Optimal transplant strategy of pediatric liver transplantation for fibropolycystic liver disease: Multicenter retrospective study in Japan.

AIM: To assess the preoperative disease characteristics and indications for living donor liver transplantation (LDLT), complications, patient survival, and prognosis after LDLT for fibropolycystic liver disease (FLD) in children. METHODS: We undertook a cross-sectional survey of patients who underwent LDLT for FLD between January 2002 and December 2020. RESULTS: A total of 35 patients (22 male and 13 female individuals) with FLD were included in this study, of whom 19 (54.3%) had isolated congenital hepatic fibrosis and 16 (45.6%) had Caroli syndrome. Refractory gastrointestinal bleeding was the most frequent symptom related to the indication for LDLT, being found in 48.6% of our patients, followed by uncontrollable cholangitis and ascites. The median age at the time of LDLT was 8.1 years old. Of the 27 patients presenting with renal involvement, 13 patients required kidney transplantation (KT). Overall, the renal function after LDLT decreased regardless of renal involvement; however, patients with renal involvement had a significantly lower estimated glomerular filtration rate than those without renal involvement throughout the course of this study (p < 0.01). The 5-year overall patient survival rate was 97.1%. Two patients died with a median follow-up of 8.9 years after LDLT; one died due to sepsis 2 weeks after simultaneous liver-kidney transplantation and the other committed suicide 10 years after LDLT. CONCLUSION: The prognosis of the pediatric patients who underwent LDLT for FLD was excellent. However, an individualized treatment approach based on the status of the renal function and liver disease is important, as a certain proportion of patients require KT.

Comprehensive analyses of neurodevelopmental outcomes and quality of life of children with biliary atresia.

OBJECTIVES: To holistically evaluate neurodevelopmental outcomes and quality of life (QOL) of Japanese patients with biliary atresia (BA) and to investigate the factors associated with the outcomes. METHODS: This study enrolled patients with BA aged 5-18 years who visited Osaka University Hospital in 2021. Neurodevelopmental assessments were performed to evaluate intellectual ability, cognitive functions and adaptive skill levels. Furthermore, emotional and behavioral issues, characteristics of attention deficit hyperactivity disorder, and QOL were concomitantly assessed in the same cohort. Biochemical and social factors associated with the results were examined. RESULTS: Fifty-three patients, with a median age of 11.2 years were included in the analyses. Patients with BA had a significantly lower Full-Scale Intelligence Quotient or developmental quotient (FSIQ/DQ) score and Vineland Adaptive Behavior Scale (VABS) composite score than the general Japanese population. Household education level and short stature were associated with low and borderline FSIQ/DQ and VABS composite scores, respectively. Among patients with low and borderline FSIQ/DQ scores, those with average or high VABS composite scores received significantly less neuroeducational care than those with low and borderline VABS composite scores. Despite the low FSIQ/DQ and VABS composite scores, the total QOL scores were higher than those of the general population. CONCLUSION: Patients with BA had intellectual and behavioral impairments. Notably, patients with intellectual impairments are overlooked and not followed up, especially if adaptive skills are maintained.

Major complications after percutaneous biopsy of native or transplanted liver in pediatric patients: a nationwide inpatient database study in Japan.

AIM: Although major complication rates following percutaneous liver biopsy (PLB) have been reported to be higher in children than in adults, scarce data are available regarding pediatric patients stratified by native and transplanted liver. We aimed to assess the factors associated with major complications after percutaneous biopsy of native or transplanted liver using a nationwide inpatient database. METHODS: Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified pediatric patients who underwent PLB between 2010 and 2018. We described major complication rates and analyzed factors associated with major complications following PLB, stratified by native and transplanted liver. RESULTS: We identified 3584 pediatric PLBs among 1732 patients from 239 hospitals throughout Japan during the study period, including 1310 in the native liver and 2274 in the transplanted liver. Major complications following PLB were observed in 0.5% (n = 18) of the total cases; PLB in the transplanted liver had major complications less frequently than those in the native liver (0.2% vs. 1.0%, p = 0.002). The occurrence of major complications was associated with younger age, liver cancers, unscheduled admission, anemia or coagulation disorders in cases with native liver, while it was associated with younger age alone in cases with transplanted liver. CONCLUSIONS: The present study, using a nationwide database, found that major complications occurred more frequently in pediatric cases with native liver and identified several factors associated with its major complications.

Clinical practice guidelines for the management of children with mother-to-child transmitted hepatitis C virus infection.

BACKGROUND: The first guidelines for care of pregnant women carrying the hepatitis C virus (HCV) and their infants were published in 2005 in Japan. Since then, evidence has gradually accumulated worldwide regarding the natural course and treatment of this condition and, especially in recent years, treatment for chronic hepatitis C in adult patients has made great progress. However, the clinical practice policy for children has not been standardized, and new clinical practice guidelines for children with mother-to-child (MTC) transmitted HCV infection have become necessary. METHODS: In the development of the current guideline, we requested cooperation from The Japanese Society for Pediatric Infectious Diseases, The Japan Society of Hepatology, and the Japan Society of Obstetrics and Gynecology. The committee members were recommended and approved by each society to participate in developing the guidelines. The guideline was also created in accordance with the Minds Guide for Practice Guideline Development. The statements were prepared by consensus-building using the Delphi method, based on the comprehensively searched academic papers and guidelines. These articles were retrieved through searching the PubMed, Cochrane Library, and the Igaku Chuo Zasshi databases. RESULTS: Eight clinical questions (CQs) with clinical statements were developed regarding etiology (CQs 1-3), diagnosis (CQs 4 and 5), and treatment (two CQs 6 and 7). In each statement, the consensus rate, evidence level, and recommendation level were determined. CONCLUSION: The guidelines will be helpful in the management of children with hepatitis C MTC transmission.

Early detection of liver fibrosis with serum Mac-2 binding protein glycosylation-modified isomer (M2BPGi) during follow-up intestinal failure patients without intestinal failure-associated liver disease (IFALD).

PURPOSE: Mac-2 binding protein glycosylation-modified isomer (M2BPGi) is a new marker for hepatic fibrosis progression. We examined the relationship between serum M2BPGi levels and liver histological findings in intestinal failure (IF) patients without IF-associated liver disease (IFALD). METHODS: This study included IF patients without IFALD followed at our hospital. All patients underwent routine liver biopsies per protocol every 1-2 years. We examined M2BPGi levels and histological findings in relation to aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and AST/ALT ratio. Liver fibrosis was evaluated based on the METAVIR score. RESULTS: Total 18 liver biopsies out of eight patients were included. The median age was 11.5 years. Mean M2BPGi was 0.44 cutoff index (COI) in patients with F0 fibrosis, 0.78 COI in patients with F1 fibrosis and 1.63 COI in patients with F2 fibrosis. Mean M2BPGi was significantly higher in patients with F2 versus F1 or F0 fibrosis (P < 0.016 and P < 0.028, respectively). M2BPGi levels were more strongly correlated with fibrosis stage than with other conventional fibrosis markers. CONCLUSION: Serum M2BPGi is a novel marker of liver fibrosis in patients with IF. It is useful for follow-up prior to IFALD. Serum M2BPGi levels can support the interpretation of liver status.

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study.

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.

Effect of microscopy-assisted portoenterostomy (MAPE) for biliary atresia.

PURPOSE: Portoenterostomy (PE) is the standard treatment for biliary atresia (BA). However, micro-bile ducts are difficult to identify with surgical loupes and dissect systematically. We report the effects of our attempts to dissect hilar tissue using a surgical microscope. METHODS: Microscopy-assisted portoenterostomy (MAPE) was initiated in 2014. Patients born between 2000 and 2013 who underwent PE until day 70 without a surgical microscope for BA were gathered as historical control. MAPE in re-do PE cases (Re-MAPE) was evaluated in the same manner. RESULTS: Ten patients underwent MAPE for BA during the study period. 17 patients in the conventional PE group were gathered. In the MAPE group, the jaundice clearance rate was 80%, compared with 53% in the conventional PE group. Re-MAPE was performed in four patients, who had a jaundice clearance rate of 75%, essentially identical to the rate with initial MAPE. At age 4 years, the native liver survival rate was 58% in the MAPE group and 38% in the conventional PE group. The native liver survival rate in the Re-MAPE group was 75%. CONCLUSION: MAPE is useful for sharing the surgical field during open PE in patients with BA. It may improve the rate of jaundice clearance.

Proposal of a liver histology-based scoring system for bile salt export pump deficiency.

AIM: Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. METHODS: After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. RESULTS: Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged. CONCLUSIONS: The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.

CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.

AIM: Bile acid biosynthesis is strictly regulated under physiological conditions. The expression of fibroblast growth factor (FGF) 19 is induced when bile acids bind to the farnesoid X receptor in the intestinal epithelium. Fibroblast growth factor 19 is then transported by the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1), a key enzyme in bile acid biosynthesis, through the extracellular signal-regulated kinase (ERK) pathway. However, the regulatory mechanisms of these signaling pathways in hepatocytes under chronic cholestasis remain unclear. We investigated the regulation of these signaling pathways in patients with biliary atresia (BA). METHODS: We analyzed the regulation of molecules in these signaling pathways using liver and serum samples from eight BA children and four non-cholestatic disease controls. RESULTS: CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. Fibroblast growth factor receptor 4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET. CONCLUSIONS: This is the first study to measure the CYP7A1 mRNA levels in human BA HET. Fibroblast growth factor 19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.

Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis.

PURPOSE: Biliary atresia (BA) is characterized by progressive liver fibrosis, but it is difficult to assess the progression after the patient develops cirrhosis. Mac-2-binding protein glycosylation isomer (M2BPGi) is a new marker for hepatic fibrosis. We examined the chronological changes in M2BPGi levels in BA patients with cirrhosis. METHODS: Patients with cirrhosis were selected from among pediatric BA patients who had their native livers. Serum M2BPGi levels and Child-Pugh classification were evaluated. A total of 11 pediatric BA patients with cirrhosis were recruited. RESULTS: Initial M2BPGi level after diagnosis of liver cirrhosis based on liver biopsy was on average 3.4, and the most recent M2BPGi level under observation was on average 4.3. The follow-up period from the initial M2BPGi measurement averaged 22.6 months. The ratio of the initial and most recent values (M2BPGi ratio) was on average 1.3 (0.5-2.4). Three cases with improved fibrosis (M2BPGi ratio < 1.0) remained in Child A, as did six cases (1.0 ≤ M2BPGi ratio < 2.0), but two cases with marked fibrosis progression (2.0 ≤ M2BPGi ratio) advanced to decompensated cirrhosis Child B. CONCLUSION: M2BPGi is useful as a prognostic factor for BA patients with liver cirrhosis. In addition, fibrosis improved even after the development of cirrhosis.

The effect of maternal grafts in early acute cellular rejection after pediatric living-donor liver transplantation.

PURPOSE: Living-donor liver transplantations (LDLTs) with maternal grafts can be more successful than those with paternal grafts because of their tolerance to non-inherited maternal antigens. We reviewed LDLT patients to investigate the relationship between acute rejection and donor sex. METHODS: LDLT patients between January 2010 and November 2015 were enrolled. ACR was defined by a rejection activity index of > 3. RESULTS: Forty-six patients (22 males and 24 females), of whom 28 had biliary atresia, were enrolled. The median age of the patients was 2.8 years and the donor types were maternal (n = 25) and paternal (n = 21). Acute cellular rejection (ACR) was observed in 22 patients. Twelve (48%) of the 25 patients in the maternal group had at least one episode of rejection compared with 10 (48%) of the 21 in the paternal group. Among the patients with ACR, the first rejection in the maternal group occurred significantly earlier than that in the paternal group (p < 0.01). In the multivariable analysis, the only variable significantly related to the first rejection day after LDLT was donor sex (male) (p < 0.005). CONCLUSION: Our results showed that maternal grafts had an effect on causing earlier ACR in LDLT.

Total Bile Acid Concentration in Duodenal Fluid Is a Useful Preoperative Screening Marker to Rule Out Biliary Atresia.

OBJECTIVES: Duodenal tube test (DTT) is used as a preoperative screening to rule out biliary atresia (BA). In previous reports, DTT was assessed by the color of the duodenal fluid, but there were no quantitative criteria. The aim of this study was to examine the efficacy of DTT based on the total bile acid (TBA) concentration in duodenal fluid. METHODS: This is a single-center retrospective study of infants with cholestasis who underwent DTT from 2008 to 2016 at the Osaka University Hospital. The cut-off values of maximum TBA in duodenal fluid (dTBA), dTBA/serum TBA ratio (sTBA), and dTBA/serum gamma-glutamyl transpeptidase (sGGT) ratio were assessed for the accuracy in excluding BA. RESULTS: A total of 37 infants were included in this study; 16 infants with BA and 21 infants with other causes of intrahepatic cholestasis. dTBA demonstrated sensitivity of 100% and specificity of 90.5% with the cut-off value of 16.8 µmol/L. Specificity was further improved to 95.2% with dTBA/sTBA ratio (cut-off value: 0.088) and 100% with dTBA/sGGT ratio (cut-off value: 0.076 µmol/U). DTT could be performed 0.8 ±â€Š1.4 days after admission. Hypoglycemia was developed in 1 infant. CONCLUSIONS: DTT evaluated by dTBA, dTBA/sTBA ratio, and dTBA/sGGT ratio had high accuracy to rule out BA and could avoid unnecessary surgery in some infants.

Clinical implications of serum Mac-2-binding protein (M2BPGi) during regular follow-up of patients with biliary atresia.

PURPOSE: The Mac-2-binding protein glycosylation-modified isomer (M2BPGi) is a new marker for progression of hepatic fibrosis. We examined the relationship between serum M2BPGi levels and liver histological findings in patients with biliary atresia (BA) who were not transplant candidates. METHODS: Patients with BA who were not transplant candidates with good liver function were included. We examined M2BPGi levels and histological findings in relation to other laboratory markers of liver fibrosis, including aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and type IV collagen 7s domain. Liver fibrosis was evaluated based on the METVIR score. RESULTS: 37 patients were included. The median age was 18 years (range 3-38 years). M2BPGi values ranged from 0.3 to 6.9 cutoff index (COI) (median 1.6). The degree of liver fibrosis varied with M2BPGi level. For predicting cirrhosis (F4) and advanced liver fibrosis (≥ F3), M2BPGi had higher areas under the curve (AUCs; 0.93, respectively) with cutoff COIs of 1.84 and 1.67, respectively, than for the four conventional markers for fibrosis. CONCLUSION: M2BPGi is a novel marker for liver fibrosis in patients with BA. It is especially useful for following patients with BA with a native liver and supporting liver biopsy interpretation findings.

Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment.

Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid ß-oxidation cycle between 22 citrin-deficient children (age, 3-13years) with normal liver functions and 37 healthy controls (age, 5-13years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p<0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p<0.001). The plasma level of 3-OH-butyrate derived from fatty acid ß-oxidation was significantly higher in the affected group (p<0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p<0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.

Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates.

BackgroundHeterozygous mutations in the gene ABCB4, encoding the phospholipid floppase MDR3 (Mdr2 in mice), are associated with various chronic liver diseases. Here we hypothesize that reduced ABCB4 expression predisposes to extrahepatic biliary atresia (EHBA).MethodsLivers from neonatal wild-type (wt) and heterozygous Mdr2-deficient mice were subjected to mass spectrometry-based lipidomics and RNA sequencing studies. Following postnatal infection with rhesus rotavirus (RRV), liver immune responses and EHBA phenotype were assessed. Hepatic microarray data from 40 infants with EHBA were mined for expression levels of ABCB4.ResultsPhosphatidylcholine (PC) and phosphatidylethanolamine (PE) were increased, whereas the PC/PE ratio was decreased in neonatal Mdr2+/- mice compared with wt mice. Following RRV challenge, hepatic expression of IFNγ and infiltration with CD8+ and NK+ lymphocytes were increased in Mdr2+/- mice. Plasma total bilirubin levels and prevalence of complete ductal obstruction were higher in these mice. In infants with EHBA, hepatic gene expression of ABCB4 was downregulated in those with an inflammatory compared with a fibrosing molecular phenotype.ConclusionDecreased expression of ABCB4 causes dysregulation in (phospho)lipid homeostasis, and predisposes to aberrant pro-inflammatory lymphocyte responses and an aggravated phenotype of EHBA in neonatal mice. Downregulated ABCB4 is associated with an inflammatory transcriptome signature in infants with EHBA.

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

PURPOSE: 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. METHODS: 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. RESULTS: The study population consisted of 88 BA patients. The median follow-up duration was 11.6 years (range 0.8-26.0 years). 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: 4 years, PoPH: 15 years, P < 0.019). Two patients (66%) with PoPH died, while all patients with HPS survivied. CONCLUSION: 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.

Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease.

UNLABELLED: Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice. CONCLUSION: The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA.

Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia.

In the United States, biliary atresia (BA) is the most frequent indication for liver transplantation in pediatric patients. BA is a complex disease, with suspected environmental and genetic risk factors. A genome-wide association study in Chinese patients identified association to the 10q24.2 (hg18) genomic region. This signal was upstream of two genes, XPNPEP1 and ADD3, both expressed in intrahepatic bile ducts. We tested association to this region in 171 BA patients and 1,630 controls of European descent and found the strongest signal to be at rs7099604 (p = 2.5 × 10(-3)) in intron 1 of the ADD3 gene. Moreover, expression data suggest that ADD3, but not XPNPEP1, is differentially expressed in BA patients. The role of ADD3 in biliary development is unclear, but our findings suggest that this gene may be functionally relevant for the development of BA.

Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2.

BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS: From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS: Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS: Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.

Biliary atresia: will blocking inflammation tame the disease?

Biliary atresia is the most common cholangiopathy of childhood. With complete obstruction of segments or the entire length of extrahepatic bile ducts, the timely pursuit of hepatoportoenterostomy is the best strategy to restore bile drainage. However, even with prompt surgical intervention, ongoing injury of intrahepatic bile ducts and progressive cholangiopathy lead to end-stage cirrhosis. The pace of disease progression is not uniform; it may relate to clinical forms of disease and/or staging of liver pathology at diagnosis. Although the etiology of disease is not yet defined, several biological processes have been linked to pathogenic mechanisms of bile duct injury. Among them, there is increasing evidence that the immune system targets the duct epithelium and disrupts bile flow. We discuss how careful clinical phenotyping, staging of disease, and basic mechanistic research are providing insights into clinical trial designs and directions for development of new therapies to block progression of disease.