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-norma...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.展开更多
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...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.展开更多
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 co...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.展开更多
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 el...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.展开更多
Intrahepatic cholestasis of pregnancy(ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late s...Intrahepatic cholestasis of pregnancy(ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries(9.2%-15.6% and 1.5%, respectively) than in Europe(0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue.展开更多
AIM: To investigate the differences in the mutation spectra of the SLC25A13 gene mutations from specific regions of China. METHODS: Genetic analyses of SLC25A13 mutations were performed in 535 patients with neonatal i...AIM: To investigate the differences in the mutation spectra of the SLC25A13 gene mutations from specific regions of China. METHODS: Genetic analyses of SLC25A13 mutations were performed in 535 patients with neonatal intrahepatic cholestasis from our center over eight years. Unrelated infants with at least one mutant allele were enrolled to calculate the proportion of SLC25A13 mutations in different regions of China. The boundary between northern and southern China was drawn at the historical border of the Yangtze River.RESULTS: A total of 63 unrelated patients (about 11% of cases with intrahepatic cholestasis) from 16 provinces or municipalities in China had mutations in the SLC25A13 gene, of these 16 (25%) were homozygotes, 28 (44%) were compound heterozygotes and 19 (30%) were heterozygotes. In addition to four well described common mutations (c.851_854del, c.1638_1660dup23, c.615+5G>A and c.1750+72_17514dup17insNM_138459.3:2667 also known as IVS16ins3kb), 13 other mutation types were identified, including three novel mutations: c.985_986insT, c.287T>C and c.1349A>G. According to the geographical division criteria, 60 mutant alleles were identified in patients from the southern areas of China, 43 alleles were identified in patients from the border, and 4 alleles were identified in patients from the northern areas of China. The proportion of four common mutations was higher in south region (56/60, 93%) than that in the border region (34/43, 79%, χ 2 = 4.621, P = 0.032) and the northern region (2/4, 50%, χ 2 = 8.288, P = 0.041). CONCLUSION: The SLC25A13 mutation spectra among the three regions of China were different, providing a basis for the improvement of diagnostic strategies and interpretation of genetic diagnosis.展开更多
BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes,resul...BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes,resulting in a hepatocellular form of cholestasis.While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause,recent scientific advancements have uncovered multiple specific responsible proteins.The variety of identified defects has resulted in an ever-broadening phenotypic spectrum,ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.AIM To review current data on defects in bile acid homeostasis,explore the expanding knowledge base of genetic based diseases in this field,and report disease characteristics and management.METHODS We conducted a systemic review according to PRISMA guidelines.We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding,diagnosis,and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC.English only articles were accessed in full.The manual search included references of retrieved articles.We extracted data on disease characteristics,associations with other diseases,and treatment.Data was summarized and presented in text,figure,and table format.RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults.A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1(ATP8B1),BSEP(ABCB11),and MDR3(ABCB4)transporter deficiencies,as well as more recently described gene mutations--TJP2(TJP2),FXR(NR1H4),MYO5B(MYO5B),and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.展开更多
AIM:To establish the real time fluorescence polymerase chain reaction(RT-PCR) with dual labeled probes for fast detection of SLC25A13 gene mutation 851del4.METHODS:Four hundred infants(< 1 year of age) with unexpla...AIM:To establish the real time fluorescence polymerase chain reaction(RT-PCR) with dual labeled probes for fast detection of SLC25A13 gene mutation 851del4.METHODS:Four hundred infants(< 1 year of age) with unexplained intrahepatic cholestasis from 18 provinces or municipalities in China were enrolled in this study for detecting their SLC25A13 gene mutation 851del4.Suitable primers and fluorescence-labeled probes for detecting SLC25A13 gene mutation 841del4 were designed.Normal and mutant sequences were detected by PCR with two fluorescence-labeled probes.After a single RT-PCR,results were obtained by analyzing the take-off curves.Twenty-four positive and 14 negative samples were retested by direct sequencing.RESULTS:Eight homozygous and 30 heterozygous mutations were detected in 46 mutant alleles with a 851del4 mutation rate of 5.8%(46/800).Twenty-six and 20 mutant alleles were observed respectively,in 474 and 242 alleles from the intermediate and southern areas of China.No mutant allele was detected in 84 alleles from northern China.Twenty-four positive samples including 4 homozygous and 20 heterozygous mutations,and 14 negative samples were retested by direct sequencing,which confirmed that the accuracy of RTPCR was 100%.CONCLUSION:RT-PCR can detect the mutation 851del4 in infants with intrahepatic cholestasis with an accuracy of 100%.展开更多
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 t...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.展开更多
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 secretio...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.展开更多
BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on'progressive familial intrahepatic ...BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on'progressive familial intrahepatic cholestasis'and'PFIC'was performed on the topic,and the relevant articles were reviewed. RESULTS:The etiologies of the three PFIC types still include unknown mechanisms.Especially in PFIC type 1,enterohepatic circulation of bile acid should be considered.Ursodeoxycholic acid,partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course. CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear,detailed studies are urgently required. Strategies for more advanced therapies are also needed.These developments in the future are indispensable,especially for PFIC type 1 patients.展开更多
Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history ...Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history of acute hepatitis at age 9 years was found to have jaundice during pregnancy in 2008, and was diagnosed as having intrahepatic cholestasis of pregnancy. In 2009, she underwent cholecystectomy for gallstones and chronic cholecystitis. However, itching and jaundice did not resolve postoperatively. She was admitted to our hospital with fatigue, jaundice, and a recently elevated γ-glutamyl transpeptidase level. Liver biopsy led to the diagnosis of biliary cirrhosis with ductopenia. Genetic testing revealed a pathogenic heterozygous mutation, ex13 c.1531G > A (p.A511 T), in the ABCB4 gene. Her father did not carry the mutation, but her mother's brother carried the heterozygous mutation. We made a definitivediagnosis of familial intrahepatic cholestasis type 3. He symptoms and liver function improved after 3 mo o treatment with ursodeoxycholic acid.展开更多
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...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.展开更多
Baicalin is one of the main active ingredients of choleretic traditional Chinese medicine drug Radix Scutellariae.The aim of this study was to explore the pharmacokinetic characteristics of baicalin in rats with 17α-...Baicalin is one of the main active ingredients of choleretic traditional Chinese medicine drug Radix Scutellariae.The aim of this study was to explore the pharmacokinetic characteristics of baicalin in rats with 17α-ethynylestradiol（EE）-induced intrahepatic cholestasis（IC） based on its choleretic effects.Firstly,rats were subcutaneously injected with EE solution（5 mg/kg,0.25 m L/100 g） for 5 consecutive days to construct an IC model.Then the bile excretion rate,serum levels of alanine aminotransferase（ALT）,aspartate aminotransferase（AST）,alkaline phosphatase（ALP） and total bile acid（TBA） and pathological changes of the liver were detected.Secondly,after successfully modeling,the rats were intragastrically given baicalin solution（200 mg/kg）（n=6）.Blood samples were collected from the tail vein at different time points after intragastric administration.The protective effects of low-（50 mg/kg）,medium-（100 mg/kg） and high-dose（200 mg/kg） baicalin on the liver in IC rats were evaluated.The content of baicalin in plasma was detected by liquid chromatography-mass spectrometry/mass spectrometry and pharmacokinetics parameters were calculated.Pharmacodynamic results showed that low-,medium-and high-dose baicalin all significantly increased the average excretion rate of bile（P〈0.05）,and significantly decreased serum levels of ALT,AST and ALP and TBA（P〈0.05）.Meanwhile,HE staining showed that baicalin significantly relieved EEinduced hepatocyte edema and necrosis.Pharmacokinetic results exhibited that the absorption of baicalin in both IC and normal control rats showed bimodal phenomenon.Cmax,AUC（0-t） and AUC（0-∞） of baicalin in IC rats were significantly higher than those of the normal control group（P〈0.01）.T1/2 of plasma baicalin in the model group was significantly extended to（11.09±1.84） h,with clearance dropping to 61.78% of that of the normal control group（P〈0.01）.The above results suggested that baicalin had protective effects on the liver of IC rats,accompanied by significantly increased in vivo exposure,delayed in vivo clearance and markedly alterative pharmacokinetic characteristics.This study provides a theoretical basis for further development of baicalin as a feasible drug for treating IC.Key words展开更多
BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have bee...BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.展开更多
Progressive familial intrahepatic cholestasis(PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile ...Progressive familial intrahepatic cholestasis(PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.展开更多
BACKGROUND Intrahepatic cholestasis in pregnancy(ICP)is the most common liver disease during pregnancy,and its exact etiology and course of progression are still poorly understood.AIM To investigate the link between t...BACKGROUND Intrahepatic cholestasis in pregnancy(ICP)is the most common liver disease during pregnancy,and its exact etiology and course of progression are still poorly understood.AIM To investigate the link between the gut microbiota and serum metabolome in ICP patients.METHODS In this study,a total of 30 patients were recruited,including 15 patients with ICP(disease group)and 15 healthy pregnant patients(healthy group).The serum nontarget metabolomes from both groups were determined.Amplification of the 16S rRNA V3-V4 region was performed using fecal samples from the disease and healthy groups.By comparing the differences in the microbiota and metabolite compositions between the two groups,the relationship between the gut microbiota and serum metabolites was also investigated.RESULTS The Kyoto Encyclopedia of Genes and Genomes analysis results showed that the primary bile acid biosynthesis,bile secretion and taurine and hypotaurine metabolism pathways were enriched in the ICP patients compared with the healthy controls.In addition,some pathways related to protein metabolism were also enriched in the ICP patients.The principal coordination analysis results showed that there was a distinct difference in the gut microbiota composition(beta diversity)between the ICP patients and healthy controls.At the phylum level,we observed that the relative abundance of Firmicutes was higher in the healthy group,while Bacteroidetes were enriched in the disease group.At the genus level,most of the bacteria depleted in ICP are able to produce short-chain fatty acids(e.g.,Faecalibacterium,Blautia and Eubacterium hallii),while the bacteria enriched in ICP are associated with bile acid metabolism(e.g.,Parabacteroides and Bilophila).Our results also showed that specific genera were associated with the serum metabolome.CONCLUSION Our study showed that the serum metabolome was altered in ICP patients compared to healthy controls,with significant differences in the bile,taurine and hypotaurine metabolite pathways.Alterations in the metabolization of these pathways may lead to disturbances in the gut microbiota,which may further affect the course of progression of ICP.展开更多
BACKGROUND Segmental intrahepatic cholestasis caused by transjugular intrahepatic portosystemic shunt(TIPS)(SIC-T),is a rare complication of this technique and only referred by case reports.Thus,we conducted a systema...BACKGROUND Segmental intrahepatic cholestasis caused by transjugular intrahepatic portosystemic shunt(TIPS)(SIC-T),is a rare complication of this technique and only referred by case reports.Thus,we conducted a systematic,retrospective analysis to provide evidence regarding prevalence and consequences of this TIPS-induced bile duct compression.AIM To assess prevalence and outcome of SIC-T in a large TIPS-cohort.METHODS In this retrospective cohort study,we screened the institutional databases for all consecutive patients that were treated by TIPS-placement or TIPS-revision between January 2005 and August 2013.We analyzed radiologic images for signs of biliary congestion.Cases that were indicative of SIC-T were reviewed by two independent radiologists and additional patient data was collected.Descriptive statistics of patient demographics,indications for TIPS and procedural details were registered.Logistic regression analysis was performed to identify predictors for the development of SIC-T.RESULTS We analyzed 135 cirrhotic patients who underwent TIPS(mean age 55 years,79%male gender).Etiology of cirrhosis was alcohol in most cases and indications for TIPS were mainly refractory ascites and recurrent variceal bleeding.TIPS revision was necessary in 31 patients.We identified 4 cases(2.9%)of SIC-T in direct proximity of the TIPS-stent.Diagnosis was confirmed by CT-scan,MRI or endoscopic retrograde cholangio pancreaticography(ERCP).In two patients TIPS was implanted via the right and in one through the medial hepatic vein.One patient received TIPS-prolongation by multiple revisions.Most patients were asymptomatic but one cholangitic abscess necessitated a transhepatic drain.Logistic regression analysis identified TIPS-placement other than from medial hepatic vein to right portal vein as risk factor(OR 21.0)for SIC-T.CONCLUSION SIC-T ads to(mostly late)complications in the interventional treatment of cirrhotic portal hypertensions and can lead to cholangitic abscesses.Patients,particularly with multiple interventions,should be screened for SIC-T.展开更多
Intrahepatic cholestasis occurs commonly after liver transplantation and may be caused by infections, drugs, and acute or chronic rejection. Some disor- ders may be managed medically, but others often re- quire re-tra...Intrahepatic cholestasis occurs commonly after liver transplantation and may be caused by infections, drugs, and acute or chronic rejection. Some disor- ders may be managed medically, but others often re- quire re-transplantation. Prompt recognition and specific treatment can improve the outcome of liver recipients.展开更多
BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has...BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.展开更多
文摘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.
基金Supported by The Medical and Health Research Project of Zhejiang Province,No.2023KY1105the Traditional Chinese Medical and Health Research Project of Zhejiang Province,No.2022ZB328.
文摘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.
文摘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.
文摘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.
文摘Intrahepatic cholestasis of pregnancy(ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries(9.2%-15.6% and 1.5%, respectively) than in Europe(0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue.
基金Supported by National Natural Science Foundation of China, No. 30973230 and No. 81070281
文摘AIM: To investigate the differences in the mutation spectra of the SLC25A13 gene mutations from specific regions of China. METHODS: Genetic analyses of SLC25A13 mutations were performed in 535 patients with neonatal intrahepatic cholestasis from our center over eight years. Unrelated infants with at least one mutant allele were enrolled to calculate the proportion of SLC25A13 mutations in different regions of China. The boundary between northern and southern China was drawn at the historical border of the Yangtze River.RESULTS: A total of 63 unrelated patients (about 11% of cases with intrahepatic cholestasis) from 16 provinces or municipalities in China had mutations in the SLC25A13 gene, of these 16 (25%) were homozygotes, 28 (44%) were compound heterozygotes and 19 (30%) were heterozygotes. In addition to four well described common mutations (c.851_854del, c.1638_1660dup23, c.615+5G>A and c.1750+72_17514dup17insNM_138459.3:2667 also known as IVS16ins3kb), 13 other mutation types were identified, including three novel mutations: c.985_986insT, c.287T>C and c.1349A>G. According to the geographical division criteria, 60 mutant alleles were identified in patients from the southern areas of China, 43 alleles were identified in patients from the border, and 4 alleles were identified in patients from the northern areas of China. The proportion of four common mutations was higher in south region (56/60, 93%) than that in the border region (34/43, 79%, χ 2 = 4.621, P = 0.032) and the northern region (2/4, 50%, χ 2 = 8.288, P = 0.041). CONCLUSION: The SLC25A13 mutation spectra among the three regions of China were different, providing a basis for the improvement of diagnostic strategies and interpretation of genetic diagnosis.
文摘BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes,resulting in a hepatocellular form of cholestasis.While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause,recent scientific advancements have uncovered multiple specific responsible proteins.The variety of identified defects has resulted in an ever-broadening phenotypic spectrum,ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.AIM To review current data on defects in bile acid homeostasis,explore the expanding knowledge base of genetic based diseases in this field,and report disease characteristics and management.METHODS We conducted a systemic review according to PRISMA guidelines.We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding,diagnosis,and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC.English only articles were accessed in full.The manual search included references of retrieved articles.We extracted data on disease characteristics,associations with other diseases,and treatment.Data was summarized and presented in text,figure,and table format.RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults.A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1(ATP8B1),BSEP(ABCB11),and MDR3(ABCB4)transporter deficiencies,as well as more recently described gene mutations--TJP2(TJP2),FXR(NR1H4),MYO5B(MYO5B),and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.
基金Supported by National Natural Science Foundation of China,No 30672257 and No 30973230Shanghai Public Health Key Subject Construction,No 08GWZX0102
文摘AIM:To establish the real time fluorescence polymerase chain reaction(RT-PCR) with dual labeled probes for fast detection of SLC25A13 gene mutation 851del4.METHODS:Four hundred infants(< 1 year of age) with unexplained intrahepatic cholestasis from 18 provinces or municipalities in China were enrolled in this study for detecting their SLC25A13 gene mutation 851del4.Suitable primers and fluorescence-labeled probes for detecting SLC25A13 gene mutation 841del4 were designed.Normal and mutant sequences were detected by PCR with two fluorescence-labeled probes.After a single RT-PCR,results were obtained by analyzing the take-off curves.Twenty-four positive and 14 negative samples were retested by direct sequencing.RESULTS:Eight homozygous and 30 heterozygous mutations were detected in 46 mutant alleles with a 851del4 mutation rate of 5.8%(46/800).Twenty-six and 20 mutant alleles were observed respectively,in 474 and 242 alleles from the intermediate and southern areas of China.No mutant allele was detected in 84 alleles from northern China.Twenty-four positive samples including 4 homozygous and 20 heterozygous mutations,and 14 negative samples were retested by direct sequencing,which confirmed that the accuracy of RTPCR was 100%.CONCLUSION:RT-PCR can detect the mutation 851del4 in infants with intrahepatic cholestasis with an accuracy of 100%.
基金a Grant from the Science Foundation of Kaunas University of Medicine and by Dr.Falk Pharma GmbH,Freiburg,Germany
文摘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.
基金Supported by NIH,No.UG3TR003289 to Soto-Gutierrez A.
文摘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.
文摘BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on'progressive familial intrahepatic cholestasis'and'PFIC'was performed on the topic,and the relevant articles were reviewed. RESULTS:The etiologies of the three PFIC types still include unknown mechanisms.Especially in PFIC type 1,enterohepatic circulation of bile acid should be considered.Ursodeoxycholic acid,partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course. CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear,detailed studies are urgently required. Strategies for more advanced therapies are also needed.These developments in the future are indispensable,especially for PFIC type 1 patients.
文摘Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history of acute hepatitis at age 9 years was found to have jaundice during pregnancy in 2008, and was diagnosed as having intrahepatic cholestasis of pregnancy. In 2009, she underwent cholecystectomy for gallstones and chronic cholecystitis. However, itching and jaundice did not resolve postoperatively. She was admitted to our hospital with fatigue, jaundice, and a recently elevated γ-glutamyl transpeptidase level. Liver biopsy led to the diagnosis of biliary cirrhosis with ductopenia. Genetic testing revealed a pathogenic heterozygous mutation, ex13 c.1531G > A (p.A511 T), in the ABCB4 gene. Her father did not carry the mutation, but her mother's brother carried the heterozygous mutation. We made a definitivediagnosis of familial intrahepatic cholestasis type 3. He symptoms and liver function improved after 3 mo o treatment with ursodeoxycholic acid.
基金supported by grants from the National Natural Science Foundation of China (Nos. 30973205,81172464)
文摘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.
基金supported by the National Natural Science Foundation of China(No.81573788 and No.81670521)
文摘Baicalin is one of the main active ingredients of choleretic traditional Chinese medicine drug Radix Scutellariae.The aim of this study was to explore the pharmacokinetic characteristics of baicalin in rats with 17α-ethynylestradiol（EE）-induced intrahepatic cholestasis（IC） based on its choleretic effects.Firstly,rats were subcutaneously injected with EE solution（5 mg/kg,0.25 m L/100 g） for 5 consecutive days to construct an IC model.Then the bile excretion rate,serum levels of alanine aminotransferase（ALT）,aspartate aminotransferase（AST）,alkaline phosphatase（ALP） and total bile acid（TBA） and pathological changes of the liver were detected.Secondly,after successfully modeling,the rats were intragastrically given baicalin solution（200 mg/kg）（n=6）.Blood samples were collected from the tail vein at different time points after intragastric administration.The protective effects of low-（50 mg/kg）,medium-（100 mg/kg） and high-dose（200 mg/kg） baicalin on the liver in IC rats were evaluated.The content of baicalin in plasma was detected by liquid chromatography-mass spectrometry/mass spectrometry and pharmacokinetics parameters were calculated.Pharmacodynamic results showed that low-,medium-and high-dose baicalin all significantly increased the average excretion rate of bile（P〈0.05）,and significantly decreased serum levels of ALT,AST and ALP and TBA（P〈0.05）.Meanwhile,HE staining showed that baicalin significantly relieved EEinduced hepatocyte edema and necrosis.Pharmacokinetic results exhibited that the absorption of baicalin in both IC and normal control rats showed bimodal phenomenon.Cmax,AUC（0-t） and AUC（0-∞） of baicalin in IC rats were significantly higher than those of the normal control group（P〈0.01）.T1/2 of plasma baicalin in the model group was significantly extended to（11.09±1.84） h,with clearance dropping to 61.78% of that of the normal control group（P〈0.01）.The above results suggested that baicalin had protective effects on the liver of IC rats,accompanied by significantly increased in vivo exposure,delayed in vivo clearance and markedly alterative pharmacokinetic characteristics.This study provides a theoretical basis for further development of baicalin as a feasible drug for treating IC.Key words
基金Supported by Sanming Project of Medicine in Shenzhen of China,No.SZSM201612074
文摘BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.
文摘Progressive familial intrahepatic cholestasis(PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.
基金Supported by the Technology Project of Shanghai Pudong New District Health and Family Planning Commission,No.PW2019D-9.
文摘BACKGROUND Intrahepatic cholestasis in pregnancy(ICP)is the most common liver disease during pregnancy,and its exact etiology and course of progression are still poorly understood.AIM To investigate the link between the gut microbiota and serum metabolome in ICP patients.METHODS In this study,a total of 30 patients were recruited,including 15 patients with ICP(disease group)and 15 healthy pregnant patients(healthy group).The serum nontarget metabolomes from both groups were determined.Amplification of the 16S rRNA V3-V4 region was performed using fecal samples from the disease and healthy groups.By comparing the differences in the microbiota and metabolite compositions between the two groups,the relationship between the gut microbiota and serum metabolites was also investigated.RESULTS The Kyoto Encyclopedia of Genes and Genomes analysis results showed that the primary bile acid biosynthesis,bile secretion and taurine and hypotaurine metabolism pathways were enriched in the ICP patients compared with the healthy controls.In addition,some pathways related to protein metabolism were also enriched in the ICP patients.The principal coordination analysis results showed that there was a distinct difference in the gut microbiota composition(beta diversity)between the ICP patients and healthy controls.At the phylum level,we observed that the relative abundance of Firmicutes was higher in the healthy group,while Bacteroidetes were enriched in the disease group.At the genus level,most of the bacteria depleted in ICP are able to produce short-chain fatty acids(e.g.,Faecalibacterium,Blautia and Eubacterium hallii),while the bacteria enriched in ICP are associated with bile acid metabolism(e.g.,Parabacteroides and Bilophila).Our results also showed that specific genera were associated with the serum metabolome.CONCLUSION Our study showed that the serum metabolome was altered in ICP patients compared to healthy controls,with significant differences in the bile,taurine and hypotaurine metabolite pathways.Alterations in the metabolization of these pathways may lead to disturbances in the gut microbiota,which may further affect the course of progression of ICP.
文摘BACKGROUND Segmental intrahepatic cholestasis caused by transjugular intrahepatic portosystemic shunt(TIPS)(SIC-T),is a rare complication of this technique and only referred by case reports.Thus,we conducted a systematic,retrospective analysis to provide evidence regarding prevalence and consequences of this TIPS-induced bile duct compression.AIM To assess prevalence and outcome of SIC-T in a large TIPS-cohort.METHODS In this retrospective cohort study,we screened the institutional databases for all consecutive patients that were treated by TIPS-placement or TIPS-revision between January 2005 and August 2013.We analyzed radiologic images for signs of biliary congestion.Cases that were indicative of SIC-T were reviewed by two independent radiologists and additional patient data was collected.Descriptive statistics of patient demographics,indications for TIPS and procedural details were registered.Logistic regression analysis was performed to identify predictors for the development of SIC-T.RESULTS We analyzed 135 cirrhotic patients who underwent TIPS(mean age 55 years,79%male gender).Etiology of cirrhosis was alcohol in most cases and indications for TIPS were mainly refractory ascites and recurrent variceal bleeding.TIPS revision was necessary in 31 patients.We identified 4 cases(2.9%)of SIC-T in direct proximity of the TIPS-stent.Diagnosis was confirmed by CT-scan,MRI or endoscopic retrograde cholangio pancreaticography(ERCP).In two patients TIPS was implanted via the right and in one through the medial hepatic vein.One patient received TIPS-prolongation by multiple revisions.Most patients were asymptomatic but one cholangitic abscess necessitated a transhepatic drain.Logistic regression analysis identified TIPS-placement other than from medial hepatic vein to right portal vein as risk factor(OR 21.0)for SIC-T.CONCLUSION SIC-T ads to(mostly late)complications in the interventional treatment of cirrhotic portal hypertensions and can lead to cholangitic abscesses.Patients,particularly with multiple interventions,should be screened for SIC-T.
文摘Intrahepatic cholestasis occurs commonly after liver transplantation and may be caused by infections, drugs, and acute or chronic rejection. Some disor- ders may be managed medically, but others often re- quire re-transplantation. Prompt recognition and specific treatment can improve the outcome of liver recipients.
文摘BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.
