BACKGROUND Benign recurrent intrahepatic cholestasis(BRIC)is a rare autosomal recessive liver disease,causing episodic cholestasis with intense pruritus.This case report highlights the effectiveness of early plasmaphe...BACKGROUND Benign recurrent intrahepatic cholestasis(BRIC)is a rare autosomal recessive liver disease,causing episodic cholestasis with intense pruritus.This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2,offering rapid symptom relief and early termination of cholestatic episodes.It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies.CASE SUMMARY A 43-year-old male with BRIC type 2 presented with fatigue,jaundice,and severe pruritus,triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection.Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase.First-line pharmacological treatments,including cholestyramine and rifampicin,failed.Endoscopic nasobiliary drainage was ineffective,prompting initiation of plasmapheresis.This intervention rapidly relieved pruritus,with complete biochemical normalisation after 11 sessions.Two years later,a similar episode occurred,and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks.The patient tolerated the procedure well,with no adverse effects observed.Follow-up showed no signs of cholestasis recurrence.CONCLUSION Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2,particularly when initiated early in cholestasis.展开更多
BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pat...BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pathogenicity and mechanism of ABCB4 variants in clinical and in vitro trials,hypothesizing that these variants are responsible for impaired biliary function and contribute to the development of cholestatic liver diseases.AIM To clarify the functional features and pathogenicity of ABCB4 variants.METHODS Clinical data were collected from five patients with cholestatic liver disease that was initially not detected by routine examinations.Later,whole-exome sequencing confirmed ABCB4 variants and the patients were treated from January 2017 to December 2023.Pathogenic mechanisms were analyzed using bioinformatics tools,and a cell model in vitro was established to investigate ABCB4 mRNA expression,multidrug resistance protein 3(MDR3)expression,cellular localization,and phosphatidylcholine secretion.Results were compared using Student's t-tests.RESULTS Five missense variants(c.1757T>A,c.1865G>A,c.2362C>T,c.2777C>T and c.3250C>T),one intron variant(c.537-32G>T),and one synonymous(c.C504T)variant were identified.Three of the five patients had various degrees of cholestasis,two presented with liver cirrhosis,and all had elevated gamma-glutamyl transferase.Three of the four patients who underwent a liver biopsy had bile duct dilation,and one had gallstones.Two of the four patients had normal and reduced MDR3 immunohistochemical levels.Bioinformatic analysis indicated that these variants were likely pathogenic except c.C504T variant.None of the missense variants influenced subcellular MDR3 Localization in vitro.However,the c.1865G>A variant significantly decreased ABCB4 mRNA values,and all missense variants down-regulated phosphatidylcholine secretion.CONCLUSION This study uncovered new ABCB4 variants and emphasized the pathogenic potential of specific variants.The findings from five patients provided insight into the pathogenic mechanisms underlying ABCB4-related diseases.展开更多
BACKGROUND Genetic disorders affecting hepatobiliary transporters can be triggered by various factors,resulting in marked cholestasis.CASE SUMMARY We report two patients who experienced a severe episode of intrahepati...BACKGROUND Genetic disorders affecting hepatobiliary transporters can be triggered by various factors,resulting in marked cholestasis.CASE SUMMARY We report two patients who experienced a severe episode of intrahepatic cholestasis triggered by an acute hepatitis E virus infection.Following an extensive clinical examination that ruled out common causes of cholestatic liver damage,we conducted next-generation sequencing to determine the genetic profiles of the patients.The analysis revealed several known and unknown variants in genes associated with hepatobiliary transporters and bile salt regulation,including ATP8B1,ABCB11,ABCB4,MYO5B,and FXR.For a comprehensive understanding of the pathophysiology,we performed ClinVar analysis and utilized PolyPhen for bioinformatic prediction of functional impact.Both patients exhibited rapid symptom improvement and a decrease in hyperbilirubinemia when treated with either rifampicin or bezafibrate.CONCLUSION Our findings introduce hepatitis E viral infection as a novel trigger for intrahepatic cholestasis,and we categorize the significance of the various genetic variants based on the current state of research.展开更多
Hepatitis E virus(HEV)infection causes acute hepatitis,chronic hepatitis,particularly in compromised hosts,and various extrahepatic manifestations.HEV infection is reportedly associated with biliary-pancreatic disease...Hepatitis E virus(HEV)infection causes acute hepatitis,chronic hepatitis,particularly in compromised hosts,and various extrahepatic manifestations.HEV infection is reportedly associated with biliary-pancreatic diseases,such as gallstones,cholangitis,choledocholithiasis,and acute pancreatitis.Severe jaundice and prolonged cholestasis are also atypical manifestations of HEV infection.The mechanism and genes involved in cholestasis,namely sinusoidal uptake of blood,bile salt synthesis and secretion from hepatocytes to the canaliculus,have been elucidated.HEV infection triggers severe jaundice and prolonged cholestasis in patients with genetic variants in adenosine triphosphatase phospholipid transporting 8B1,adenosine triphosphate-binding cassette(ABC)protein B4,ABCB11,Myosin VB,and/or farnesoid X receptor(FXR/NR1H4).Although prolonged cholestasis associated with these gene mutations does not seem to be specific to HEV infection,these mutations may be risk factors related to the severity of HEV infection.The use of the pregnane X receptor agonist rifampicin and the peroxisome proliferator-activated receptor activator bezafibrate may be useful for the treatment of cholestasis.These studies provide new insights into under-standing the mechanisms of severe jaundice and prolonged cholestasis caused by HEV infection.展开更多
BACKGROUND Progressive familial intrahepatic cholestasis type 1(PFIC-1)is a genetic cholestatic disease causing end-stage liver disease,which needs liver transplantation(LT).Simultaneous biliary diversion(BD)was recom...BACKGROUND Progressive familial intrahepatic cholestasis type 1(PFIC-1)is a genetic cholestatic disease causing end-stage liver disease,which needs liver transplantation(LT).Simultaneous biliary diversion(BD)was recommended to prevent allograft steatosis after transplantation,while increasing the risk of infection.Here,an attempt was made to perform BD using appendix to prevent bacterial translocation after LT.CASE SUMMARY An 11-month-old boy diagnosed with PFIC-1 received ABO compatible living donor LT due to refractory jaundice and pruritus.His mother donated her left lateral segment with a graft-to-recipient weight ratio of 2.9%.Internal BD was constructed during LT using the appendix by connecting its proximal end with the intrahepatic biliary duct and the distal end with colon.Biliary leakage was suspected on the 5th day after transplantation and exploratory laparotomy indicated biliary leakage at the cutting surface of liver.The liver function returned to normal on the 9th day post-operation and maintained normal during the 15-month follow-up.Cholangiography at 10 months after transplantation confirmed the direct secretion of bile into colon.Computerized tomography scan(4 months and 10 months)and liver biopsy(10 months)indicated no steatosis in the allograft.No complaint of recurrent diarrhea,infection or growth retardation was reported during follow-up.CONCLUSION Internal BD using appendix during LT is effective in preventing allograft steatosis and post-transplant infection in PFIC-1 recipients.展开更多
Progressive familial intrahepatic cholestasis(PFIC)is a group of rare,inherited cholestatic liver disorders presenting in infants and children and are associated with impaired bile flow(i.e.,cholestasis),pruritus and ...Progressive familial intrahepatic cholestasis(PFIC)is a group of rare,inherited cholestatic liver disorders presenting in infants and children and are associated with impaired bile flow(i.e.,cholestasis),pruritus and progressive liver disease.Historically there has been no effective or approved pharmacologic treatments for these disorders and standard medical treatment has only been supportive.The impaired bile flow within the liver,leads to accumulation in the liver and inflammation.Historically there has been no effective or approved pharmacologic treatments for these disorders and standard medical treatment has only been supportive.A potential for reducing pathologic bile accumulation in the liver is surgical biliary diversion,with an aim to interrupt the enterohepatic circulation.These procedures have demonstrated a positive effect in PFIC by normalizing serum bile acids,reducing pruritus and liver injury and improving the patient quality of life.Nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter(IBAT).IBAT inhibition has demonstrated efficacy in reducing serum bile acids and pruritus.We aim to present the 13 types of PFIC and the current evidence on the use of IBAT inhibitors in treating children with PFIC.展开更多
[Objectives]To explore the target and mechanism of Schaftoside on cholestasis and steatosis based on network pharmacology and molecular docking.[Methods]The targets of"cholestasis"and"steatosis"wer...[Objectives]To explore the target and mechanism of Schaftoside on cholestasis and steatosis based on network pharmacology and molecular docking.[Methods]The targets of"cholestasis"and"steatosis"were predicted using databases(OMIM and GeneCards),and the key targets were obtained after screening the retrieval data.The binding relationship between Schaftoside and key targets was analyzed by molecular docking.[Results]There were 3370 and 4433 targets for"cholestasis"and"steatosis",respectively,and 1767 overlapping genes were obtained.The results of molecular docking showed that Schaftoside had high binding energy with key targets.[Conclusions]Schaftoside can alleviate cholestasis and steatosis by regulating SREBP-1,CYP7,PPAR-gamma and other key targets to protect liver.展开更多
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 Paracoccidioidomycosis(PCM)may involve the hepatic pedicle and peripan creatic lymph nodes,cause damage to the bile duct and manifest,exceptionally,in combination with extrahepatic cholestasis(EHC),making i...BACKGROUND Paracoccidioidomycosis(PCM)may involve the hepatic pedicle and peripan creatic lymph nodes,cause damage to the bile duct and manifest,exceptionally,in combination with extrahepatic cholestasis(EHC),making investigation and treatment challenging.AIM To investigate the management of patients with visceral PCM admitted with EHC.METHODS All patients diagnosed with PCM treated in a public,tertiary teaching hospital between 1982 and 2020 were retrospectively evaluated.Those also identified with EHC were allocated to two groups according to the treatment approach for the purpose of comparing clinical,laboratory,and imaging findings,resources used for etiological diagnosis,treatment results,and prognosis.Statistical analyses were performed using the linear mixed-effects model(random and fixed effects),which was adjusted using the PROC MIXED procedure of the SAS®9.0 software,and Fisher’s exact test.RESULTS Of 1645 patients diagnosed with PCM,40(2.4%)had EHC.Of these,20(50.0%)lived in the rural area and 29(72.5%)were men,with a mean age of 27.1 years(3-65 years).Jaundice as first symptom and weight loss of at least 10 kg were observed in 16 patients(40.0%),and a mass in the head of the pancreas was observed in 8(20.0%).The etiological diagnosis was made by tissue collection during surgery in 4 cases(10.0%)and by endoscopic methods in 3 cases(7.5%).Twenty-seven patients(67.5%)received drug treatment alone(Group 1),whereas 13(32.5%)underwent endoscopic and/or surgical procedures in combination with drug treatment(Group 2).EHC was significantly reduced in both groups(40.7% in Group 1,with a mean time of 3 months;and 38.4% in Group 2,with a mean time of 7.5 months),with no statistically significant difference between them.EHC recurrence rates,associated mainly with treatment nonadherence,were similar in both groups:37% in Group 1 and 15.4% in Group 2.The mortality rate was 18.5% in Group 1 and 23% in Group 2,with survival estimates of 71.3% and 72.5%,respectively,with no statistically significant difference.CONCLUSION Although PCM-related EHC is rare,it needs to be included in the differential diagnosis of malignancies,as timely treatment can prevent hepatic and extrahepatic sequelae.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
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
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while bili...Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.展开更多
AIM:To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies. METHODS:Patients under 6 mo of age who were referred for ...AIM:To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies. METHODS:Patients under 6 mo of age who were referred for investigation of conjugated hyperbiliru-binaemia from June 2003 to December 2010 were eligible for this study. After excluding diseases affecting the extrahepatic biliary system, all patients were screened for the two most common SLC25A13 mutations; the coding exons of the entire SLC25A13 gene was sequenced and Western blotting of citrin protein performed in selected cases. Patients in whom homo-zygous or compound heterozygous SLC25A13 mutation and/or absence of normal citrin protein was detected were defined as having NICCD. Cases in which no specific etiological factor could be ascertained after a com-prehensive conjugated hyperbilirubinaemia work-up were defined as idiopathic neonatal cholestasis (INC). Thirty-two NICCD patients, 250 INC patients, and 39 infants with cholangiography-confirmed biliary atresia (BA) were enrolled. Laboratory values at their first visit were abstracted from medical files and compared. RESULTS:Compared with BA and INC patients, the NICCD patients had significantly higher levels of total bile acid (TBA) [all measures are expressed as median (inter-quartile range):178.0 (111.2-236.4) μmol/L in NICCD vs 112.0 (84.9-153.9) μmol/L in BA and 103.0 (70.9-135.3) μmol/L in INC, P = 0.0001]. The NICCD patients had significantly lower direct bilirubin [D-Bil 59.6 (43.1-90.9) μmol/L in NICCD vs 134.0 (115.9-151.2) μmol/L in BA and 87.3 (63.0-123.6) μmol/L in INC, P = 0.0001]; alanine aminotransferase [ALT 34.0 (23.0-55.0) U/L in NICCD vs 108.0 (62.0-199.0) U/L in BA and 84.5 (46.0-166.0) U/L in INC, P = 0.0001]; aspartate aminotransferase [AST 74.0 (53.5-150.0) U/L in NICCD vs 153.0 (115.0-239.0) U/L in BA and 130.5 (81.0-223.0) U/L in INC, P = 0.0006]; albumin [34.9 (30.7-38.2) g/L in NICCD vs 38.4 (36.3-42.2) g/L in BA and 39.9 (37.0-42.3) g/L in INC, P = 0.0001]; glucose [3.2 (2.0-4.4) mmol/L in NICCD vs 4.1 (3.4-5.1) mmol/L in BA and 4.0 (3.4-4.6) mmol/L in INC, P = 0.0014] and total cholesterol [TCH 3.33 (2.97-4.00) mmol/L in N ICCD vs 4.57 (3.81-5.26) mmol/L in BA and 4.00 (3.24-4.74) mmol/L in INC, P = 0.0155] levels. The D-Bil to total bilirubin (T-Bil) ratio was significantly lower in NICCD patients [all measures are expressed as median (inter-quartile range):0.54 (0.40-0.74)] than that in BA patients [0.77 (0.72-0.81), P = 0.001] and that in INC patients [0.74 (0.59-0.80), P = 0.0045]. A much higher AST/ALT ratio was found in NICCD patients [2.46 (1.95-3.63)] compared to BA patients [1.38 (0.94-1.97), P = 0.0001] and INC patients [1.48 (1.10-2.26), P = 0.0001]. NICCD patients had significantly higher TBA/D-Bil ratio [3.36 (1.98-4.43) vs 0.85 (0.72-1.09) in BA patients and 1.04 (0.92-1.14) in INC patients, P = 0.0001], and TBA/TCH ratio [60.7 (32.4-70.9) vs 24.7 (19.8-30.2) in BA patients and 24.2 (21.4-26.9) in INC patients, P = 0.0001] compared to the BA and INC groups. CONCLUSION:NICCD has significantly different bio- chemical indices from BA or INC. TBA excretion in NICCD appeared to be more severely disturbed than that of bilirubin and cholesterol.展开更多
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 con...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.展开更多
The different methods in differentiating biliary atresia(BA)from non-BA-related cholestasis were evaluated in order to provide a practical basis for a rapid,early and accurate differential diagnosis of the diseases.39...The different methods in differentiating biliary atresia(BA)from non-BA-related cholestasis were evaluated in order to provide a practical basis for a rapid,early and accurate differential diagnosis of the diseases.396 infants with cholestatic jaundice were studied prospectively during the period of May 2007 to June 2011.The liver function in all subjects was tested.All cases underwent abdominal ultrasonography and duodenal fluid examination.Most cases were subjected to hepatobiliary scintigraphy,magnetic resonance cholangiopancreatography(MRCP)and a percutaneous liver biopsy.The diagnosis of BA was finally made by cholangiography or histopathologic examination.The accuracy,sensitivity,specificity and predictive values of these various methods were compared.178 patients(108 males and 70 females with a mean age of 58±30 days)were diagnosed as having BA.218 patients(136 males and 82 females with a mean age of 61±24 days)were diagnosed as having non-BA etiologies of cholestasis jaundice during the follow-up period in which jaundice faded after treatment with medical therapy.For diagnosis of BA,clinical evaluation,hepatomegaly,stool color,serum gamma-glutamyltranspeptidase(GGT),duodenal juice color,bile acid in duodenal juice,ultrasonography(gallbladder),ultrasonography(griangular cord or strip-apparent hyperechoic foci),hepatobiliary scintigraphy,MRCP,liver biopsy had an accuracy of 76.0%,51.8%,84.3%,70.0%,92.4%,98.0%,90.4%,67.2%,85.3%,83.2%and 96.6%,a sensitivity of 83.1%,87.6%,96.1%,73.7%,90.4%,100%,92.7%,27.5%,100%,89.0%and 97.4%,a specificity of 70.2%,77.5%,74.8%,67.0%,94.0%,96.3%,88.5%,99.5%,73.3%,75.4%and 94.3%,a positive predictive value of 69.0%,72.6%,75.7%,64.6%,92.5%,95.7%,86.8%,98.0%,75.4%,82.6%and 98.0%,and a negative predictive value of 83.6%,8.5%,95.9%,75.7%,92.3%,100%,84.2%,93.7%,100%,84.0%and 92.6%,respectively.It was concluded that all the differential diagnosis methods are useful.The test for duodenal drainage and elements is fast and accurate.It is helpful in the differential diagnosis of BA and non-BA etiologies of cholestasis.It shows good practical value clinically.展开更多
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account...Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T > A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found.展开更多
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family ...Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family with ARC syndrome. All 23 coding exons and flanking introns of the VPS33B gene were amplified and sequenced using peripheral lymphocyte genomic DNA of the patient and her parents. Genetic testing revealed two novel mutations (c.1033delA and c.1567C>T) in the VPS33B gene. The patient is a compound heterozygote and her parents were heterozygous for each of the mutations.展开更多
Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation inATP8B1.We present a 23-year-old male who experienced persistent...Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation inATP8B1.We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years,in addition to cholestasis that eventually became fatal.Genetic sequencing studies of the entire coding(exon) sequences of ATP8B1 and ABCB11 uncovered a novel heterozygous missense 3035G>T mutation(S1012I) and a synonymous 696T>C mutation in ATP8B1.The patient's progression was associated with not only impaired familial intrahepatic cholestasis 1(FIC1) function but also impaired bile salt export pump expression due to the impaired FIC1 function.Our findings show that patients with intermittent cholestasis can develop progressive liver disease even after several decades and require regular follow up.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
To analyze time intervals of inflammation and regeneration in a cholestatic rat liver model.METHODSIn 36 Lewis rats, divided into six groups of 6 animals (postoperative observation periods: 1, 2, 3, 4, 6, 8 wk), the m...To analyze time intervals of inflammation and regeneration in a cholestatic rat liver model.METHODSIn 36 Lewis rats, divided into six groups of 6 animals (postoperative observation periods: 1, 2, 3, 4, 6, 8 wk), the main bile duct was ligated with two ligatures and observed for the periods mentioned above. For laboratory evaluation, cholestasis parameters (bilirubin, γ-GT), liver cell parameters (ASAT, ALAT) and liver synthesis parameters (quick, albumin) were determined. For histological analysis, HE, EvG, ASDCL and HMGB-1 stainings were performed. Furthermore, we used the mRNA of IL-33, GADD45a and p-21 for analyzing cellular stress and regeneration in cholestatic rats.RESULTSIn chemical laboratory and histological evaluation, a distinction between acute and chronic cholestatic liver injury with identification of inflammation and regeneration could be demonstrated by an increase in cholestasis (bilirubin: 1-wk group, 156.83 ± 34.12 μmol/L, P = 0.004) and liver cell parameters (ASAT: 2-wk group, 2.1 ± 2.19 μmol/L.s, P = 0.03; ALAT: 2-wk group, 1.03 ± 0.38 μmol/L.s, P = 0.03) after bile duct ligation (BDL). Histological evaluation showed an increase of bile ducts per portal field (3-wk group, 48 ± 6.13, P = 0.004) during the first four weeks after bile duct ligation. In addition to inflammation, which is an expression of acute cholestasis, there was an increase of necrotic areas in the histological sections (2-wk group, 1.38% ± 2.28% per slide, P = 0.002). Furthermore, the inflammation could be verified by ASDCL (4-wk group, 22 ± 5.93 positive cells per portal field, P = 0.041) and HMGB-1 [2-wk group, 13 ± 8.18 positive cells per field of view (FoV), P = 0.065] staining. Therefore, in summary of the laboratory evaluation and histological studies, acute cholestasis could be found during the first four weeks after bile duct ligation. Subsequently, the described parameters declined so that chronic cholestasis could be assumed. For quantification of secondary biliary cirrhosis, eosin staining was performed, which did not reveal any signs of liver remodeling, thus precluding the development of a chronic cholestasis model. Additionally, to establish the chronic cholestasis model, we evaluated liver regeneration capacity through measurements of IL-33, p-21 and GADD45a mRNA.CONCLUSIONWe created a chronic cholestasis model. The point of inflammatory and regenerative balance was reached after four weeks. This finding should be used for experimental approaches dealing with chronic cholestatic liver damage.展开更多
文摘BACKGROUND Benign recurrent intrahepatic cholestasis(BRIC)is a rare autosomal recessive liver disease,causing episodic cholestasis with intense pruritus.This case report highlights the effectiveness of early plasmapheresis as a therapeutic option for BRIC type 2,offering rapid symptom relief and early termination of cholestatic episodes.It contributes to the limited evidence supporting plasmapheresis as a treatment for BRIC flares resistant to conventional therapies.CASE SUMMARY A 43-year-old male with BRIC type 2 presented with fatigue,jaundice,and severe pruritus,triggered by a recent mild severe acute respiratory syndrome coronavirus 2 infection.Laboratory results confirmed cholestasis with elevated bilirubin and alkaline phosphatase.First-line pharmacological treatments,including cholestyramine and rifampicin,failed.Endoscopic nasobiliary drainage was ineffective,prompting initiation of plasmapheresis.This intervention rapidly relieved pruritus,with complete biochemical normalisation after 11 sessions.Two years later,a similar episode occurred,and early reinitiation of plasmapheresis led to symptom resolution within two sessions and biochemical recovery within two weeks.The patient tolerated the procedure well,with no adverse effects observed.Follow-up showed no signs of cholestasis recurrence.CONCLUSION Plasmapheresis is a safe and effective option for therapy-refractory BRIC type 2,particularly when initiated early in cholestasis.
基金Supported by the National Natural Science Foundation of China,No.81970454.
文摘BACKGROUND ATP-binding cassette subfamily B member 4(ABCB4)deficiency is associated with cholestatic liver disease primarily because of missense mutations,and many variants remain unidentified.Here,we validate the pathogenicity and mechanism of ABCB4 variants in clinical and in vitro trials,hypothesizing that these variants are responsible for impaired biliary function and contribute to the development of cholestatic liver diseases.AIM To clarify the functional features and pathogenicity of ABCB4 variants.METHODS Clinical data were collected from five patients with cholestatic liver disease that was initially not detected by routine examinations.Later,whole-exome sequencing confirmed ABCB4 variants and the patients were treated from January 2017 to December 2023.Pathogenic mechanisms were analyzed using bioinformatics tools,and a cell model in vitro was established to investigate ABCB4 mRNA expression,multidrug resistance protein 3(MDR3)expression,cellular localization,and phosphatidylcholine secretion.Results were compared using Student's t-tests.RESULTS Five missense variants(c.1757T>A,c.1865G>A,c.2362C>T,c.2777C>T and c.3250C>T),one intron variant(c.537-32G>T),and one synonymous(c.C504T)variant were identified.Three of the five patients had various degrees of cholestasis,two presented with liver cirrhosis,and all had elevated gamma-glutamyl transferase.Three of the four patients who underwent a liver biopsy had bile duct dilation,and one had gallstones.Two of the four patients had normal and reduced MDR3 immunohistochemical levels.Bioinformatic analysis indicated that these variants were likely pathogenic except c.C504T variant.None of the missense variants influenced subcellular MDR3 Localization in vitro.However,the c.1865G>A variant significantly decreased ABCB4 mRNA values,and all missense variants down-regulated phosphatidylcholine secretion.CONCLUSION This study uncovered new ABCB4 variants and emphasized the pathogenic potential of specific variants.The findings from five patients provided insight into the pathogenic mechanisms underlying ABCB4-related diseases.
文摘BACKGROUND Genetic disorders affecting hepatobiliary transporters can be triggered by various factors,resulting in marked cholestasis.CASE SUMMARY We report two patients who experienced a severe episode of intrahepatic cholestasis triggered by an acute hepatitis E virus infection.Following an extensive clinical examination that ruled out common causes of cholestatic liver damage,we conducted next-generation sequencing to determine the genetic profiles of the patients.The analysis revealed several known and unknown variants in genes associated with hepatobiliary transporters and bile salt regulation,including ATP8B1,ABCB11,ABCB4,MYO5B,and FXR.For a comprehensive understanding of the pathophysiology,we performed ClinVar analysis and utilized PolyPhen for bioinformatic prediction of functional impact.Both patients exhibited rapid symptom improvement and a decrease in hyperbilirubinemia when treated with either rifampicin or bezafibrate.CONCLUSION Our findings introduce hepatitis E viral infection as a novel trigger for intrahepatic cholestasis,and we categorize the significance of the various genetic variants based on the current state of research.
基金Supported by the Japan Agency for Medical Research and Development(AMED),No.JP24fk0210132(Kanda T,Sasaki-Tanaka R and Terai S)the JSPS KAKENHI,No.JP23K15055(Sasaki-Tanaka R).
文摘Hepatitis E virus(HEV)infection causes acute hepatitis,chronic hepatitis,particularly in compromised hosts,and various extrahepatic manifestations.HEV infection is reportedly associated with biliary-pancreatic diseases,such as gallstones,cholangitis,choledocholithiasis,and acute pancreatitis.Severe jaundice and prolonged cholestasis are also atypical manifestations of HEV infection.The mechanism and genes involved in cholestasis,namely sinusoidal uptake of blood,bile salt synthesis and secretion from hepatocytes to the canaliculus,have been elucidated.HEV infection triggers severe jaundice and prolonged cholestasis in patients with genetic variants in adenosine triphosphatase phospholipid transporting 8B1,adenosine triphosphate-binding cassette(ABC)protein B4,ABCB11,Myosin VB,and/or farnesoid X receptor(FXR/NR1H4).Although prolonged cholestasis associated with these gene mutations does not seem to be specific to HEV infection,these mutations may be risk factors related to the severity of HEV infection.The use of the pregnane X receptor agonist rifampicin and the peroxisome proliferator-activated receptor activator bezafibrate may be useful for the treatment of cholestasis.These studies provide new insights into under-standing the mechanisms of severe jaundice and prolonged cholestasis caused by HEV infection.
基金Supported by the National Natural Science Foundation of China,No.82471804.
文摘BACKGROUND Progressive familial intrahepatic cholestasis type 1(PFIC-1)is a genetic cholestatic disease causing end-stage liver disease,which needs liver transplantation(LT).Simultaneous biliary diversion(BD)was recommended to prevent allograft steatosis after transplantation,while increasing the risk of infection.Here,an attempt was made to perform BD using appendix to prevent bacterial translocation after LT.CASE SUMMARY An 11-month-old boy diagnosed with PFIC-1 received ABO compatible living donor LT due to refractory jaundice and pruritus.His mother donated her left lateral segment with a graft-to-recipient weight ratio of 2.9%.Internal BD was constructed during LT using the appendix by connecting its proximal end with the intrahepatic biliary duct and the distal end with colon.Biliary leakage was suspected on the 5th day after transplantation and exploratory laparotomy indicated biliary leakage at the cutting surface of liver.The liver function returned to normal on the 9th day post-operation and maintained normal during the 15-month follow-up.Cholangiography at 10 months after transplantation confirmed the direct secretion of bile into colon.Computerized tomography scan(4 months and 10 months)and liver biopsy(10 months)indicated no steatosis in the allograft.No complaint of recurrent diarrhea,infection or growth retardation was reported during follow-up.CONCLUSION Internal BD using appendix during LT is effective in preventing allograft steatosis and post-transplant infection in PFIC-1 recipients.
文摘Progressive familial intrahepatic cholestasis(PFIC)is a group of rare,inherited cholestatic liver disorders presenting in infants and children and are associated with impaired bile flow(i.e.,cholestasis),pruritus and progressive liver disease.Historically there has been no effective or approved pharmacologic treatments for these disorders and standard medical treatment has only been supportive.The impaired bile flow within the liver,leads to accumulation in the liver and inflammation.Historically there has been no effective or approved pharmacologic treatments for these disorders and standard medical treatment has only been supportive.A potential for reducing pathologic bile accumulation in the liver is surgical biliary diversion,with an aim to interrupt the enterohepatic circulation.These procedures have demonstrated a positive effect in PFIC by normalizing serum bile acids,reducing pruritus and liver injury and improving the patient quality of life.Nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter(IBAT).IBAT inhibition has demonstrated efficacy in reducing serum bile acids and pruritus.We aim to present the 13 types of PFIC and the current evidence on the use of IBAT inhibitors in treating children with PFIC.
基金Supported by Qingmiao Talent Funding Research Project of Guangxi ProvinceNational College Student Innovation and Entrepreneurship Training Program(202310601031).
文摘[Objectives]To explore the target and mechanism of Schaftoside on cholestasis and steatosis based on network pharmacology and molecular docking.[Methods]The targets of"cholestasis"and"steatosis"were predicted using databases(OMIM and GeneCards),and the key targets were obtained after screening the retrieval data.The binding relationship between Schaftoside and key targets was analyzed by molecular docking.[Results]There were 3370 and 4433 targets for"cholestasis"and"steatosis",respectively,and 1767 overlapping genes were obtained.The results of molecular docking showed that Schaftoside had high binding energy with key targets.[Conclusions]Schaftoside can alleviate cholestasis and steatosis by regulating SREBP-1,CYP7,PPAR-gamma and other key targets to protect liver.
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.
文摘BACKGROUND Paracoccidioidomycosis(PCM)may involve the hepatic pedicle and peripan creatic lymph nodes,cause damage to the bile duct and manifest,exceptionally,in combination with extrahepatic cholestasis(EHC),making investigation and treatment challenging.AIM To investigate the management of patients with visceral PCM admitted with EHC.METHODS All patients diagnosed with PCM treated in a public,tertiary teaching hospital between 1982 and 2020 were retrospectively evaluated.Those also identified with EHC were allocated to two groups according to the treatment approach for the purpose of comparing clinical,laboratory,and imaging findings,resources used for etiological diagnosis,treatment results,and prognosis.Statistical analyses were performed using the linear mixed-effects model(random and fixed effects),which was adjusted using the PROC MIXED procedure of the SAS®9.0 software,and Fisher’s exact test.RESULTS Of 1645 patients diagnosed with PCM,40(2.4%)had EHC.Of these,20(50.0%)lived in the rural area and 29(72.5%)were men,with a mean age of 27.1 years(3-65 years).Jaundice as first symptom and weight loss of at least 10 kg were observed in 16 patients(40.0%),and a mass in the head of the pancreas was observed in 8(20.0%).The etiological diagnosis was made by tissue collection during surgery in 4 cases(10.0%)and by endoscopic methods in 3 cases(7.5%).Twenty-seven patients(67.5%)received drug treatment alone(Group 1),whereas 13(32.5%)underwent endoscopic and/or surgical procedures in combination with drug treatment(Group 2).EHC was significantly reduced in both groups(40.7% in Group 1,with a mean time of 3 months;and 38.4% in Group 2,with a mean time of 7.5 months),with no statistically significant difference between them.EHC recurrence rates,associated mainly with treatment nonadherence,were similar in both groups:37% in Group 1 and 15.4% in Group 2.The mortality rate was 18.5% in Group 1 and 23% in Group 2,with survival estimates of 71.3% and 72.5%,respectively,with no statistically significant difference.CONCLUSION Although PCM-related EHC is rare,it needs to be included in the differential diagnosis of malignancies,as timely treatment can prevent hepatic and extrahepatic sequelae.
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.
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Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.
基金Supported by National Science Foundation of China, No. 30973230 and No. 81070281
文摘AIM:To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies. METHODS:Patients under 6 mo of age who were referred for investigation of conjugated hyperbiliru-binaemia from June 2003 to December 2010 were eligible for this study. After excluding diseases affecting the extrahepatic biliary system, all patients were screened for the two most common SLC25A13 mutations; the coding exons of the entire SLC25A13 gene was sequenced and Western blotting of citrin protein performed in selected cases. Patients in whom homo-zygous or compound heterozygous SLC25A13 mutation and/or absence of normal citrin protein was detected were defined as having NICCD. Cases in which no specific etiological factor could be ascertained after a com-prehensive conjugated hyperbilirubinaemia work-up were defined as idiopathic neonatal cholestasis (INC). Thirty-two NICCD patients, 250 INC patients, and 39 infants with cholangiography-confirmed biliary atresia (BA) were enrolled. Laboratory values at their first visit were abstracted from medical files and compared. RESULTS:Compared with BA and INC patients, the NICCD patients had significantly higher levels of total bile acid (TBA) [all measures are expressed as median (inter-quartile range):178.0 (111.2-236.4) μmol/L in NICCD vs 112.0 (84.9-153.9) μmol/L in BA and 103.0 (70.9-135.3) μmol/L in INC, P = 0.0001]. The NICCD patients had significantly lower direct bilirubin [D-Bil 59.6 (43.1-90.9) μmol/L in NICCD vs 134.0 (115.9-151.2) μmol/L in BA and 87.3 (63.0-123.6) μmol/L in INC, P = 0.0001]; alanine aminotransferase [ALT 34.0 (23.0-55.0) U/L in NICCD vs 108.0 (62.0-199.0) U/L in BA and 84.5 (46.0-166.0) U/L in INC, P = 0.0001]; aspartate aminotransferase [AST 74.0 (53.5-150.0) U/L in NICCD vs 153.0 (115.0-239.0) U/L in BA and 130.5 (81.0-223.0) U/L in INC, P = 0.0006]; albumin [34.9 (30.7-38.2) g/L in NICCD vs 38.4 (36.3-42.2) g/L in BA and 39.9 (37.0-42.3) g/L in INC, P = 0.0001]; glucose [3.2 (2.0-4.4) mmol/L in NICCD vs 4.1 (3.4-5.1) mmol/L in BA and 4.0 (3.4-4.6) mmol/L in INC, P = 0.0014] and total cholesterol [TCH 3.33 (2.97-4.00) mmol/L in N ICCD vs 4.57 (3.81-5.26) mmol/L in BA and 4.00 (3.24-4.74) mmol/L in INC, P = 0.0155] levels. The D-Bil to total bilirubin (T-Bil) ratio was significantly lower in NICCD patients [all measures are expressed as median (inter-quartile range):0.54 (0.40-0.74)] than that in BA patients [0.77 (0.72-0.81), P = 0.001] and that in INC patients [0.74 (0.59-0.80), P = 0.0045]. A much higher AST/ALT ratio was found in NICCD patients [2.46 (1.95-3.63)] compared to BA patients [1.38 (0.94-1.97), P = 0.0001] and INC patients [1.48 (1.10-2.26), P = 0.0001]. NICCD patients had significantly higher TBA/D-Bil ratio [3.36 (1.98-4.43) vs 0.85 (0.72-1.09) in BA patients and 1.04 (0.92-1.14) in INC patients, P = 0.0001], and TBA/TCH ratio [60.7 (32.4-70.9) vs 24.7 (19.8-30.2) in BA patients and 24.2 (21.4-26.9) in INC patients, P = 0.0001] compared to the BA and INC groups. CONCLUSION:NICCD has significantly different bio- chemical indices from BA or INC. TBA excretion in NICCD appeared to be more severely disturbed than that of bilirubin and cholesterol.
基金Supported by Grants from the Gebert Rüf Foundation, the Forschungskredit of the University Zurichthe Swiss National Science Foundation, Grants PP00B-108511/1 and 31-64140.00
文摘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.
文摘The different methods in differentiating biliary atresia(BA)from non-BA-related cholestasis were evaluated in order to provide a practical basis for a rapid,early and accurate differential diagnosis of the diseases.396 infants with cholestatic jaundice were studied prospectively during the period of May 2007 to June 2011.The liver function in all subjects was tested.All cases underwent abdominal ultrasonography and duodenal fluid examination.Most cases were subjected to hepatobiliary scintigraphy,magnetic resonance cholangiopancreatography(MRCP)and a percutaneous liver biopsy.The diagnosis of BA was finally made by cholangiography or histopathologic examination.The accuracy,sensitivity,specificity and predictive values of these various methods were compared.178 patients(108 males and 70 females with a mean age of 58±30 days)were diagnosed as having BA.218 patients(136 males and 82 females with a mean age of 61±24 days)were diagnosed as having non-BA etiologies of cholestasis jaundice during the follow-up period in which jaundice faded after treatment with medical therapy.For diagnosis of BA,clinical evaluation,hepatomegaly,stool color,serum gamma-glutamyltranspeptidase(GGT),duodenal juice color,bile acid in duodenal juice,ultrasonography(gallbladder),ultrasonography(griangular cord or strip-apparent hyperechoic foci),hepatobiliary scintigraphy,MRCP,liver biopsy had an accuracy of 76.0%,51.8%,84.3%,70.0%,92.4%,98.0%,90.4%,67.2%,85.3%,83.2%and 96.6%,a sensitivity of 83.1%,87.6%,96.1%,73.7%,90.4%,100%,92.7%,27.5%,100%,89.0%and 97.4%,a specificity of 70.2%,77.5%,74.8%,67.0%,94.0%,96.3%,88.5%,99.5%,73.3%,75.4%and 94.3%,a positive predictive value of 69.0%,72.6%,75.7%,64.6%,92.5%,95.7%,86.8%,98.0%,75.4%,82.6%and 98.0%,and a negative predictive value of 83.6%,8.5%,95.9%,75.7%,92.3%,100%,84.2%,93.7%,100%,84.0%and 92.6%,respectively.It was concluded that all the differential diagnosis methods are useful.The test for duodenal drainage and elements is fast and accurate.It is helpful in the differential diagnosis of BA and non-BA etiologies of cholestasis.It shows good practical value clinically.
基金Supported by National Natural Science Foundation of China,No.81070281
文摘Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T > A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found.
基金Supported by National Natural Science Foundation of China,No.81070281
文摘Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family with ARC syndrome. All 23 coding exons and flanking introns of the VPS33B gene were amplified and sequenced using peripheral lymphocyte genomic DNA of the patient and her parents. Genetic testing revealed two novel mutations (c.1033delA and c.1567C>T) in the VPS33B gene. The patient is a compound heterozygote and her parents were heterozygous for each of the mutations.
文摘Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation inATP8B1.We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years,in addition to cholestasis that eventually became fatal.Genetic sequencing studies of the entire coding(exon) sequences of ATP8B1 and ABCB11 uncovered a novel heterozygous missense 3035G>T mutation(S1012I) and a synonymous 696T>C mutation in ATP8B1.The patient's progression was associated with not only impaired familial intrahepatic cholestasis 1(FIC1) function but also impaired bile salt export pump expression due to the impaired FIC1 function.Our findings show that patients with intermittent cholestasis can develop progressive liver disease even after several decades and require regular follow up.
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.
文摘To analyze time intervals of inflammation and regeneration in a cholestatic rat liver model.METHODSIn 36 Lewis rats, divided into six groups of 6 animals (postoperative observation periods: 1, 2, 3, 4, 6, 8 wk), the main bile duct was ligated with two ligatures and observed for the periods mentioned above. For laboratory evaluation, cholestasis parameters (bilirubin, γ-GT), liver cell parameters (ASAT, ALAT) and liver synthesis parameters (quick, albumin) were determined. For histological analysis, HE, EvG, ASDCL and HMGB-1 stainings were performed. Furthermore, we used the mRNA of IL-33, GADD45a and p-21 for analyzing cellular stress and regeneration in cholestatic rats.RESULTSIn chemical laboratory and histological evaluation, a distinction between acute and chronic cholestatic liver injury with identification of inflammation and regeneration could be demonstrated by an increase in cholestasis (bilirubin: 1-wk group, 156.83 ± 34.12 μmol/L, P = 0.004) and liver cell parameters (ASAT: 2-wk group, 2.1 ± 2.19 μmol/L.s, P = 0.03; ALAT: 2-wk group, 1.03 ± 0.38 μmol/L.s, P = 0.03) after bile duct ligation (BDL). Histological evaluation showed an increase of bile ducts per portal field (3-wk group, 48 ± 6.13, P = 0.004) during the first four weeks after bile duct ligation. In addition to inflammation, which is an expression of acute cholestasis, there was an increase of necrotic areas in the histological sections (2-wk group, 1.38% ± 2.28% per slide, P = 0.002). Furthermore, the inflammation could be verified by ASDCL (4-wk group, 22 ± 5.93 positive cells per portal field, P = 0.041) and HMGB-1 [2-wk group, 13 ± 8.18 positive cells per field of view (FoV), P = 0.065] staining. Therefore, in summary of the laboratory evaluation and histological studies, acute cholestasis could be found during the first four weeks after bile duct ligation. Subsequently, the described parameters declined so that chronic cholestasis could be assumed. For quantification of secondary biliary cirrhosis, eosin staining was performed, which did not reveal any signs of liver remodeling, thus precluding the development of a chronic cholestasis model. Additionally, to establish the chronic cholestasis model, we evaluated liver regeneration capacity through measurements of IL-33, p-21 and GADD45a mRNA.CONCLUSIONWe created a chronic cholestasis model. The point of inflammatory and regenerative balance was reached after four weeks. This finding should be used for experimental approaches dealing with chronic cholestatic liver damage.
