Expression and clinical significance of short-chain fatty acids in patients with intrahepatic cholestasis of pregnancy

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a pregnancy-specific liver condition that typically arises in the middle and late stages of pregnancy.Short-chain fatty acids(SCFAs),prominent metabolites of the gut microbiota,have significant connections with various pregnancy complications,and some SCFAs hold potential for treating such complications.However,the metabolic profile of SCFAs in patients with ICP remains unclear.AIM To investigate the metabolic profiles and differences in SCFAs present in the maternal and cord blood of patients with ICP and determine the clinical significance of these findings.METHODS Maternal serum and cord blood samples were collected from both patients with ICP(ICP group)and normal pregnant women(NP group).Targeted metabolomics was used to assess the SCFA levels in these samples.RESULTS Significant differences in maternal SCFAs were observed between the ICP and NP groups.Most SCFAs exhibited a consistent declining trend in cord blood samples from the ICP group,mirroring the pattern seen in maternal serum.Correlation analysis revealed a positive correlation between maternal serum SCFAs and cord blood SCFAs[r(Pearson)=0.88,P=7.93e-95].In both maternal serum and cord blood,acetic and caproic acids were identified as key metabolites contributing to the differences in SCFAs between the two groups(variable importance for the projection>1).Receiver operating characteristic analysis demonstrated that multiple SCFAs in maternal blood have excellent diagnostic capabilities for ICP,with caproic acid exhibiting the highest diagnostic efficacy(area under the curve=0.97).CONCLUSION Compared with the NP group,significant alterations were observed in the SCFAs of maternal serum and cord blood in the ICP group,although they displayed distinct patterns of change.Furthermore,the SCFA levels in maternal serum and cord blood were significantly positively correlated.Notably,certain maternal serum SCFAs,specifically caproic and acetic acids,demonstrated excellent diagnostic efficiency for ICP.

Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump

AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.

Liver stiffness in pregnant women with intrahepatic cholestasis of pregnancy:A case control study

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a rare but severe complication for both the mother and the unborn child.The diagnosis is primarily based on elevated serum levels of bile acids.In a large ICP cohort,we here study in detail liver stiffness(LS)using transient elastography(TE),now widely used to noninvasively screen for liver cirrhosis within minutes.AIM To specifically explore LS in a large cohort of women with ICP compared to a control group with uncomplicated pregnancy.METHODS LS and hepatic steatosis marker controlled attenuation parameter(CAP)were measured in 100 pregnant women with ICP using TE(Fibroscan,Echosens,Paris,France)between 2010 and 2020.In 17 cases,LS could be measured postpartum.450 women before and 38 women after delivery with uncomplicated pregnancy served as control group.Routine laboratory,levels of bile acids and apoptosis marker caspase-cleaved cytokeratin 18 fragment(M30)were also measured.RESULTS Women with ICP had significantly elevated transaminases but normal gammaglutamyl transferase(GGT).Mean LS was significantly increased at 7.3±3.0 kPa compared to the control group at 6.2±2.3 kPa(P<0.0001).Postpartum LS decreased significantly in both groups but was still higher in ICP(5.8±1.7 kPa vs 4.2±0.9 kPa,P<0.0001),respectively.In ICP,LS was highly significantly correlated with levels of bile acids and M30 but not transaminases.No correlation was seen with GGT that even increased significantly after delivery in the ICP group.Bile acids were mostly correlated with the liver apoptosis marker M30,LS and levels of alanine aminotransferase,aspartate aminotransferase,and bilirubin.In multivariate analysis,LS remained the sole parameter that was independently associated with elevated bile acids.CONCLUSION In conclusion,LS is significantly elevated in ICP which is most likely due to toxic bile acid accumulation and hepatocyte apoptosis.In association with conventional laboratory markers,LS provides additional non-invasive information to rapidly identify women at risk for ICP.

Analysis on Therapeutic Effect of Western and Chinese Drug in Treating Intrahepatic Cholestasis of Pregnancy

Objective: To evaluate the therapeutic effect of Yinchenghao decoction (YCHD, 茵陈蒿汤) and S-adenosy-L-methionine (SAM) in treating intra-hepatic cholestasis of pregnancy (TCP) and improving prognosis of perinatal newborn babies. Methods: Sixty in-patients of TCP were randomly divided into two groups, the group A treated with YCHD and the group B treated with SAM. The symptom of itching and serum biochemical indexes, including glycocholic acid, bilirubin and transaminase, were observed after 3 weeks treat-ment, and the prognosis of perinatal newborn babies between the two groups was compared after delivery. Results: After treatment, the symptom of itching, serum levels of glycocholic acid, bilirubin and transaminase improved significantly (P< 0.05) in both groups, and the prognosis of newborn in the two groups was similar (P>0. 05). Conclusion: Both YCHD and SAM could effectively treat ICP. The former is rather cheaper, so it is more feasible for spreading.Original article on CJITWM (Chin) 2004 ;24(4): 309

Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy

The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.

Placental expressions of estrogen receptor α,estrogen receptor β in intrahepatic cholestasis of pregnancy

To investigate the association of the expression of estrogen receptor ct, estrogen receptor 13 in placenta with intrahepatic cholestasis of pregnancy （ICP） susceptibility. Methods： In 14 cases of mild ICP, 14 cases of severe ICP and 14 cases of normal cases （control group） with corresponding age and gestation weeks, the expressions of ERa and ERD were detected by means of immunohistochemical method S-P. Results： The mean grey numbers of ERa in each group mentioned above were 151.684±3.76, 149.854±3.69, 153.184±3.18, without significant difference （P〉0.05） The mean grey numbers of ERβ in each group mentioned above were 146.51±3.81, 139.434±9.97, 149.87±4.17, with significant difference （P〉0.05）; the expression of ERI3 of severe ICP group was significantly higher than that of the mild ICP group and the control group （P〈0.05）. The expression of ERβ in every group was higher than that of ERa （P〈0.05）. Conclusion： ERβ maybe play an important part in the etiology and development of ICP

Fetal lung surfactant and development alterations in intrahepatic cholestasis of pregnancy

AIM: To investigate the association between total bile acid(TBA) level during intrahepatic cholestasis of pregnancy(ICP) and fetal lung surfactant alteration. METHODS: We recruited 42 ICP and 32 normal pregnancy women in this study. The maternal blood, fetal blood and amniotic fluid TBA level were detected using a circulating enzymatic method. Umbilical blood pulmonary surfactant protein A(SP-A) was evaluated with enzyme-linked immunosorbent assay. High performance liquid chromatography was used for the determination of phosphatidyl choline(PC), phosphatidyl inositol(PI), lysolecithin(LPC) and sphingomyelin(SM). Amniotic fluid lamellar body was counted with a fully automatic blood cell counter. Fetal lung area and fetal body weight were calculated from data obtained with an iu22 color supersonic diagnostic set. Clinical information of a nonstress test, amniotic fluid properties and neonatal Apgar score, and birth weight were recorded for review. RESULTS: The TBA level in maternal blood, fetal blood and amniotic fluid in the ICP group were significantly higher than that in the control group(maternal blood: 34.11 ± 6.75 mmol/L vs 4.55 ± 1.72 mmol/L, P < 0.05; fetal blood: 11.9 ± 2.23 mmol/L vs 3.52 ± 1.56 mmol/L, P < 0.05; amniotic fluid: 3.89 ± 1.99 mmol/L vs 1.43 ± 1.14 mmol/L, P < 0.05). Amniotic fluid PC and PI in the ICP group were significantly lower than that in the control group(PC: 65.71 ± 7.23 μg/m L vs 69.70 ± 6.68 μg/m L, P < 0.05; PI: 3.87 ± 0.65 μg/m L vs 4.28 ± 0.74 μg/m L, P < 0.05). PC/LPC ratio of the ICP group was lower than that of the control group(14.40 ± 3.14 vs 16.90 ± 2.52, P < 0.05). Amniotic LB in the ICP group was significantly lower than that of the control group((74.13 ± 4.37) × 109/L vs(103.0 ± 26.82) × 109/L, P < 0.05). Fetal umbilical blood SP-A level in the ICP group was significantly higher than that of the control group(30.26 ± 7.01 ng/m L vs 22.63 ± 7.42 ng/m L, P < 0.05). Fetal lung area/body weight ratio of the ICP group was significantly lower than that of the control group(5.76 ± 0.63 cm2/kg vs 6.89 ± 0.48 cm2/kg, P < 0.05). In the ICP group, umbilical cord blood TBA concentration was positively correlated to the maternal blood TBA concentration(r = 0.746, P < 0.05) and umbilical blood SP-A(r = 0.422, P < 0.05), but it was negatively correlated to the amniotic fluid lamellar corpuscle(r = 0.810, P < 0.05) and fetal lung area/body weight ratio(r = 0.769, P < 0.05). Furthermore, umbilical blood TBA showed a negative correlation to PC, SM and PI(r pc = 0.536, r sm = 0.438, r pi = 0.387 respectively, P < 0.05). The neonatal asphyxia, neonatal respiratory distress syndrome, fetal distress and perinatal death rates in the ICP group are higher than that of theCONCLUSION: ICP has higher TBA in maternal and fetal blood and amniotic fluid. The high concentration of TBA may affect fetal pulmonary surfactant production and fetal lung maturation.

Effect of polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine on pregnancy outcomes in intrahepatic cholestasis

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a liver disorder that occurs in pregnant women and can lead to a range of adverse pregnancy outcomes.The condition is typically marked by pruritus(itching)and elevated levels of liver enzymes and bile acids.The standard treatment for ICP has generally been ursodeoxycholic acid and ademetionine 1,4-butanedisulfonate,but the efficacy of this approach remains less than optimal.Recently,polyene phosphatidylcholine has emerged as a promising new therapeutic agent for ICP due to its potential hepatoprotective effects.AIM To evaluate the effect of polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate on bile acid levels,liver enzyme indices,and pregnancy outcomes in patients with ICP.METHODS From June 2020 to June 2021,600 patients with ICP who were diagnosed and treated at our hospital were recruited and assigned at a ratio of 1:1 via randomnumber table method to receive either ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate(control group,n=300)or polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate(combined group,n=300).Outcome measures included bile acids levels,liver enzyme indices,and pregnancy outcomes.RESULTS Prior to treatment,no significant differences were observed between the two groups(P>0.05).Post-treatment,patients in both groups had significantly lower pruritus scores,but the triple-drug combination group had lower scores than the dual-drug combination group(P<0.05).The bile acid levels decreased significantly in both groups,but the decrease was more significant in the triple-drug group(P<0.05).The triple-drug group also exhibited a greater reduction in the levels of certain liver enzymes and a lower incidence of adverse pregnancy outcomes compared to the dual-drug group(P<0.05).CONCLUSION Polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate effectively relieves pruritus and reduces bile acid levels and liver enzyme indices in patients with ICP,providing a positive impact on pregnancy outcome and a high safety profile.Further clinical trials are required prior to clinical application.

Why more attentions to fetus in cases of intrahepatic cholestasis of pregnancy?

Intrahepatic cholestasis of pregnancy(ICP) is a peculiar disease in middle-late pregnancy with the pathological characteristics of hepatic capillary bile duct silts and is accompanied by clinical presentations of pruritus and bile acid(BA) elevation in serum. Maternal outcomes for patients diagnosed with ICP are usually good. However, fetal outcomes can be devastating with high frequencies of perinatal complications. Patients with ICP generally have an early delivery due to fetal complications. The current hypothesis is that ICP has higher frequencies of fetal complications due to high concentrations of BA which has toxic cellular effects to many organs. In lungs, it destroys the AT-II cells, decreasing phospholipids synthesis leading to the alveolar capillary permeability to increase and pulmonary surfactant to decrease. In heart, cholate can cross into the fetal compartment and causing fetal arrhythmias and decreased contractility. In the nervous system, high BAs can cause nerve cell denaturation and necrosis, mitochondria edema and membrane dissolve. In the placenta, high BA concentration can cause edema of the villous, decrease number of villous, intervillous thickening and balloon formation.In addition, high total BA can result in chorionic vein constriction and impaired fetal adrenal function.

Effect of the maternal-fetal interface immunoregulation on the occurrence of intrahepatic cholestasis of pregnancy

Maternal immune tolerance of the fetus is indispensable for a healthy pregnancy. Currently, the study of the immune microenvironment of the maternal-fetal interface has been a heated topic in reproductive immunology research. More and more studies show that the immune imbalance in the maternal-fetal interface plays a very important role in the incidence of intrahepatic cholestasis of pregnancy(ICP). However, the precise etiology and mechanism of immune imbalance in the occurrence of ICP is still unknown. In order to clarify the potential immunologic mechanisms of ICP, this review summarizes the recent studies of the decidual immunology microenvironment and the potential immunologic mechanisms related to the development of ICP.

Predictors of premature delivery in patients with intrahepatic cholestasis of pregnancy

AIM： To evaluate the predictive value of clinical symptoms and biochemical parameters for prematurity in intrahepatic cholestasis of pregnancy （ICP）. METHODS： Sixty symptomatic patients with ICP were included in this retrospective analysis. Preterm delivery was defined as delivery before 37 wk gestation. Predictors of preterm delivery were disclosed by binary multivariate logistic regression analysis. RESULTS： Mean time of delivery was 38.1 ± 1.7 wk. No stillbirths occurred. Premature delivery was observed in eight （13.3%） patients. Total fasting serum bile acids were higher （47.8 ±15.2 vs 41.0 ± 10.0 μmol/L, P 〈 0.05）, and pruritus tended to start earlier （29.0 ± 3.9 vs 31.6 ± 3.3 wk, P = 0.057） in patients with premature delivery when compared to those with term delivery. Binary multivariate logistic regression analysis revealed that early onset of pruritus （OR 1.70, 95% CI 1.23-2.95, P = 0.038） and serum bile acid （OR 2.13, 95% CI 1.13-3.25, P = 0.013） were independent predictors of preterm delivery. CONCLUSION： Early onset of pruritus and high levels of serum bile acids predict preterm delivery in ICP, and define a subgroup of patients at risk for poor neonatal outcome.

Bile Acid Effects on Placental Damage in Intrahepatic Cholestasis of Pregnancy

Aims: The abnormal increase of bile acid is found in intrahepatic cholestasis of pregnancy (ICP). It also can be observed the damage of placental tissue in ICP. The aim of this study was to find the associations of the bile acid in umbilical vein and the damage of placental tissue. Methods: Thirty women diagnosed with ICP and fifty normal pregnant women between September 2015 and September 2017 at Nanshan District Maternity & Child Healthcare Hospital of Shenzhen were included in this study. The glycocholic acid (GA), total bile acids (TBA), total bilirubin (TB), direct bilirubin (DB) and albumin level in umbilical vein were measured by cycle enzyme method in ICP and control group. The placental damage was analyzed by morphologic study using hematoxylin dyes in two groups. The correlation between the level of the bile acid in the umbilical vein and the damage of the placenta was assessed using SPSS software. Results: The GA, TBA, TB, DB and albumin level in umbilical vein were significantly higher in ICP than those of pregnant women, respectively. The placental villis were expanded and the structure was destroyed in ICP. The vessel was damaged and the cell trophoblast hyperplasia in ICP. It also can be seen that there was obvious nodules and a typical fibrous necrotic substance in ICP but not in control group. There is a positive correlation between the level of the TBA in the umbilical vein and the damage of the placenta in ICP. Conclusion: The TBAs were significantly higher in umbilical vein and were related to the placental damage in ICP.

Health behavior after intrahepatic cholestasis of pregnancy

Background: Pregnancy is an opportunity to adopt favorable health behaviors. We studied whether intrahepatic cholestasis of pregnancy (ICP) promotes favorable health behavior in later life. Design: A prospective controlled cohort study. The method was a questionnaire survey in 2010 among 575 women with ICP and 1374 controls, all having delivered between the years 1969 and 1988 in Tampere University Hospital in Finland. Questionnaires were sent to 544 ICP patients and 1235 controls. Responses were received from 1178 (response rate 66.2%). The main outcome measures concerning recent or current health behavior were smoking, alcohol consumption, physical activity, body mass index (BMI) and special diet. Results: Current smoking was less common in the ICP group than among controls (10.5% vs 15.7%, p = 0.017). Assessed by smoking pack years there was a similar difference: in the ICP group 11.7% of women had at least 10 smoking pack years compared to 18.0% of the controls (p = 0.006). Recent alcohol consumption did not separate the two groups. The groups did not differ as to reported physical activity assessed in MET units. Fewer ICP women had had BMIs of 30 or more during pregnancy compared with controls (18.8% vs 25.1%, p = 0.023). In other points of life the BMI differences were not statistically significant. Weight-loss diet and gallbladder diet were more common in the ICP group (6.3% vs 3.6%, p = 0.044, and 3.0% vs 1.3%, p = 0.038). Conclusions: Having developed ICP two to four decades earlier seemed to constitute an effective intervention for smoking habits but not for other aspects of health behavior.

Effect of preeclampsia on blood biochemical parameters and pregnancy outcome in patients with intrahepatic cholestasis of pregnancy

Objective:To investigate the effects of pre-eclampsia (PE) on blood biochemical parameters and pregnancy outcomes in patients with intrahepatic cholestasis of pregnancy (ICP). Methods: The study subjects selected 180 patients with ICP who were admitted to our hospital from January 2016 to January 2018. Among them, 45 patients with PE were marked as observation group, and the remaining 135 patients with ICP were labeled as control group. The liver function indicators, serum inflammatory factor index levels, and differences between pregnancy outcomes and neonatal outcomes were compared between the two groups.Results:The liver function indexes (ALT, AST, GGT, TBA, TBIL) in the observation group were significantly higher than those in the control group, and the differences were statistically significant (P<0.01). The levels of serum IL-12, TNF-α and SOCS-3 in the observation group were significantly higher than those in the control group, and the differences were statistically significant (P<0.01). The gestational weeks (36.89±0.55) of the observation group were significantly shorter than the control group (38.68±0.59), and the difference was statistically significant (t=18.56,P=0.00). The cesarean section rate and amniotic fluid rate in the observation group were observed. They were significantly higher than the control group, and the differences were statistically significant (P<0.01). The neonatal weight of the observation group (3.05±0.32) was significantly lower than that of the control group (3.39±0.45), and the difference was statistically significant (t=5.53,P=0.00). The premature birth rate, fetal distress rate, neonate in the observation group. The asphyxiation rate was significantly higher than that of the control group, and the difference was statistically significant (P<0.05).Conclusion:Preeclampsia can aggravate liver function damage and serum inflammatory factor levels in patients with intrahepatic cholestasis of pregnancy. It is an important risk factor for pregnancy outcome and neonatal outcome, and it is worthy of attention in clinical diagnosis and treatment.

Effects of low molecular heparin combined with ursodeoxycholic acid on liver function, immunologic function and pregnancy outcome in patients with intrahepatic cholestasis of pregnancy

Objective: To investigate the effects of low molecular heparin (LMWH) combined with ursodeoxycholic acid (UDCA) on liver function, immunologic function and pregnancy outcome in patients with intrahepatic cholestasis of pregnancy (ICP). Methods: A total of 110 patients with ICP were randomly divided into the observation group (n=55) and the control group (n=55). Patients in the control group received conventional therapy, while patients in the observation group were treated with LMWH hypodermic injection and UDCA orally on the basis of the treatment plan of the control group. Before and after treatment, the levels of serum total bile acid (TBA), glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (ALP) and immunoglobulin (IgG, IgA, IgM) between the two groups were compared. The changes of T lymphocyte subsets of peripheral blood in the two groups were analyzed, and the pregnancy outcomes of the two groups were observed. Results: After treatment, the serum levels of TBA, ALT, AST, TBIL, DBIL and ALP in the two groups were significantly lower than those before treatment, and the change of each index in the observation group was more obvious than that in the control group. The serum levels of IgG, IgA and IgM in the observation group after treatment were significantly higher than those before treatment and those in the control group after treatment. However, the percentage of CD4+T cells and the ratio of CD4+/CD8+ in the observation group after treatment were significantly lower than those before treatment and those in the control group after treatment. Conclusions: LMWH combined with UDCA could effectively reduce serum bile acid level, improve liver function and regulate immune balance in patients with ICP, and improve outcomes of maternal and fetal.

Diagnosis and management of benign recurrent intrahepatic cholestasis and psychosocial stressors in an adolescent:A case report

BACKGROUND Benign recurrent intrahepatic cholestasis(BRIC)is a rare autosomal recessive disorder,characterized by episodes of intense pruritus,elevated serum levels of alkaline phosphatase and bilirubin,and near-normal-glutamyl transferase.These episodes may persist for weeks to months before spontaneously resolving,with patients typically remaining asymptomatic between occurrences.Diagnosis entails the evaluation of clinical symptoms and targeted genetic testing.Although BRIC is recognized as a benign genetic disorder,the triggers,particularly psychosocial factors,remain poorly understood.CASE SUMMARY An 18-year-old Chinese man presented with recurrent jaundice and pruritus after a cold,which was exacerbated by self-medication involving vitamin B and paracetamol.Clinical and laboratory evaluations revealed elevated levels of bilirubin and liver enzymes,in the absence of viral or autoimmune liver disease.Imaging excluded biliary and pancreatic abnormalities,and liver biopsy demonstrated centrilobular cholestasis,culminating in a BRIC diagnosis confirmed by the identification of a novel ATP8B1 gene mutation.Psychological assessment of the patient unveiled stress attributable to academic and familial pressures,regarded as potential triggers for BRIC.Initial relief was observed with ursodeoxycholic acid and cetirizine,followed by an adjustment of the treatment regimen in response to elevated liver enzymes.The patient's condition significantly improved following a stress-related episode,thanks to a comprehensive management approach that included psychosocial support and medical treatment.CONCLUSION Our research highlights genetic and psychosocial influences on BRIC,emphasizing integrated diagnostic and management strategies.

Molecular overview of progressive familial intrahepatic cholestasis

Cholestasis is a clinical condition resulting from the imapairment of bile flow.This condition could be caused by defects of the hepatocytes,which are responsible for the complex process of bile formation and secretion,and/or caused by defects in the secretory machinery of cholangiocytes.Several mutations and pathways that lead to cholestasis have been described.Progressive familial intrahepatic cholestasis(PFIC)is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes.PFIC 1,also known as Byler’s disease,is caused by mutations of the ATP8B1 gene,which encodes the familial intrahepatic cholestasis 1 protein.PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump(BSEP)expression via variations in the ABCB11 gene.Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein,leading to the third type of PFIC.Newer variations of this disease have been described.Loss of function of the tight junction protein 2 protein results in PFIC 4,while mutations of the NR1H4 gene,which encodes farnesoid X receptor,an important transcription factor for bile formation,cause PFIC 5.A recently described type of PFIC is associated with a mutation in the MYO5B gene,important for the trafficking of BSEP and hepatocyte membrane polarization.In this review,we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

Intrahepatic Cholestasis of Pregnancy: Biochemical Predictors of Adverse Perinatal Outcomes

Summary： This study aimed to identify biochemical predictors of adverse perinatal outcomes in in- trahepatic cholestasis of pregnancy （ICP）. A total of 106 ICP cases were analyzed retrospectively by the combination of receiver operating characteristic curve and binary logistic regression analysis. ＂Adverse perinatal outcomes＂ included spontaneous preterm labor, meconium-staining of amniotic fluid, stillbirth and Apgar score ≤7 at 1 or 5 min. Total bile acid （TBA） [AUC=0.658, 95%CI （0.536, 0.781）, P=0.031] was a valuable predictor for adverse perinatal outcomes. The critical value of TBA above which adverse perinatal outcomes were observed was 40.15 μmol/L （Youden＇s index=0.3）. Binary multivariate logistic regression analysis revealed that the risk of adverse perinatal outcomes increased when TBA ≥40.15 /.tmol/L [OR=3.792, 95%CI （1.226, 11.727）, P=0.021]. It is concluded that the risk of adverse perinatal outcomes in ICP increases when maternal TBA ≥40.15 gmol/L.

Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems

Intrahepatic cholestasis of pregnancy （ICP） is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICR

Intrahepatic cholestasis of pregnancy:When should you look further?

Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy(ICP),a condition associated with significant fetal complications.Although the etiology of ICP is unclear in many cases,certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease.We report a kindred of Anglo-Celtic descent,among whom many members present with ICP,gallstones or cholestasis related to use of oral contraception.Genetic studies revealed a novel mutation in the ABCB4 gene,which codes for a phospholipid transport protein.The clinical significance of this mutation and the importance of identifying such patients are discussed.