The effect of intrahepatic cholestasis in pregnancy combined with different stages of hepatitis B virus infection on pregnancy outcomes: a retrospective study.

BACKGROUND AND AIMS: To investigate the impact of intrahepatic cholestasis of pregnancy (ICP) with hepatitis B virus (HBV) infection on pregnancy outcomes. METHODS: We selected 512 pregnant women, collected the data including maternal demographics, main adverse pregnancy outcomes and maternal HBV infected markers HBeAg and HBV-DNA loads status, then have a comparative analysis. RESULTS: There were 319 solitary ICP patients without HBV infection (Group I) and 193 ICP patients with HBV infection. Of the latter, there were 118 cases with abnormal liver function(Group II) and 80 cases with normal liver function(Group III). All HBV-infected pregnant women with ICP were divided into hepatitis Be antigen (HBeAg)-positive group (102 cases) and HBeAg-negative group (91 cases), according to the level of the serum HBeAg status; and into high viral load group (92 cases), moderate viral load group (46 cases) and low viral load group (55 cases) according to the maternal HBV-DNA level. Group II had a higher level of serum total bile acids, transaminase, bilirubin as well as a higher percentage of premature delivery, neonatal intensive care unit (NICU) admission and meconium-stained amniotic fluid (MSAF) compared with the other two groups(P < 0.05), but there were no significant differences in the above indicators between the Group I and Group III. Among the HBV-infected patients with ICP, HBeAg-positive group had a higher level of serum transaminase, bilirubin and bile acid as well as earlier gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission than HBeAg-negative group (P < 0.05). Those with a high viral load (HBV-DNA > 106 IU/ml) had a higher level of transaminase, bilirubin, and bile acid as well as shorter gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission compared with those with a low or moderate viral load (P < 0.05). CONCLUSION: HBV-infected pregnant women with ICP combined with abnormal liver function have more severe liver damage, a higher percentage of preterm birth and NICU admission. HBeAg-positive status and a high HBV-DNA load will increase the severity of conditions in HBV-infected pregnant women with ICP. HBV-infected patients with ICP who have abnormal liver function, HBeAg-positive or a high viral load should be treated more actively.

Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY: This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS: A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS: Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1ß, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS: In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.

Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults.

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

[Characteristics and diagnostic value of serum bile acids profile in pregnant women with intrahepatic cholestasis of pregnancy and asymptomatic hypercholanemia of pregnancy].

Objective: To analyze serum bile acid profiles in pregnant women with normal pregnancy, intrahepatic cholestasis of pregnancy (ICP) and asymptomatic hypercholanemia of pregnancy (AHP), and to evaluate the application value of serum bile acid profiles in the diagnosis of ICP and AHP. Methods: The clinical data of 122 pregnant women who underwent prenatal examination in Xuzhou Maternal and Child Health Care Hospital from June 2022 to May 2023 were collected, including 54 cases of normal pregnancy group, 28 cases of ICP group and 40 cases of AHP group. Ultraperformance liquid chromatography-tandem mass spectrometry was used to measure the levels of 15 serum bile acids in each group, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), glycolcholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA) and tauroursodeoxycholic acid (TUDCA). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to screen differential bile acids. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of differential bile acids and combined indicators between groups. Results: (1) Compared with normal pregnancy group, the serum levels of LCA, GCA, GCDCA, GDCA, GLCA, UDCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in ICP group were significantly different (all P<0.05), while the levels of LCA, DCA, GCA, GCDCA, GDCA, GLCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). Compared with ICP group, the serum levels of CDCA, DCA, UDCA, TDCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). (2) In the OPLS-DA model, the differential bile acids between ICP group and AHP group were TUDCA, TCA, UDCA, GUDCA and GCA, and their variable importance in projection (VIP) were 1.489, 1.345, 1.344, 1.184 and 1.111, respectively. TCA, GCDCA, GCA, TDCA, GDCA and TCDCA were the differentially expressed bile acids between AHP group and normal pregnancy group, and their VIP values were 1.236, 1.229, 1.197, 1.145, 1.139 and 1.138, respectively. (3) ROC analysis showed that the area under the curve (AUC) of TUDCA, TCA, UDCA, GUDCA and GCA in the differential diagnosis of ICP and AHP was 0.860, and the sensitivity and specificity were 67.9% and 95.0%, respectively. The AUC of TCA, GCDCA, GCA, TDCA, GDCA and TCDCA in the diagnosis of AHP was 0.964, and the sensitivity and specificity were 95.0% and 93.1%, respectively. Conclusions: There are differences in serum bile acid profiles among normal pregnant women, ICP and AHP. The serum bile acid profiles of pregnant women have potential application value in the differential diagnosis of ICP and AHP and the diagnosis of AHP.

NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

[Analysis of clinical characteristic of children with progressive familial intrahepatic cholestasis type 3].

Objective: To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3). Methods: This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity. Results: Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment. Conclusions: Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.

Intrahepatic Cholestasis of Pregnancy during COVID-19 Pandemic.

Background and Objectives: Intrahepatic cholestasis of pregnancy (ICP) stands as one of the most prevalent concerns in maternal-fetal medicine, presenting a significant risk to fetal health and often associated with liver dysfunction. Concurrently, the coronavirus-19 (COVID-19) infection can lead to hepatic cell injury through both direct and indirect pathways. Hypothetically, these two conditions may coincide, influencing each other. This study aimed to comparatively assess the incidence and severity of ICP before and during the COVID-19 pandemic. Methods: A retrospective cohort study was conducted, comparing the incidence and severity of ICP between January 2018 and February 2020 (pre-COVID-19 period) and March 2020 to March 2022 (COVID-19 period) across two hospitals, encompassing 7799 deliveries. The diagnosis of ICP was established using the ICD-10 code and defined as total bile acids (BA) levels ≥ 10 µmol/L. Statistical analysis included descriptive statistics, Chi-square and Mann-Whitney U tests, as well as multiple or logistic regression analysis. Results: A total of 226 cases of ICP were identified. The incidence of mild cholestasis (BA < 40 µmol/L) was lower during the pandemic compared to before (3% before versus 2%, p < 0.05), while the incidence of moderate and severe ICP remained unchanged (0.6% before vs. 0.4%, p = 0.2). Overall, the total incidence of ICP was lower during the pandemic (3.6% before versus 2.4%, p = 0.01). No significant differences were observed in severity (as defined by BA and liver function test levels), rates of caesarean section, or neonatal birth weights. Conclusions: During the COVID-19 pandemic, the total incidence of ICP appeared to be lower. However, this reduction was primarily observed in cases of mild ICP, potentially indicating challenges in detection or reduced access to medical services during this period. The incidence of moderate and severe ICP remained unchanged, suggesting that these forms of the condition were unaffected by the pandemic's circumstances.

The role of Ca2+ signalling and InsP3R in the pathogenesis of intrahepatic cholestasis of pregnancy.

BACKGROUND: In order to contribute new insights for future prevention and treatment of intrahepatic cholestasis of pregnancy (ICP), and to promote positive pregnancy outcomes, we evaluated serum Ca2+ levels and inositol 1,4,5-trisphosphate receptor (InsP3R) expression in the liver tissue of a rat ICP model. METHODS: After establishing the model by injection of oestradiol benzoate and progesterone into pregnant rats, animals were divided into normal control (n = 5) and ICP model groups (n = 5). The expression of InsP3R protein in the liver, and serum levels of Ca2+, glycocholic acid and bile acid were detected. RESULTS: InsP3R mRNA and protein were significantly lower in the ICP model group compared to the normal group, as determined by qPCR and immunohistochemistry, respectively. Serum enzyme-linked immunosorbent assay results revealed significantly higher levels of glycocholic acid and bile acid in the ICP model group compared to the normal group, while Ca2+ levels were significantly lower. The levers of Ca2+ were significantly and negatively correlated with the levels of glycocholic acid. The observed decrease in Ca2+ was associated with an increase in total bile acids, but there was no significant correlation. CONCLUSIONS: Our results revealed that the expression of InsP3R and serum Ca2+ levels was significantly decreased in the liver tissue of ICP model rats. Additionally, Ca2+ levels were found to be negatively correlated with the level of glycocholic acid.

This study investigated the relationship between serum Ca²⁺ levels, inositol 1,4,5-trisphosphate receptor (InsP3R) expression and intrahepatic cholestasis of pregnancy (ICP) in a rat model. The results indicated a significant decrease in InsP3R expression and Ca²⁺ in the disease group compared to the control group, alongside elevated levels of glycocholic acid and bile acid. The levels of Ca²⁺ exhibited a negative correlation with the levels of glycocholic acid. These findings indicated that the decrease of InsP3R expression and Ca²⁺ levels may be related to the pathogenesis of ICP. The study provides further insight into the treatment of this disease.

Metabolomic profiling of serum and tongue coating of pregnant women with intrahepatic cholestasis in pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of cesarean section and adverse fetal outcomes. Currently, ICP diagnosis depends largely on serum levels of bile acids and lacks sensitivity and specificity for accurate diagnosis. Tongue diagnosis is an important diagnostic tool in traditional Chinese medicine (TCM) and is used in our clinic as complementary treatment and personalized medicine for ICP. However, the molecular basis of the manifestation of greasy white tongue coatings in ICP remains unknown. In this study, we performed untargeted metabolomic profiling of the serum, tongue coating, and saliva of 66 pregnant women, including 22 with ICP. The metabolomic profiles of the serum and tongue coatings showed marked differences between the two clinical groups. Forty-six differentially abundant metabolites were identified, and their relative concentrations correlated with total bile acid levels. These differential metabolites included bile acids, lipids, microbiota- and diet-related metabolites, and exposomes. Conventional biochemical markers, including serum aminotransferases and bilirubin, were not significantly increased in the ICP group, whereas the total cholesterol and triglyceride levels were significantly increased as early as the first trimester. Our data provide insights into the pathophysiology of ICP and implicate the gut-liver axis and environmental exposure. Tongue coating has the potential to be a non-invasive diagnostic approach. Further studies are required to validate the clinical utility of these findings.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

Molecular Insights of Cholestasis in MDR2 Knockout Murine Liver Organoids.

MDR3 (multidrug resistance 3) deficiency in humans (MDR2 in mice) causes progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 is a lethal disease characterized by an early onset of intrahepatic cholestasis progressing to liver cirrhosis, a preneoplastic condition, putting individuals at risk of hepatocellular carcinoma (HCC). Hepatocyte-like organoids from MDR2-deficient mice (MDR2KO) were used in this work to study the molecular alterations caused by the deficiency of this transporter. Proteomic analysis by mass spectrometry allowed characterization of 279 proteins that were differentially expressed in MDR2KO compared with wild-type organoids. Functional enrichment analysis indicated alterations in three main cellular functions: (1) interaction with the extracellular matrix, (2) remodeling intermediary metabolism, and (3) cell proliferation and differentiation. The affected cellular processes were validated by orthogonal molecular biology techniques. Our results point to molecular mechanisms associated with PFIC3 that may drive the progression to liver cirrhosis and HCC and suggest proteins and cellular processes that could be targeted for the development of early detection strategies for these severe liver diseases.

Baicalein alleviates intrahepatic cholestasis by regulating bile acid metabolism via an FXR-dependent manner.

Cholestasis is characterized by impaired bile secretion and flow, leading to the accumulation of toxic bile acids in the liver, further causing inflammatory reaction, fibrosis, and ultimately liver transplantation. Although first-line clinical agents such as Ursodeoxycholic acid (UDCA) and Obeticholic acid (OCA) are available, serious side effects still exist. Therefore, pharmacologic treatment of cholestatic liver disease remains challenging. Here, we used a murine model of cholestasis treated with or without intraperitoneal injection of baicalein and found that baicalein could attenuate 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammatory response, ductular reaction, liver fibrosis, and bile acid metabolism disorders. Furthermore, the therapeutic effect of baicalein was hampered in the presence of Guggulsterone (GS), an Farnesoid X receptor (FXR) antagonist. These results indicated that baicalein alleviated DDC diet-induced cholestatic liver injury in an FXR-dependent manner.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Outcomes of pregnancies complicated by cirrhosis: a retrospective cohort study.

BACKGROUND: Although pregnancy complicated by liver cirrhosis is rare, women with cirrhosis experience increased adverse pregnancy outcomes. This study aimed to evaluate pregnancy outcomes in women with liver cirrhosis and develop a predictive model using maternal factors for preterm birth in such pregnancies. METHODS: A retrospective analysis was conducted on pregnancy outcomes of a cirrhosis group (n = 43) and a non-cirrhosis group (n = 172) in a university hospital between 2010 and 2022. Logistic regression evaluated pregnancy outcomes, and a forward stepwise logistic regression model was designed to predict preterm birth in pregnant women with cirrhosis. The model's predictive performance was evaluated using the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). RESULTS: The incidence of cirrhosis during pregnancy was 0.06% (50/81,554). Pregnant women with cirrhosis faced increased risks of cesarean section, preterm birth, intrahepatic cholestasis of pregnancy, thrombocytopenia, and postpartum hemorrhage. In pregnant women with cirrhosis, preterm birth risk significantly increased at an incidence rate of 46.51% (20/43). According to the prediction model, the key predictors of preterm birth in pregnant women with cirrhosis were intrahepatic cholestasis of pregnancy and total bilirubin. The model demonstrated accurate prediction, with an AUC of 0.847, yielding a model accuracy of 81.4%. CONCLUSIONS: Pregnant women with cirrhosis face a heightened risk of adverse obstetric outcomes, particularly an increased incidence of preterm birth. The preliminary evidence shows that the regression model established in our study can use the identified key predictors to predict preterm birth in pregnant women with cirrhosis, with high accuracy.

The correlation between serum total bile acid and adverse perinatal outcomes in pregnant women with intrahepatic cholestasis of pregnancy (ICP) and non-ICP hypercholanemia of pregnancy.

BACKGROUND: The association between excessive serum total bile acid (TBA) and adverse perinatal outcomes in individuals with non-intrahepatic cholestasis of pregnancy (non-ICP) hypercholanemia has not been determined, and it is unclear if this link is similar to that observed in patients with ICP. OBJECTIVE: To examine the adverse perinatal outcomes in two specific subcategories: those with ICP and those with non-ICP, including individuals with liver disease and asymptomatic hypercholanemia of pregnancy (AHP), at different levels of TBA. Investigate the correlation between TBA levels and adverse perinatal outcomes of ICP, liver disease, and AHP. METHODS: From 2013 to 2021, pregnant women with excessive TBA levels were taken from the electronic medical record database of our hospital and categorized into three groups: ICP (n = 160), liver disease (n = 164), and AHP (n = 650). This was done as part of a retrospective cohort research project. Multivariable regression and subgroup analyses were performed to examine the association between TBA levels and adverse perinatal outcomes in each group. RESULTS: The study found no significant differences in adverse perinatal outcomes between the ICP and liver disease groups at different TBA levels. However, at moderate TBA levels, both groups had a higher risk of adverse perinatal outcomes than the AHP group (p < 0.017). Among liver disease cases with TBA ≥ 100µmol/L, three cases of perinatal deaths (6.67%) associated with moderate-to-severe acute hepatitis occurred between 27 and 33 weeks of gestation. A 59% higher chance of perinatal death was found for every 10 µmol/L rise in TBA, even after significant variables and confounders were taken into account (adjusted odds ratio (aOR) = 1.59; 95% confidence interval (CI): 1.06-2.40; p = 0.03). CONCLUSIONS: If a pregnant woman has moderate-to-severe liver disease and TBA ≥ 100µmol/L, preterm termination of pregnancy (before 34 weeks) may be considered.

If someone doesn't have ICP but does have moderate-to-severe hepatitis and TBA levels of 100 µmol/L or more, they should be treated more aggressively, and their pregnancies should be terminated earlier (before 34 weeks) than what is usually done for ICP.

Clinical outcomes of ABCB4 heterozygosity in infants and children with cholestatic liver disease.

OBJECTIVES: Biallelic variants in the adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease. METHODS: The clinical and genotypic data on pediatric patients seen at King's College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed. RESULTS: Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease. CONCLUSIONS: Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

Exosomes from Intrahepatic Cholestasis of Pregnancy Induce Cell Apoptosis Through the miRNA-6891-5p/YWHAE Pathway.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse pregnancy outcomes; however, the underlying mechanisms are not fully understood. AIMS: This study aimed to determine the role of exosomal miR-6891-5p in placental trophoblast dysfunction in ICP and identify new biomarkers for ICP diagnosis. METHODS: Serum samples were collected from ICP patients and healthy pregnant women, and serum exosomes were extracted and identified. Fluorescent dye labeling of exosomes and cell-verified cell phagocytosis were performed. In vitro experiments were conducted by adding taurocholic acid to simulate the ICP environment. Cell proliferation and apoptosis levels were detected using flow cytometry and the cell counting kit-8 assay. Mimics were constructed to overexpress miR-6891-5p in cells, and the binding site between miR-6891-5p and YWHAE was verified using luciferase reporter genes. RESULTS: miR-6891-5p expression was significantly decreased in serum exosomes of ICP patients. Co-culturing with exosomes derived from ICP patients' serum (ICP-Exos) decreased HTR-8/SVeno cell proliferation and increased apoptosis levels. miR-6891-5p upregulation in HTR-8/SVeno cells significantly increased cell viability and reduced cell apoptosis levels, as determined by the cell counting kit-8 assay and flow cytometry. A double luciferase assay confirmed that miR-6891-5p affected the expression of the downstream YWHAE protein. CONCLUSIONS: This study indicates that serum exosomes from ICP patients can impact the apoptosis of placental trophoblast HTR-8/SVeno cells through the miR-6891-5P/YWHAE pathway and can serve as specific molecular markers for ICP diagnosis.

Gradual dosing of ursodeoxycholic acid in mothers with intrahepatic cholestasis of pregnancy may improve composite neonatal outcome.

INTRODUCTION AND OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) is often accompanied by fetal and maternal complications. MATERIALS AND METHODS: Retrospective review of the clinical course of women with ICP and their neonates treated at our medical center over a 10-year period. Special attention was paid to the maternal and neonatal response to 2 different modes of ursodeoxycholic acid (UDCA) administration. RESULTS: Neonates of mothers with high total bile acid levels had a poorer composite neonatal outcome. Twenty-seven women who presented at an advanced stage of their pregnancies did not receive UDCA. UDCA was administered in 2 modes: either a full dose at admission (76 women) or a gradually increasing dose until the desired dosage was reached (25 women). The mean gestational age at delivery for the 94 neonates that were exposed to full UDCA dose was the lowest (36±2.3 weeks for the full dose, 37±1.4 weeks for the 30 neonates from the gradually increasing dose, 38±1.6 weeks for the 29 neonates from the no treatment group, p<0.001). The group of neonates that were exposed to full UDCA dose had the highest rate of unfavorable composite neonatal outcome (53% for full dose, 30% for gradually increasing dose, 24% for the no treatment group, p=0.006). CONCLUSIONS: Compared to the administration of a full UDCA dose, the administration of a gradually increasing dose of UDCA may be associated with a greater gestational age at delivery and fewer events of unfavorable composite neonatal outcomes. These novel findings should be retested prospectively in a large cohort of patients.