Biliary Atresia Patients Research Articles

Clinical and pathological features of patients with biliary atresia who survived for more than 5years with native liver.

The objective of this study was to determine the predictive index for prognosis in patients with biliary atresia (BA). A total of 71 patients were divided into two groups. Group A included 39 postoperative BA patients who survived for more than 5 years with normal liver function and did not present cirrhosis, and group B included 32 patients who died from liver failure within 1 year after surgery. The clinical data of the two study groups were compared, and liver pathology was evaluated using a scoring system. The average age and weight were similar in the two groups (64.1±16.8days vs. 60.7±19.3 days, p>0.05; 4.9±0.9 kg vs. 4.7±0.8 kg, p>0.05). There were no significant intergroup differences in preoperative total bilirubin (TB), direct bilirubin (DB), alanine transaminase, aspartate transaminase, and international normalized ratio. The preoperative levels of gamma-glutamyl transpeptidase (γ-GT) and albumin in group A were significantly higher than those in group B (γ-GT: 956.8±503.8 IU/L vs. 620.2±437.1 IU/L, p=0.00; ALB: 40.8±2.5 g/L vs. 36.8±3.6 g/L, p=0.04), whereas alkaline phosphatase was significantly lower in group A compared to group B (512.2±224.6 IU/L vs. 631.7±254.7 IU/L, p=0.02). The postoperative TB and DB after 2 weeks of the Kasai procedure decreased significantly more in group A than in group B (TB: 53.9 vs. 21.4%, p=0.00; DB: 51.0 vs. 22.7%, p=0.00), whereas γ-GT increased significantly less in group A than in group B (48.3 vs. 142.1%, p=0.00). Cystic structures were observed at the porta hepatis on ultrasound in more patients from group A (28.2 vs. 3.2%, p<0.00). There was no significant difference in the total pathological score between the two groups (p=0.38) whereas the score of bile plugs was significantly higher in group A (0.95 vs. 0.38, p=0.03). The cystic structures observed at the porta hepatis on ultrasound preoperatively and the rapid decrease in TB and DB within 2 weeks postoperatively predict good long-term prognosis, whereas a significant increase in γ-GT with a lower preoperative level predicts poor long-term prognosis. The development of bile plugs may be an indicator of favorable prognosis.

Early differential diagnosis methods of biliary atresia: a meta-analysis.

To evaluate the accuracy of early differential diagnosis methods of biliary atresia in patients with infantile cholestasis. We searched PubMed, EMBASE and the Web of Science databases for articles evaluated the early differential diagnosis methods of biliary atresia. The methodological quality of each study was assessed with version 2 of the Quality Assessment of Diagnostic Accuracy Studies tool. Two reviewers extracted data independently. Pooled sensitivity, specificity, positive likelihood ratio (LR +), negative likelihood ratio (LR -), diagnostic odds ratio (DOR) with 95% CIs were calculated to assess each diagnosis method. A total of 38 articles were included. Summary sensitivity and specificity were 77% (95% CI 74-80%) and 93% (95% CI 91-94%), respectively, for B-US in 23 studies; 96% (95% CI 92-98%) and 58% (95% CI 51-65%), respectively, for MRCP in five studies; 87% (95% CI 82-91%) and 78% (95% CI 74-82%), respectively, for acholic stool in seven studies; 84% (95% CI 78-89%) and 97% (95% CI 97-98%), respectively, for serum liver function test in seven studies; 96% (95% CI 94-97%) and 73% (95% CI 70-76%), respectively, for hepatobiliary scintigraphy in 18 studies; 98% (95% CI 96-99%) and 93% (95% CI 89-95%), respectively, for percutaneous liver biopsy in 11 studies. The accuracy rate of percutaneous liver biopsy is better than all of the noninvasive methods. Take into consideration the advantages and disadvantages of the six methods, combination of multidisciplinary noninvasive diagnosis methods is the first choice for differential diagnosis of BA from other causes of neonatal cholestasis.

Mitochondrial Mutations in Cholestatic Liver Disease with Biliary Atresia

Biliary atresia (BA) results in severe bile blockage and is caused by the absence of extrahepatic ducts. Even after successful hepatic portoenterostomy, a considerable number of patients are likely to show progressive deterioration in liver function. Recent studies show that mutations in protein-coding mitochondrial DNA (mtDNA) genes and/or mitochondrial genes in nuclear DNA (nDNA) are associated with hepatocellular dysfunction. This observation led us to investigate whether hepatic dysfunctions in BA is genetically associated with mtDNA mutations. We sequenced the mtDNA protein-coding genes in 14 liver specimens from 14 patients with BA and 5 liver specimens from 5 patients with choledochal cyst using next-generation sequencing. We found 34 common non-synonymous variations in mtDNA protein-coding genes in all patients examined. A systematic 3D structural analysis revealed the presence of several single nucleotide polymorphism-like mutations in critical regions of complexes I to V, that are involved in subunit assembly, proton-pumping activity, and/or supercomplex formation. The parameters of chronic hepatic injury and liver dysfunction in BA patients were also significantly correlated with the extent of hepatic failure, suggesting that the mtDNA mutations may aggravate hepatopathy. Therefore, mitochondrial mutations may underlie the pathological mechanisms associated with BA.

Ratio of Preoperative and Postoperative Serum Bilirubin Levels Predicts Early Outcome Following Biliary Atresia Surgery.

Aim:This study investigates the fall in total serum bilirubin levels within 1 week after surgery, as a marker to predict early outcome in biliary atresia (BA) patients post-Kasai portoenterostomy (KP).Methods:The ratio of total serum bilirubin levels at the 7th postoperative day to the preoperative level (TB7/TB0) in patients undergoing KP was calculated (January 2011–July 2015). Patients were stratified after 3-months follow-up into outcome groups depending on the clinical clearance of jaundice and TB7/TB0 ratio was correlated to outcome and liver histopathological changes in these groups.Results:Sixty-one patients (M:F = 44:17), median age 75 days were included. At the end of 3 months, 27 (44.39%) were anicteric while 26 (42.6%) were still clinically jaundiced. Patients with a higher median value of TB7/TB0, that is, 0.856 were more likely to have jaundice at the end of 3 months as compared to patients with a lower median value of 0.615 (P < 0.0001). A cutoff TB7/TB0 ratio >0.723 predicted the KP outcome with 84.6% sensitivity and 81.5% specificity. The difference in TB7/TB0 ratio between patients with varying severity of liver histopathological changes was also significant, namely, cholestasis (P = 0.01), hepatocellular damage (P = 0.03), portal inflammation (P = 0.04), and portal fibrosis (P = 0.02).Conclusions:The rapidity of fall in the total serum bilirubin levels within 1 week post-KP was able to predict the likely outcome in BA patients.

The Prognostic Value of CD8+ and CD45RO+ T Cells Infiltration and Beclin1 Expression Levels for Early Postoperative Cholangitis of Biliary Atresia Patients after Kasai Operation.

BackgroundPostoperative cholangitis is a common but severe complication after Kasai portoenterostomy for biliary atresia (BA). This study aimed to identify its prognostic factors.MethodsTwo sets of liver paraffin-embedded tissue samples were collected from BA patients who received Kasai portoenterostomy (n = 25 and n = 31, respectively). Patients were divided into non-cholangitis and cholangitis groups. The infiltration of CD4+, CD8+, CD45RO+, CD68+ cells and expression of Beclin1 were quantitatively evaluated in immunohistochemical analysis.ResultsCholangitis group had a significantly lower CD8+ T cell infiltration but a higher CD45RO+ cell infiltration, and a lower Beclin1 level than non-cholangitis group (all P < 0.01). Multivariate logistic regression analysis indicated that infiltration of CD8+ cells (odds ratio [OR], 0.112; 95% confidence interval [CI], 0.022–0.577) and CD45RO+ cells (OR, 3.88; 95% CI, 1.37–11.03), and Beclin1 level (OR, 0.088; 95% CI, 0.018–0.452) were independent influence factors for early postoperative cholangitis. Receiver operating characteristic (ROC) analysis showed that area under ROC curve (AUROC) values for CD8+ cells, CD45RO+ cells and Beclin1 were 0.857, 0.738 and 0.900, respectively.ConclusionOur findings demonstrated the CD8+ cells, CD45RO+ cells and Beclin1 level possessed the prognostic value for early postoperative cholangitis following Kasai operation, which may be helpful to develop new prevention and treatment strategies for postoperative cholangitis.

Indocyanine green clearance test to evaluate liver function in rat model of extrahepatic biliary atresia.

Background:Indocyanine green clearance test (ICG-K) has been shown as a sensitive marker of liver function in patients with cirrhosis. However, its role in the assessment of liver function in children with biliary atresia is not well established. The present study was undertaken to evaluate the ICG-K in an experimental model of cholangitis and partial biliary obstruction.Materials and Methods:Thirty albino rats were divided into 3 groups of 10 each. After exploration under anesthesia, a vial of OK-432 diluted in 0.2 ml of normal saline was injected into the common bile duct (CBD) in rats of Groups B and C. In the control Group A, only saline was injected. Re-exploration was done at 3 weeks in Groups A and B and at 6 weeks in Group C, and freshly prepared ICG was injected into the inferior vena cava. Blood samples were collected at periodic intervals, optical density of the serum was measured, and half-life of ICG and fractional clearance (K) were calculated. Blood and tissue samples were obtained for biochemical tests and histological examination.Results:The histological changes in CBD and liver were maximum in Group B; this correlated well with the K-value in this group, which was significantly delayed. In Group C, clearance was delayed than the control group with histological changes ranged from mild to moderate inflammation. The control group had normal histology of liver and CBD, and only four rats showed mild portal inflammation.Conclusion:ICG clearance rate is a reliable marker of liver function and can be utilized for evaluation of liver function in postoperative extrahepatic biliary atresia patients.

Serum level of interleukin-13 receptor alpha 2 in infants with biliary atresia - is it of value?

Aim of the studyWe aimed to assess the utility of serum level IL-13Rα2 receptors as a non-invasive marker for early diagnosis of biliary atresia (BA) and selection of BA patients indicated for Kasai portoenterostomy.Material and methodsThe study included 60 infants with neonatal cholestasis in three groups; early BA group (n = 20), delayed BA group (n = 20) and non-BA cholestasis group (n = 20). A fourth group of 20 healthy neonates (n = 20) served as controls. IL-13Rα2 was measured by enzyme-linked immunosorbent assay in all patients and controls.ResultsThe mean value of IL-13Rα2 was significantly higher in delayed BA group (11.05 ± 10.9 ng/ml) compared to early BA (0.34 ± 0.37 ng/ml), non-BA (0.54 ± 0.85 ng/ml) and control (0.24-0.2 ng/ml) groups. The levels of serum IL-13Rα2 increase with the severity of the degree of fibrosis. IL-13Rα2 at a cutoff level > 0.782 ng/ml could predict late fibrosis with accuracy of 77.55% (p < 0.0001). IL-13Rα2 could differentiate between preserved and disturbed liver architecture at a cut off value of more than 0.42 ng/ml with an accuracy of 81.6%.ConclusionsSerum IL-13Rα2 not a diagnostic marker for BA however it could be used as a noninvasive marker for detection of advanced liver fibrosis and presence of disturbed liver architecture that helps in patient selection for undergoing Kasai operation. Serum IL-13Rα2 could be a future therapeutic target for management of BA patients and any fibrotic liver disease.

Association of polymorphism in the VEGFA gene 3'-UTR +936T/C with susceptibility to biliary atresia in a Southern Chinese Han population.

Biliary atresia (BA) is a neonatal disease characterized by chronic inflammation of the bile ducts and progressive aggravation of jaundice, but with a poor prognosis and high mortality. The etiology of BA is still uncertain which may be related to gene defect, virus infection, immune disorder, gene polymorphism. As a proinflammatory cytokine, VEGFA gene polymorphism (rs3025039) has been shown to be related to the pathogenesis of BA in Taiwanese population. We investigated the association between VEGFA gene polymorphism (rs3025039) and BA susceptibility using the largest case-control cohort, totaling with 506 BA patients and 1473 healthy controls in a Southern Chinese Han population. VEGFA gene polymorphism (rs3025039) was genotyped using the MassARRAY iPLEX Gold system (Sequenom). Odds ratios (OR) and 95% confidence intervals (CIs) were used to access the association between the VEGFA gene polymorphism (rs3025039) and BA risk. No significant association was found between the VEGFA gene polymorphism (rs3025039) and BA risk in the overall analysis. These results suggest that VEGFA gene polymorphism (rs3025039) may not be associated with the risk of BA in the Southern Chinese Han population.

Liver transplantation for deterioration in native liver function after portoenterostomy for biliary atresia in Japan: Short- versus long-term survivors

PurposeWe reviewed our post-Kasai portoenterostomy biliary atresia (BA) patients who required liver transplantation (LTx) for deterioration in native liver (NL) function to investigate mortality in relation to age at LTx. MethodsBA patients indicated for LTx when less than 18years old (U18; n=17) and when 18 or older (18+; n=13) were compared. All achieved jaundice clearance postoperatively (TBil ≤1.2mg/dL (≈20μmol/L)). ResultsIn U18, living-donor (LD) LTxs were performed at a median of 6.1years (range: 0.5–16.7; n=14) and cadaveric (CD) LTxs at a median of 1.3years (1.1–1.5; n=3). In 18+, LDLTxs were performed at a median of 28years (18–37; n=8), and 1 case died from graft versus host disease. CDLTxs were indicated in 5, but 4 died at a median of 30years (26–32), a mean of 1.4years (0.7–1.8) after NL deterioration commenced. One case is awaiting CDLTx. At the time of review, all U18 and 7 LDLTx cases in 18+ were clinically stable. Mortality rates were 0% in U18 and 38% in 18+ (P=.006). ConclusionOur results highlight the extremely grave prognosis for long-term BA patients requiring LTx when 18 or older because of poor donor availability in Japan. Level of evidenceLevel III.

Expression of intrahepatic CD3, CD4, and CD8 T cells in biliary atresia.

Aim of the studyAssessment of the expression of cluster of differentiation (CD)3, CD4, and CD8 T cells in biliary atresia (BA) cases in comparison to neonatal cholestasis other than BA.Material and methodsThis study included 79 patients: 34 patients with BA (BA group) and 35 patients with neonatal cholestasis due to causes other than BA (cholestasis group), and 10 normal liver donor as a control group. Immunohistochemical staining or CD3, CD4, and CD8 T cells in liver tissues for the 3 groups were evaluated.ResultsPresence of clay stool, high gamma-glutamyl transferase levels, thrombocytosis, and non-contractibility of the gallbladder was the main clinical, laboratory, and radiological findings, distinguishing BA from other disorders causing neonatal cholestasis. Portal ductular proliferation, bile plugs in portal ductules, and advanced grades of fibrosis were more predominant in liver biopsy specimens of BA patients. The CD3+, CD4+, and CD8+ expression in patients with BA were significantly higher than in both cholestasis and control groups, while it was comparable in the cholestasis and control groups, with cutoff values of 25, 12, and 2.5 cells/portal tract, respectively, differentiating between BA and cholestatic patients.ConclusionsImmune-mediated destruction of bile ducts is incriminated in the pathogenesis of BA. Lymphocytic infiltrate in portal tract is primarily composed of CD3, CD4, and CD8 T cells. Immunostaining of liver tissue for CD3, CD4, and CD8 T cells can help in ensuring diagnosis of BA.

Laparoscopic finding of a hepatic subcapsular spider-like telangiectasis sign in biliary atresia.

AIMTo assess the diagnostic value of a laparoscopic finding of a hepatic subcapsular spider-like telangiectasis (HSST) sign in biliary atresia.METHODSA retrospective study was conducted first and then a validation set was used to investigate the value of an HSST sign in predicting biliary atresia (BA). In the retrospective study, laparoscopic images of the liver surface were reviewed in 126 patients with infantile cholestasis (72 BA patients and 54 non-BA cholestasis patients) and a control group of 38 patients with non-hepatic conditions. Analysis was first made by two observers separately and finally, a consensus conclusion was achieved. Then, the diagnostic value of the HSST sign was validated in an independent cohort including 45 BA and 45 non-BA patients.RESULTSIn the retrospective investigation, an amplified HSST sign was found in all BA patients, while we were unable to detect the HSST sign in 98.1% of the 54 non-BA patients. There was no HSST sign in any of the control subjects. In the first review, the sensitivity and specificity from one reviewer were 100% and 98.1%, respectively, and the results from the other reviewer were both 100%. The consensus sensitivity and specificity were 100% and 98.1%, respectively. The HSST sign was defined as being composed of several enlarged tortuous spider-like vascular plexuses with two to eight branches distributed on all over the liver surface, which presented as either a concentrated type or a dispersed type. In the independent validation group, the sensitivity, specificity, positive predictive value and negative predictive value of the HSST sign were 100%, 97.8%, 97.8% and 100%, respectively.CONCLUSIONThe HSST sign is characteristic in BA, and laparoscopic exploration for the HSST sign is valuable in the diagnosis of BA.

Unique manifestations of biliary atresia provide new immunological insight into its etiopathogenesis.

Biliary atresia (BA) is a unique cholestatic disease of newborns with a background of exaggerated immune response in the liver of unknown mechanism. Three hypotheses have been proposed; autoimmune type of cholangiopathy triggered by virus infection, graft-versus-host disease type of immune-mediated disease associated with maternal microchimerism and ductal plate malformation theory. Researchers on virus infection theory have experimentally explored immune process causing cholangiopathy on murine models of this disease, while in maternal microchimerism hypothesis were detected maternal cells in the BA patients' liver, of which roles are yet to be determined. Ductal plate malformation theory is an intriguing hypothesis in the sense that it suggests the onset of this disease is in the first trimester. This theory can be secondary to either one of these two immune-related insults. In this review, four unique points are focused; (1) the timing of onset, (2) hepatitis-like pathological picture, (3) heterogenous atrophy of the liver segments when advanced, and (4) swollen lymph nodes at the porta hepatis. These unique clinicopahtological aspects of this disease should be well explained by these hypotheses.

Correlation between gamma-glutamyl transpeptidase activity and outcomes after Kasai portoenterostomy for biliary atresia

Background/purposeThe role of serum gamma-glutamyl transpeptidase (GGT) levels in predicting clinical outcomes after Kasai portoenterostomy (KPE) is unknown. This study analyzed whether postoperative GGT along with the aspartate aminotransferase-to-platelet ratio index (APRi) predicted prognosis of biliary atresia (BA). MethodsData were retrospectively reviewed for 169 BA patients categorized into jaundice-free (JF) (total bilirubin <2.0 mg/dL ≤6 months post-KPE) and persistent jaundice (PJ) groups (total bilirubin ≥2.0 mg/dL ≤6 months post-KPE). Serum biochemical markers, including GGT levels, were measured monthly after KPE, and mean GGT levels and APRi were compared between groups. Factors predicting native liver survival (NLS) were determined using a Cox regression analysis. ResultsGGT concentrations >550 IU/L at month 5 (hazard ratio: 1.74, P < 0.05), an APRi >0.605 at month 4 (hazard ratio: 3.78, P = 0.001), and being jaundice-free at 6 months (hazard ratio: 5.49, P < 0.001) were independent risk factors for decreased NLS. ConclusionsSerum GGT concentrations >550 IU/L at month 5 and an APRi >0.605 at month 4 post-KPE were associated with significantly lower NLS rates. Among JF patients, those with GGT concentrations >550 IU/L at month 5 and APRi >0.605 at month 4 showed poorer outcomes. Type of studyRetrospective comparative study Level of evidenceLevel III.

Living donor liver transplantation for biliary atresia: An analysis of 2085 cases in the registry of the Japanese Liver Transplantation Society.

Biliary atresia (BA) is the most common indication for liver transplantation (LT) in pediatric population. This study analyzed the comprehensive factors that might influence the outcomes of patients with BA who undergo living donor LT by evaluating the largest cohort with the longest follow-up in the world. Between November 1989 and December 2015, 2,085 BA patients underwent LDLT in Japan. There were 763 male and 1,322 female recipients with a mean age of 5.9years and body weight of 18.6kg. The 1-, 5-, 10-, 15-, and 20-year graft survival rates for the BA patients undergoing LDLT were 90.5%, 90.4%, 84.6%, 82.0%, and 79.9%, respectively. The donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were found to be significant predictors of the overall graft survival. Adolescent age (12 to <18years) was associated with a significantly worse long-term graft survival rate than younger or older ages. We conclude that LDLT for BA is a safe and effective treatment modality that does not compromise living donors. The optimum timing for LT is crucial for a successful outcome, and early referral to transplantation center can improve the short-term outcomes of LT for BA. Further investigation of the major cause of death in liver transplanted recipients with BA in the long-term is essential, especially among adolescents.

Treatment Policy and Liver Histopathology Predict Biliary Atresia Outcomes: Results after National Centralization and Protocol Biopsies

Different treatment policies can influence biliary atresia outcomes, but the pathophysiology of expanding fibrosis occurring even after successful portoenterostomy remains unclear. Clearance of jaundice (COJ) (bilirubin <20 μmol/L), native liver survival, and overall survival rates of biliary atresia patients were analyzed before and after national centralization of management, as well as in relation to native liver histopathology of protocol biopsies. Of the 59 patients, 35 were managed after centralization and received standardized postoperative adjuvant therapy, including corticosteroids. After centralization, age at portoenterostomy decreased from 73 days to 54 days (p= 0.014) and COJ rate increased from 42% to 80% (p= 0.005), 5-year native liver survival increased from 38% to 70% (p= 0.014), and 5-year overall survival increased from 68% to 94% (p= 0.007). High-grade portal inflammation at portoenterostomy predicted COJ (odds ratio 3.66; p= 0.011) and slower fibrosis progression (β=-0.74; p= 0.005). Native liver survival was extended in patients with high-grade portal inflammation (p= 0.002) and in patients whose bilirubin normalized within 3 months (p < 0.001). Portal inflammation and cholestasis reduced only after COJ (p < 0.001), and persisting ductal reaction, reflected by cytokeratin 7-positive proliferating bile ductules and periportal hepatocytes, correlated with follow-up fibrosis (r= 0.454 to 0.763; p < 0.001 to 0.003). Cytokeratin 7 immunopositivity of periportal hepatocytes increased after COJ (p= 0.015) and was the only predictor of follow-up liver fibrosis (β= 0.36; p= 0.002) in multiple regression. Biliary atresia outcomes improved significantly after centralization and standardized management. Resolution of cholestasis and reduction of high-grade portal inflammation postoperatively predict slower fibrosis progression and improved native liver survival, and persisting ductal reaction parallels progressive native liver fibrosis despite COJ.

Objectification of facial color inspection to differentiate obstructive/nonobstructive jaundice in neonates by spectrophotometer

PurposeThe purpose of this study was to study whether color difference in facial color truly exists between neonates with obstructive and nonobstructive jaundice, and whether the color difference could be objectified by spectrophotometer. MethodsTwelve biliary atresia patients were enrolled in an obstructive jaundice group and 15 neonates admitted for non-conjugated hyperbilirubinemia in a nonobstructive group. Nine patients with syphilis (n=6) and sacrococcygeal teratoma (n=3) were studied as control. Transcutaneous total bilirubin (TB) and hemoglobin were recorded. Face color was measured by spectrophotometer. Spectral reflection curve and L*a*b* model parameters were studied. ResultsFacial color of jaundiced neonates were characteristic in waveform that reflectivity at wavelength of 550nm was significantly decreased compared with control by 16.4±3.4%, while not significantly different between obstructive and nonobstructive jaundice (p=0.124). At 650nm, reflection in nonobstructive jaundice was decreased by 8.4±2.3% (p<0.01), and reflection in obstructive jaundice was (9.6±3.2) % lower compared with nonobstructive jaundice (p<0.01). In L*a*b* model, mean color difference between obstructive and nonobstructive jaundice was 9.60. L* was significantly different: control (71.84±3.75%)>obstructive jaundice (58.09±1.25%)>nonobstructive jaundice (54.25±7.27%). Value b* was higher in jaundiced patients compared to normal control (11.88±2.16, p<0.001), but not significantly different in obstructive and nonobstructive jaundice (20.12±2.17vs18.25±4.58). Value a* was not significantly different between normal control (5.57±2.38) and obstructive jaundice (5.25±1.19), but was lower than nonobstructive jaundice (14.03±3.29, p<0.001). TB was significantly correlated with b* (R=0.526, p=0.014), while hemoglobin was correlated with a* (R=0.791, p<.001) and L* (R=−0.707, p<.001). ConclusionsObstructive and nonobstructive jaundice could be objectively differentiated through facial color inspection by spectrophotometer. Type of studyStudy of Diagnostic Test. Level of evidenceLevel II.

Onset ages of hepatopulmonary syndrome and pulmonary hypertension in patients with biliary atresia.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are extrahepatic complications of biliary atresia (BA). Their detection is sometimes delayed, which may result in missed opportunities for liver transplantation. The aim of this study was to determine the onset ages of HPS and PoPH in BA patients. BA patients followed at our institution were identified. Patients visited our clinic for routine blood work, as well as regular electrocardiography, chest X-rays, and arterial blood gas tests. Lung perfusion scintigraphy and cardiac ultrasound were performed to diagnose HPS. Cardiac catheterization was conducted to diagnose PoPH. The study population consisted of 88 BA patients. The median follow-up duration was 11.6years (range 0.8-26.0years). Six patients (6.8%) developed HPS and three patients (3.4%) developed PoPH. The median age of onset of HPS was significantly younger than that of PoPH (HPS: 4years, PoPH: 15years, P<0.019). Two patients (66%) with PoPH died, while all patients with HPS survivied. The onset of HPS was significantly earlier than that of PoPH. The mortality rate was high in patients with PoPH. Teenagers with BA should receive routine cardiac echocardiograms to detect PH in its early stages.

Derivation of a disease-specific human induced pluripotent stem cell line from a biliary atresia patient

Biliary atresia (BA) is a common cause of pediatric end-stage liver disease. While its etiology is not yet clear, evidence has suggested that BA results from interactions between genetic susceptibility and environmental factors. Disease relevant human cellular models of BA will facilitate identification of both genetic and environmental factors that are important for disease prevention and treatment. Here we report the generation of a human induced pluripotent stem cell line from a BA patient using episomal vectors. Patient-specific BA iPSC lines provide valuable tools for disease mechanism study and drug development.

Imaging findings of Alagille syndrome in young infants: differentiation from biliary atresia.

To compare the imaging findings using ultrasonography, MR cholangiopancreatography (MRCP), and intraoperative cholangiography (IOC) between Alagille syndrome (AGS) and biliary atresia (BA) in young infants with cholestatic jaundice. The institutional review board approved this retrospective study. Ultrasonography (n = 55), MRCP (n = 33), and IOC (n = 22) studies were performed in 55 infants (all younger than 3 months) with AGS (n = 7) and BA (n = 48). The ultrasound images were reviewed focusing on gallbladder (GB) abnormalities, triangular cord sign, hepatic artery enlargement and signs of portal hypertension. Visualization of the extrahepatic biliary tree was assessed by MRCP and IOC. Six (86%) AGS patients showed a small GB on ultrasound; this was comparable to that in BA patients (81%, 35/43). The images were negative for triangular cord sign and hepatic artery enlargement in all AGS patients, whereas they were positive in 48% (23/48) (p = 0.034) and 77% (33/43) (p < 0.001) of the BA patients, respectively. Signs of portal hypertension were less common in AGS patients than in BA patients (p = 0.010). Although non-visualization of the extrahepatic biliary tree by MRCP did not differ significantly between patients with AGS and BA, AGS patients showed a higher proportion of visible common bile ducts with IOC, compared to BA patients. The diagnosis of AGS was made in four infants (57%) before ultrasonography, based on extrahepatic manifestations. The small GB visualized on ultrasonography and non-visualization of extrahepatic biliary tree by MRCP commonly occurred in patients with either AGS or BA. However, triangular cord sign, hepatic artery enlargement and signs of portal hypertension onultrasonography and non-visualized common bile duct with IOC were less frequent in AGS patients than in BA patients. Advances in knowledge: Atypical imaging findings for BA should prompt a meticulous evaluation for the extrahepatic manifestations of AGS to avoid possibly harmful surgery.

Association of common genetic variants in VEGFA with biliary atresia susceptibility in Northwestern Han Chinese

Biliary atresia (BA) is a major neonatal obliterative cholangiopathy, resulting in progressive cirrhosis. The gene VEGFA encodes a heparin-binding protein that is a regulator of angiogenesis and a mediator of inflammatory reactions, and accumulating evidence have indicated that VEGFA may play a possible role in the pathogenesis of BA. Our study aim was to evaluate the association of common variants within the VEGFA gene with BA susceptibility in Northwestern Han Chinese population. Forty tag SNPs within the VEGFA gene were selected in the study, and then subsequently genotyped in 1336 Northwestern Han Chinese individuals, consisting of 311 BA patients and 1025 healthy controls. The SNP rs3025039 was found to be strongly associated with BA risk (additive P=0.000264) in our sample, and the CC genotype of rs3025039 had higher prevalence than the other two genotypes, indicating the C allele is a risk allele with an odds ratio (OR) of 1.56 and 95% confidence interval (CI) of 1.23–1.99. Haplotype analyses showed that a LD block containing rs3025039 significantly correlated with BA risk (global P<0.001). Moreover, bioinformatics analysis indicated that hsa-mir-591 and VEGFA formed miRNA/SNP target duplexes if the rs3025039 allele was in the T form, suggesting that rs3025039 may alter VEGFA expression by affecting hsa-miR-591/single-nucleotide polymorphism target duplexes. Our results indicate additional evidence supporting that there is an important role of the VEGFA gene in the increased susceptibility of BA. AbbreviationsImage 1BABiliary atresiaGWASgenome-wide association studiesSNPsingle-nucleotide polymorphismMAFminor allele frequenciesHWEHardy-Weinberg equilibriumORsOdds ratiosCIsconfidence intervalsLDlinkage disequilibriumUTRuntranslated region