or combined with UDCA (25 mg/kg). CoQ10 supplementation prevented bile flow decline (P < 0.05) and the increase in serum alkaline phosphatase and bile acids, particularly lithocholic acid (P < 0.05) in cholestatic rats. Furthermore, it also improved oxidative stress parameters in the liver, increased both CoQ10 and CoQ9 plasma levels and partially prevented the fall in α-tocopherol (P < 0.05). UDCA also prevented cholestasis, but it was less efficient than CoQ10 to improve the liver redox environment. Combined administration of CoQ10 and UDCA resulted in additive effects. In conclusion, present findings show that CoQ10 supplementation attenuated EE-induced cholestasis by promoting a favorable redox environment in the liver, and further suggest that it may represent an alternative therapeutic option for ICP.

Pregnancy-specific liver diseases

Liver disease presenting in pregnancy may be due to a pregnancy-specific liver disorder, due to previously unrecognised pre-existing liver disease, or de novo liver disorders coincidentally presenting in a pregnant woman. The pregnancy-specific liver diseases can span from mild disease with limited impact on maternal and foetal health to severe disorders that can result in significant morbidity and mortality for mother and foetus. Swift identification of these disorders is essential to allow timely and appropriate management via a multi-disciplinary approach. The pregnancy-specific conditions, including their presentation, investigations, and management are reviewed in this chapter in detail.

419. Detection of additional abnormalities or co-morbidities in women with intrahepatic cholestasis of pregnancy

Introduction Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease, affecting around0.7% of pregnancies. It is a multifactorial condition with genetic, hormonal and environmental components. ICP is a diagnosis of exclusion, and guidelines often state that clinicians should test for viral and autoimmune causes of raised bile acids and liver transaminases. However, the detection rate for alternative diagnoses or co-morbidities is uncertain in the literature. Objective To assess the detection rate of new diagnoses of viral, autoimmune or ultrasonic abnormalities in women presenting with ICP. Methods All women with raised bile acid concentrations were identified over a 2-year period between 1 Jan 2016 and 31 Dec 2017 at a maternity unit in London, UK; electronic patients records were searched for additional investigations, and documentation around diagnoses. Results 324 women had a raised bile acid concentration (median 18 (IQR) 13–32 μ mol/L) at a median gestation age of 35.1 (IQR 32.0–37.1) weeks’ gestation at first presentation. 28.4% were tested for all liver function tests, virology and autoimmune tests. All positive results for hepatitis B surface antigen and hepatitis C IgG were previously known. No new diagnoses of EBV, CMV or hepatitis A were made. From a panel of autoimmune antibody testing, some positive results were found (at varying titres), but none led to a new diagnosis of liver disease. Varying liver (n = 26) and gall bladder (n = 43) pathology was noted on ultrasound, but none of new clinical significance. Discussion In our study cohort, there were no new co-existing abnormalities of clinical significance detected during additional investigations for ICP. Guidelines should review the evidence base and need for comprehensive screening of all women with ICP and consider whether a more targeted approach should be used, based on clinical symptomatology or unusual features.

Resveratrol regulates the silent information regulator 1-nuclear factor-κB signaling pathway in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease characterized by raised serum bile acids and adverse fetal outcomes. In this study, we aimed to explore the molecular and biochemical mechanism of resveratrol in regulating the silent information regulator 1-nuclear factor-κB (SIRT1-NF-κB) signaling pathway and bile acid biosynthesis in ICP. We analyzed serum and placenta samples from 30 normal and ICP pregnancy women. Then we treated HTR-8/SVneo cells with taurocholic acid (TCA) to mimic ICP conditions before treating these cells with resveratrol, as an activator of SIRT1, and EX-57, as an inhibitor of SIRT1. We established an ICP rat model to analyze the therapeutic effect of resveratrol. The expression of SIRT1 protein was higher in normal placenta tissues than in ICP, and the expression of NF-κB was lower in the normal group than in the ICP group. We found that SIRT1 was downregulated, whereas NF-κB and tuor necrosis factor-α (TNF-α) were upregulated, in syncytiotrophoblast HTR-8 cells treated with TCA. This phenomenon could be reversed by resveratrol, and these effects could be blocked by Ex-527. These data indicate that resveratrol might protect syncytiotrophoblast against TCA-induced inflammatory injury by upregulation of SIRT1 and downregulation of NF-κB and TNF-α. Resveratrol could be a potential therapeutic target for ICP.

Elevated red blood cell distribution width is associated with intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy is the most common pregnancy specific liver disease and related with adverse maternal and perinatal outcome. Red blood cell distribution width, an anisocytosis marker in a complete blood count, has been used as an inflammation marker in various diseases. However the association of red blood cell distribution width with intrahepatic cholestasis of pregnancy is unknown. We aimed to evaluate the relationship between red blood cell distribution width and intrahepatic cholestasis of pregnancy. Ninety pregnant women with intrahepatic cholestasis of pregnancy and ninety healthy pregnant women were included in the study. Their clinical and laboratory characteristics including red blood cell distribution width, liver function tests, fasting and postprandial bile acid concentrations were analyzed. Serum red blood cell distribution width cell levels were significantly higher in pregnants with intrahepatic cholestasis of pregnancy than healthy pregnants. We also demonstrated that red blood cell distribution Width levels were higher in severe disease than mild disease and was significantly correlated with fasting and postprandial bile acid concentration in intrahepatic cholestasis of pregnancy group. Our study showed that red blood cell distribution width, an easy and inexpensive marker; were associated with intrahepatic cholestasis of pregnancy and can be used as a diagnostic and prognostic marker in intrahepatic cholestasis of pregnancy.