Native Liver Survival Research Articles

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n= 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n= 30), and with two PPTMs (BSEP3/3; n= 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p= 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.

Identification of Early Clinical and Histological Factors Predictive of Kasai Portoenterostomy Failure.

It is impossible to predict which patients with biliary atresia (BA) will fail after Kasai portoenterostomy (KPE). We evaluated the predictive nature of pre-KPE clinical and histological factors on transplant-free survival (TFS) and jaundice clearance. A retrospective review of patients who received a KPE at our institution (1997-2018) was performed. Primary outcomes were two-year TFS, five-year TFS, and jaundice clearance 3 months after KPE. p &lt; 0.05 was considered significant. Fifty-four patients were included in this study. The two-year TFS was 35.1%, five-year TFS was 24.5%, and 37% patients reached a direct bilirubin (DB) ≤ 2.0 mg/dL 3 months post KPE. The median age at biopsy was younger in the five-year TFS (39.0 (24.5-55.5) vs. 56.0 days (51.0-67.0), p = 0.011). Patients with DB ≤ 1.0 mg/dL 3 months after KPE were statistically younger at biopsy (DB ≤ 1.0 44.0 (26.0-56.0) vs. DB &gt; 1.0 56.0 days (51.0-69.0), p = 0.016). Ductal plate malformation was less frequent in the five-year TFS (16/17, 94.1%, vs. 1/17, 5.9%, p = 0.037). Portal fibrosis (19/23, 82.6%, vs. 4/23, 17.4%, p = 0.028) and acute cholangitis (6/7, 85.7%, vs. 1/7, 14.3%, p = 0.047) occurred less frequently in two-year TFS. Older age at biopsy, acute cholangitis, portal fibrosis, and ductal plate malformation were associated with lower native liver survival. Evaluation in a larger study population is needed to validate these results.

Different clinical and genetic features of Alagille patients with progressive disease versus a jaundice-free course.

Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with different outcomes and analyzed the liver pathology at liver transplantation (LT) compared with that in biliary atresia (BA). We report the clinical characteristics, outcomes, and genetic mutations of 25 children with ALGS followed for a median of 7.3 years. Patients were classified into (i) jaundice-free (JF) group (resolving jaundice after 2 years of age); (ii) progressive disease (PD) group (persistent jaundice or progressive cholestasis). In addition, we analyzed the explant liver in 10 ALGS patients compared with 20 age-matched BA patients at the time of LT. Nine patients (36%) in the JF group had a favorable outcome, with longer native liver survival than patients with PD (n=16, P < 0.001). Fourteen of the PD group patients received LT or died. We identified 18 different JAG1 mutations in 22 patients. Three unrelated probands in the JF group had the same de novo mutation in JAG1, c.2122-2125delCAGT. Compared with BA children, ALGS patients had lower METAVIR scores in liver pathology, higher serum albumin levels, and lower weight-for-age z-scores when receiving LT. One-third of ALGS patients had JF and a favorable course. Children with ALGS presenting with persistent jaundice beyond 2 years of age should be cautioned for poor prognosis. ALGS patients tend to have a lesser extent of cirrhosis, and more growth problems than BA patients at the time of LT.

The outcome of Kasai portoenterostomy after day 70 of life.

The age at Kasai portoenterostomy (KPE) was reported to correlate with the prognosis of patients with biliary atresia (BA) and that a late KPE is bounded to be failure. Herewith, we reported the outcome of patients receiving KPE after day 70 of life. In addition, the prognostic indicators were evaluated. This was a retrospective analysis and all BA patients receiving KPE after day 70 of life in a tertiary centre between 1980 and 2018 were evaluated. A total of 164 KPE procedures were performed during the study period and 62 cases were done after day 70 of life which were included in this study. The median follow up period of these patients was 10.6 years (range: 4.5 to 41.5 years). Thirty-nine patients (62.9%) patients were able to achieve jaundice clearance at 6 months after KPE. The NLS rate was 53.2% (n = 33) as recorded at the time of writing. There was no statistical difference in the age at KPE between native liver survivors and patients requiring liver transplant. For complications among the native liver survivors (n = 33), portal hypertension and recurrent cholangitis were found in 63.6% and 30.3% of these patients. There was also no significant difference in the age at KPE between those who developed portal hypertension and recurrent cholangitis (p = 0.451 and p = 0.173 respectively). Regarding the prognostic indicators in predicting NLS, pre-KPE bilirubin, alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were significantly higher among patients requiring liver transplant (p = 0.012, =0.011 and =0.017 respectively). The bilirubin level at 6 months after KPE was also higher among patients who required liver transplant (p = 0.016). More than half of the BA patients can survive for 10 years with their native liver despite KPE was performed after day 70 of life. However, they have a higher chance to develop BA-related complications. The level of pre-KPE bilirubin and ductal enzymes as well as post-KPE bilirubin are prognostic indicators to predict NLS.

A Comparison of Laparoscopic-Modified Kasai Versus Conventional Open Kasai for Biliary Atresia in Infants: A Single-Center Experience.

Background: The purpose of this study was to evaluate the efficacy of our modified laparoscopic Kasai portoenterostomy for type III biliary atresia (BA) in children. Methods: A total of 56 type III BA patients underwent laparoscopic-modified Kasai procedure from January 2015 to July 2021. Conventionally control group of 45 BA patients from January 2012 to January 2016 were operated by open Kasai. The clinical data between the two groups were retrospectively compared. Results: The mean operating time was 235.5 ± 20.5 minutes (range, 210-275 minutes) in Group I, whereas 180.5 ± 25.5 minutes (range, 155-210 minutes) in Group II. The oral intake resumption was faster in Group I than that in Group II (mean 3.5 days versus 4.5 days). The follow-up time was mean 18.5 months in Group I and 24 months in Group II. The clearance of jaundice (total bilirubin <20 μmol/L) was significant different in Group I (78.6%) (44/56) versus that of Group II (74.3%) (33/45). The native liver survival rate was 71.4% (40/56) in Group I and was 66.7% (30/45) in Group II at the follow-up time, respectively. Conclusion: The laparoscopic-modified Kasai would improve the outcome of BA patients.

Accumulation of Postoperative Unexpected Events Assessed by the Comprehensive Complication Index® as Prognostic Outcome Parameters for Kasai Procedure.

Introduction The Kasai procedure in children with biliary atresia (BA) is associated with several complications in the short-term. The Comprehensive Complication Index (CCI®) is a validated metric in adult surgery for the analysis of complications and morbidity in surgical patients. We aimed to analyze the CCI® for the first time in BA infants and to correlate its association with outcomes. Material and Methods We conducted a retrospective review of medical records of infants with type III BA undergoing the Kasai procedure between January 2011 and December 2021 at our institution. All unexpected events were ranked according to the Clavien–Dindo classification, and the CCI® per patient was subsequently calculated. Clavien–Dindo grades, individual events, CCI®, and total event numbers per patient were correlated with one- and two-year outcomes post-surgery. Results A total of 131 events were identified in 101 patients (ranging 0–11 per patient). Forty-four Grade I (33.6%), 67 Grade II (51.1%), 18 Grade III (13.7%), and two sentinel events [>Grade IV] (1.5%) were documented according to Clavien–Dindo, including one death in a cardiac-associated BA patient. None of the complications significantly correlated with a poor outcome. Sixty-three (62.4%) CCI® scores were calculated (range 0–100). The mean CCI® score during the in-patient treatment post-surgery was significantly higher in patients with a poorer outcome than patients with native liver survival at one- and two-year follow-up (22.7 ± 21.7 vs. 13.2 ± 18.1; p = 0.02). Conclusion Not the severity of complications, but the accumulation of numerous events related to Kasai procedure were associated with a poorer outcome. Therefore, the CCI® is an excellent instrument for the postoperative morbidity assessment of BA patients.

Low gamma-glutamyl transpeptidase levels at presentation are associated with severity of liver illness and poor outcome in biliary atresia.

ObjectiveTo investigate the clinical features and prognosis of biliary atresia (BA) with normal or minimally elevated gamma-glutamyl transpeptidase (GGT).MethodsThe clinical data of patients with BA in our hospital between 2012 and 2017 were retrospectively studied. The patients were divided into a low-GGT group (GGT ≤ 300 IU/L) and a high-GGT group (GGT > 300 IU/L) according to the preoperative GGT level. The perioperative clinical parameters, the postoperative jaundice clearance within 6 months, and the 2-year native liver survival were compared among the groups.ResultsA total of 1,998 children were included in this study, namely, 496 in the low-GGT group and 1,502 in the high-GGT group. The ages and weights at the surgery in the low-GGT group were significantly lower than those in the high-GGT group (64.71 ± 21.35 vs. 68.64 ± 22.42 days, P = 0.001; 4.67 ± 1.03 vs. 4.89 ± 0.98 kg, P < 0.001). The levels of serum ALP, ALT, and AST in the low-GGT group were significantly higher than those in the high-GGT group before and 2 weeks after the surgery (ALP: 647.52 ± 244.10 vs. 594.14 ± 228.33 U/L, P < 0.001; ALT: 119.62 ± 97.14 vs. 96.01 ± 66.28 U/L, P < 0.001; AST: 218.00 ± 173.82 vs. 160.71 ± 96.32 U/L; P < 0.001). The INR of the low-GGT group was higher than that of the high-GGT group (1.05 ± 0.34 vs. 0.98 ± 0.20, P < 0.001), while FIB was lower than the high-GGT group (2.54 ± 0.67 vs. 2.73 ± 1.44 g/L; P = 0.006). The decreasing amplitude of TB and DB within 2 weeks after surgery in the low-GGT group was smaller than those in the high-GGT group (TB: 51.62 ± 71.22 vs. 61.67 ± 53.99 μmol/L, P = 0.003; DB: 33.22 ± 35.57 vs. 40.20 ± 35.93 μmol/L, P < 0.001). The jaundice clearance rate in the low-GGT group was significantly lower than that in the high-GGT group at 1, 3, and 6 months after surgery (17.70 vs. 26.05%; 35.17 vs. 48.58%; 38.62 vs. 54.64%, P < 0.001). In addition, the 2-year native liver survival rate in the low-GGT group was significantly lower than that of the high-GGT group (52.5 vs. 66.3%, P < 0.001 HR 1.80, 95% CI 1.38–2.33).ConclusionCompared to patients with high GGT, patients with normal or minimally elevated pre-operative GGT in BA were found to have poorer pre-operative liver function parameters, and post-operatively had lower jaundice clearance rates and worse 2-year native liver survival. This suggests a lower GGT at presentation in biliary atresia could be a sign of more severe liver injury.

Biochemical markers to predict the development of gastrointestinal bleeding and esophageal varices after portoenterostomy in biliary atresia

Gastrointestinal bleeding (GIB) due to esophageal varices (EV) is one of the factors that negatively impact native liver survival of patients with biliary atresia (BA). Gastrointestinal fibroscopy (GIF) is usually used to determine the presence of EVs; however, it requires general anesthesia. The aim of this study is to search for markers in blood tests obtained during routine check-ups that can predict the development of GIB. Data of patients with BA who underwent portoenterostomy at our hospital from 2014 to 2020 were retrospectively reviewed. The patients' data were assigned to three groups according to specific time points: Group B, which included data at GIB; Group NB-T, which included data at GIF and EV treatment; and Group NB-NT, which included data at GIF without treatment. The data in Group B were compared to those of other groups. In our study, GIB occurred in 11 patients, and 12 cases and 8 cases were classified into Groups NB-NT and NB-T, respectively. Compared with the other groups, only ChE and M2BPGi in Group B showed statistically significant differences. ChE and M2BPGi are useful for predicting GIB.

Impact of EFEMP1 on the survival outcome of biliary atresia in Thai infants

Genome-wide association studies (GWASs) have identified a genetic associated between EFEMP1 and biliary atresia (BA). To examine the susceptibility of single nucleotide polymorphisms (SNPs) in EFEMP1 in Thai BA patients, we performed an analysis of the genetic associations and biological interactions with previously reported key SNPs in ADD3, a key gene associated with BA. The study also used high-throughput sequencing to detect novel variants in both genes. In addition, the clinical impact of EFEMP1 SNPs in terms of survival association was also evaluated. The genotypes of 60 BA patients and 179 controls were evaluated using a TaqMan genotyping assay for rs2501577 and rs17095355 in ADD3 and rs6761893 and rs727878 in EFEMP1. The genotype frequencies were analyzed together with the SNP-SNP interactions. Fine mapping by whole-exome sequencing was performed to identify deleterious variants within both genes, and the survival analysis results were analyzed with the EFEMP1 SNPs. The recessive genotypes of rs2501577, rs17095355 and rs6761893 showed significantly higher frequencies in the BA patients than the controls, and a logistic regression showed that minor alleles of those SNPs increased the BA risk by ORs of 1.86, 1.67, and 1.84, respectively. Moreover, the SNP-SNP interference suggested that a combination of recessive alleles from the 2 genes resulted in an additive risk to BA. In addition, rare missense variants in the gene coding sequences were identified in 7 cases. Immunohistochemical studies revealed a pattern of ADD3 downregulation and EFEMP1 overexpression in the bile ducts of BA patients. Patients with the AA genotype of rs6761893 had significantly lower 5-year native liver survival (34.0%) than those with AT/TT (75.0%), with a log-rank p value of 0.041. Variants in EFEMP1 are associated with the occurrence of BA in Thai patients. In addition, these variants have an additive influence on BA risk when combined with ADD3 variants. Moreover, rs6761893 in EFEMP1 was indicative of survival in Thai BA patients.

Laparoscopic revision of Kasai portoenterostomy after initial laparoscopic portoenterostomy in patients with biliary atresia: a limited but positive effect on native liver survival.

It is important for patients with biliary atresia (BA) to retain the native liver after Kasai portoenterostomy (PE). Laparoscopic PE (Lap-PE) is standard, whereas laparoscopic revision of PE (Lap-revision) is performed as needed. We report the medium-term outcomes of Lap-revision. We retrospectively reviewed the demographics and outcomes of 63 patients who underwent Lap-PE between 2013 and 2021. Indications for revision included recurrent jaundice, repeat cholangitis, and persistent jaundice with temporary biliary excretion following the initial PE. We compared liver transplantation (LT) data of patients who underwent Lap-revision with those of patients who did not. Lap-revision was performed in 20 patients. Of those 17 (excluding the two who were jaundice-free before the age of 1, and the one who underwent open conversion for bleeding), 11 (65%) were jaundice-free 1year after Lap-revision. The surgical parameters of LT did not differ between patients who underwent Lap-revision and those who did not. Lap-revision for patients with BA had a limited but positive effect on native liver survival and did not adversely affect subsequent LT. Therefore, Lap-revision could be second-line standard therapy in patients with BA who have demonstrated biliary drainage at least once after initial PE.

Impact of early Kasai portoenterostomy on short-term outcomes of biliary atresia: A systematic review and meta-analysis.

BackgroundGood outcomes of biliary atresia (BA) are conventionally achieved after early Kasai portoenterostomy (KP). However, in some recent pieces of literature, there are discrepancies in the influence of age in Kasai procedure on postoperative short-term prognosis. This meta-analysis aims to evaluate the effects of earlier KP on short-term surgical prognosis of BA and clarify these discrepancies in recent studies.MethodsTo identify related studies, PubMed, Embase, Web of Science, Cochrane, and the Chinese National Knowledge Infrastructure database were searched up to March 2022. Data for the impact of age at KP on clinical prognosis were extracted, including jaundice clearance rate (JCR) and native liver survival rate (NLSR).ResultsA total of 14 articles were included in the present study, which involve a total of 3,276 patients with BA who underwent Kasai procedure. Compared with patients older than 91 days of age, patients 90 days of age or younger exhibited significantly better JCR [odds ratio (OR), 3.05; 95% confidence interval (CI), 2.23–4.17; P < .001] and a more favorable NLSR (OR, 1.72; 95% CI, 1.37–2.15; P < .001). The NLSR of patients younger than 60 days of age was significantly higher than those of patients from 61 to 90 days of age (OR, 1.41; 95% CI, 1.18–1.68; P < .001). There was no significant difference in JCRs between patients aged 60 days of age or younger and those aged 61–90 days of age (OR, 1.31; 95% CI, 0.95–1.81; P = 0.10). Among patients 30 days of age or younger, 31–45 days of age, and 46–60 days of age, there were also no significant differences in JCR.ConclusionA significantly better short-term JCR and NLSRs were achieved among patients with BA treated using a KP procedure at ≤90 days of age compared with those treated at >90 days of age. There was no further improvement in the short-term JCR when the procedure was performed at ≤60 days compared with those treated at 61–90 days of age. However, treatment at ≤60 days of age was associated with a significant improvement in NLSR. Therefore, the timing of KP does exert an important effect on short-term clinical outcomes of patients with BA.

The Outcome of Patients With Cystic Biliary Atresia With Intact Proximal Hepatic Ducts Following Hepatic-Cyst-Jejunostomy.

To determine the outcomes of patients with cystic biliary atresia by correlating the anatomy of the hepatic ducts with the choice of biliary reconstruction surgery. The Kasai hepatoportoenterostomy (Kasai) is the initial surgical procedure offered to most patients with biliary atresia. In contrast, a hepatic-cyst-jejunostomy has been reported to be effective in patients with the cystic form of biliary atresia. We performed an international multicenter retrospective review. Two hundred eighty-seven patients were included, and 33 cases of cystic biliary atresia were identified. Outcomes were the serum total bilirubin level 3 months post-surgery and native liver survival at 2 years of age and were compared between cases who received the Kasai versus hepatic-cyst-jejunostomy in correlation to the anatomy of proximal hepatic ducts. The patients were categorized into 3 anatomical groups: patent intact hepatic ducts (n = 10), patent hypoplastic hepatic ducts (n = 13), and obliterated hepatic ducts (n = 10). All 10 patients with patent intact hepatic duct group underwent hepatic-cyst-jejunostomy, and 9 experienced bile drainage and native liver survival. Among the 13 patients with hypoplastic hepatic ducts, 11 underwent the Kasai procedure, and 9 had bile drainage, whereas 2 underwent hepatic-cyst-jejunostomy, and one survived with the native liver. All of the patients with obliterated hepatic ducts underwent the Kasai procedure; 5 established biliary drainage and survived with the native liver. Of 5 who did not drain, 3 underwent liver transplantation. In patients with cystic biliary atresia, the subset with a connection between cyst and intrahepatic bile ducts via intact proximal hepatic ducts had favorable clinical outcomes following hepatic-cyst-jejunostomy.

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia

Biliary atresia (BA) is a chronic neonatal cholangiopathy characterized by fibroinflammatory bile duct damage. Reliable biomarkers for predicting native liver survival (NLS) following portoenterostomy (PE) surgery are lacking. Herein we explore the utility of 22 preidentified profibrotic molecules closely connected to ductular reaction (DR) and prevailing after successful PE (SPE), in predicting PE outcomes and liver injury. We used qPCR and immunohistochemistry in a BA cohort including liver samples obtained at PE (n = 53) and during postoperative follow-up after SPE (n = 25). Of the 13 genes over-expressed in relation to cholestatic age-matched controls at PE, only secretin receptor (SCTR) expression predicted cumulative 5-year NLS and clearance of jaundice. Patients in the highest SCTR expression tertile showed 34–55% lower NLS than other groups at 1–5 years after PE (P = 0.006–0.04 for each year). SCTR expression was also significantly lower [42 (24–63) vs 75 (39–107) fold, P = 0.015] among those who normalized their serum bilirubin after PE. Liver SCTR expression localized in cholangiocytes and correlated positively with liver fibrosis, DR, and transcriptional markers of fibrosis (ACTA2) and cholangiocytes (KRT7, KRT19) both at PE and after SPE. SCTR is a promising prognostic marker for PE outcomes and associates with liver injury in BA.

Long-Term Outcomes of Patients With Progressive Familial Intrahepatic Cholestasis After Biliary Diversion.

Progressive familial intrahepatic cholestasis is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis. Patients with this disease typically present with cholestasis and pruritus early in life and often progress to end-stage liver disease. The clinical symptoms that patients with progressive familial intrahepatic cholestasis encounter are usually refractory to medical treatment. Although the effects of biliary diversion surgery on native liver survival are not exactly known, this procedure may provide a positive impact on pruritus and laboratory parameters in these patients. We retrospectively evaluated the clinical and laboratory characteristics of patients with progressive familial intrahepatic cholestasis who underwent partial external biliary diversion between 2002 and 2020 at our center. Diagnosis of progressive familial intrahepatic cholestasis was made by clinical, biochemical, and histopathological characteristics as well as genetic testing. Nine patients were included in the study. Five patients required liver transplant during follow-up, with 4 having liver transplant as a result of endstage liver disease (median interval of 5 years). In 1 patient, partial external biliary diversion was performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up (median follow-up time of 7.6 years). Pruritus responded well to partial external biliary diversion in all patients. Among laboratory values evaluated 6 months after biliary diversion, only albumin showed significant improvement. Partial external biliary diversion had favorable results on long-term follow-up. This procedure can provide the relief of pruritus and delay the requirement for liver transplant in patients with progressive familial intrahepatic cholestasis. In our view, partial external biliary diversion should be considered the first-line surgical management for patients with this disease.

Biliary atresia: graft-versus-host disease with maternal microchimerism as an etiopathogenesis

Biliary atresia (BA) is an inflammatory disease of the biliary system in newborns and infants. The etiology is largely unknown. Approximately half of BA patients require liver transplantation by 20 years of age, even after surgical correction due to progressive fibrosis of the liver. Regarding the disease mechanism, there is circumstantial evidence to support the hypothesis of graft-versus-host disease because of the existence of maternal cells in the liver (maternal microchimerism, MMC), histopathological similarity of the liver and an intense maternal response to the BA patient with mixed lymphocyte culture. Immune dysregulation with decreased Treg and increased Th1 and Th17 cells are the pathogenic features of BA, which are homologous to the pathogenic features of GvHD.Further elucidation of the etiopathogenetic mechanism of BA is warranted for development of new therapeutic strategies for native liver survival.

SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury.

The transcription factor sex-determining region Y-box 9 (SOX9) is a biliary epithelial marker ectopically expressed in hepatocytes (SOX9 + hepatocytes). SOX9 + hepatocytes are believed to function in ductular reaction (DR), recognized as an essential phenomenon related to liver regeneration; however, the functional role of SOX9 and clinical implications of SOX9 + hepatocytes in DR progression are unclear. Human and mouse liver samples were subjected to immunohistochemical and gene functional analyses to investigate the functional role of SOX9 and the clinical significance of SOX9 + hepatocytes. SOX9 + hepatocytes were observed in a bile duct ligation (BDL) mouse model. Forced Sox9 expression in mouse hepatocytes by hydrodynamic injection converted them into cholangiocyte-like cells. DR progression was slower in liver epithelium-specific Sox9-knockout BDL mice than in wild-type BDL mice. SOX9 + hepatocytes were also observed in rare pediatric liver disease biliary atresia (BA). In patients with BA who underwent liver transplantation (LT), the median number of SOX9 + hepatocytes at LT was significantly lower than that at Kasai portoenterostomy (KP) performed prior to LT (P < 0.001). The high SOX9 + hepatocyte group at KP demonstrated significantly better native liver survival rates than the low SOX9 + hepatocyte group at a cut-off of 390 cells/mm2 (P = 0.019, log-rank test). Ectopic expression of SOX9 in hepatocytes of chronically injured livers may exert protective effects in DR progression. To our knowledge, this is the first study showing that SOX9 + hepatocyte count at KP can be a promising biomarker to predict native liver survival after KP in patients with BA.

A Novel Model for Predicting the Clearance of Jaundice in Patients With Biliary Atresia After Kasai Procedure.

BackgroundThe failed clearance of jaundice (CJ) in patients with biliary atresia (BA) after the Kasai procedure (KP) often leads to a shorter native liver survival (NLS) time and earlier liver transplantation. We aimed to investigate risk factors of failed CJ and establish a novel nomogram model to predict the status of CJ.MethodsWe retrospectively reviewed institutional medical records from January 2015 to April 2020 and enrolled BA patients post-KP, randomly divided into training and testing cohorts at a ratio of 7:3, and further subdivided into cleared and uncleared jaundice groups. Univariate and multiple logistic regression analyses were used to select risk factors to establish the nomogram in the training cohort. The performance of the nomogram was evaluated by calculating the areas under the receiver operating curve (AUC) in both cohorts.ResultsThis study included 175 BA patients post-KP. After univariate and multiple logistic regression analyses, Cytomegalovirus IgM +ve associated BA (OR = 3.38; 95% CI 1.01–11.32; P = 0.04), ln γ-glutamyl transpeptidase (GGT) (OR = 0.41; 95% CI 0.22–0.80; P = 0.009), thickness of the fibrous portal plate (OR = 0.45; 95% CI 0.27–0.76; P = 0.003), liver stiffness measurement (LSM) (OR = 1.19; 95% CI 1.06–1.34; P = 0.002), and multiple episodes of cholangitis (OR = 1.65; 95% CI 1.13–2.41; P = 0.01) were identified as independent risk factors of unsuccessful CJ to construct the nomogram. The receiver operating characteristic curve (ROC) analysis suggested good nomogram performance in both the training (AUC = 0.96) and testing cohorts (AUC = 0.91).ConclusionOur nomogram model including several risk factors effectively predicts CJ in patients post-KP, which could aid in clinical decision-making.

Laparoscopic Kasai portoenterostomy can be a standard surgical procedure for treatment of biliary atresia.

BACKGROUNDBiliary atresia (BA) is a rare pediatric disease.AIMTo compare the outcomes of laparoscopic portoenterostomy (Lap-PE) with those of laparotomy (Open-PE) at a single institution. METHODSThe surgical outcomes of PE were retrospectively analyzed for patients with a non-correctable type of BA from 2003 to 2020.RESULTSThroughout the assessment period, 119 patients received PE for BA treatment, including 66 Open-PE and 53 Lap-PE cases. Although the operation duration was longer (medians: for Open-PE, 242 min; for Lap-PE, 341 min; P < 0.001), blood loss was considerably less (medians: for Open-PE, 52 mL; for Lap-PE, 24 mL; P < 0.001) in the Lap-PE group than in the Open-PE group. The postoperative recovery of the Lap-PE group was more favorable; specifically, both times to resume oral intake and drain removal were significantly shorter in the Lap-PE group. Complete resolution of jaundice was observed in 45 Open-PE cases and 42 Lap-PE cases, with no statistically significant difference (P = 0.176). Native liver survival rates were >80% for both groups for the first half year post surgery, followed by a gradual decrease with time; there were no statistically significant differences in the native liver survival rates for any durations assessed.CONCLUSIONLap-PE could be a standard therapy for BA.

Usefulness of Living Donor Liver Transplantation for Patients After Undergoing the Kasai Operation for Biliary Atresia

Living donor liver transplantation (LDLT) has been actively performed for patients with poor clearance of jaundice after the Kasai operation for biliary atresia (BA). The present study clarified the usefulness of LDLT for BA. Between 2000 and 2020, 24 patients (late group) underwent radical surgery for BA in our institute. The overall survival rate, native liver survival rate, and proportion of LDLT in the late group were retrospectively compared with those of 47 patients treated before 1999 (early group). P values <.05 was considered statistically significant. The overall survival rates at 5, 10, and 15 years were 57%, 54%, and 49%, respectively, in the early group and 100%, 100%, and 100% in the late group (P < .001). The native liver survival rates at 5, 10, and 15 years were 57%, 52%, and 39%, respectively, in the early group and 57%, 49%, and 42% (P=.993) in the late group. In the early group, LDLT was performed in 7 of 47 patients (15%), and the overall survival rate after LDLT was 71%. In the late group, LDLT was performed in 11 of 24 patients (46%), and the overall survival rate after LDLT was 100%. The long-term outcomes after the Kasai operation for BA have improved in recent years. There were no marked differences in long-term native liver survival before and after 2000. LDLT was actively introduced for patients with poor clearance of jaundice after the Kasai operation, and the survival rate significantly improved.

Cholangitis Definition and Treatment after Kasai Hepatoportoenterostomy for Biliary Atresia: A Delphi Process and International Expert Panel.

(1) Background: Acute cholangitis during the first year after Kasai hepatoportoenterostomy (HPE) has a negative impact on patient and native liver survival. There are no consistent guidelines for the definition, treatment, and prophylaxis of cholangitis after HPE. The aim of this study was to develop definition, treatment, and prophylaxis guidelines to allow for expeditious management and for standardization in reporting. (2) Methods: the Delphi method, an extensive literature review, iterative rounds of surveys, and expert panel discussions were used to establish definition, treatment, and prophylaxis guidelines for cholangitis in the first year after HPE. (3) Results: Eight elements (pooled into two groups: clinical and laboratory/imaging) were identified to define cholangitis after HPE. The final proposed definitions for suspected and confirmed cholangitis are a combination of one element, respectively, two elements from each group; furthermore, the finding of a positive blood culture was added to the definition of confirmed cholangitis. The durations for prophylaxis and treatment of suspected and confirmed cholangitis were uniformly agreed upon by the experts. (4) Conclusions: for the first time, an international consensus was found for guidelines for definition, treatment, and prophylaxis for cholangitis during the first year after Kasai HPE. Applicability will need further prospective multicentered studies.