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The article presents the current views on genetics, features of metabolic disorders, course of various clinical manifestations, diagnostic criteria, and treatment principles for monogenic enzymopathy — an inherited α1;antitrypsin (AAT) deficiency. Inherited AAT deficiency manifests itself as four clinical syndromes: respiratory disease (pulmonary emphysema, chronic obstructive pulmonary disease (COPD), bronchial asthma, spontaneous pneumothorax, bronchiectasis); liver disease and blood vessel damage. Respiratory disease manifests itself between the ages of 20–40 years. Chronic pulmonary emphysema is typical for homozygous PiZZ gene carriers. The most unfavorable clinical course variant including persistent cough, COPD development, bronchial asthma, pneumonia, co-existence of various respiratory diseases and severe disorders of external respiration is the PISZ phenotype. Bronchial asthma has severe clinical course with torpid purulent endobronchitis; is often uncontrolled despite background therapy. In COPD patients, exacerbations are frequent, severe, and prolonged. The reduction in the vessels of the pulmonary circulation results in pulmonary hypertension, right ventricular failure. In AAT deficiency, there is a high incidence of bronchiectasis, lung cancer. Liver diseases manifest themselves as neonatal hepatitis, biliary atresia, liver cirrhosis, infectious complications. Chronic form is characterized by subclinical changes in the biochemical parameters of liver function most of which (up to 70%) normalize before the age of 18 years. In patients until the age of 20 years, disease slowly progresses and leads to the development of liver cirrhosis in 30% of cases, while older patients develop liver cirrhosis in 30–50% of cases. Some patients have a benign course of liver disease and present with hepatomegaly. Hemorrhagic syndrome occurs when protease inhibitor gene product acquires the properties of antithrombin. Vascular disease manifests itself as necrotizing panniculitis, severe hemorrhagic vasculitis with serum antineutrophil cytoplasmic antibodies to proteinase (С-АNСА). AAT deficiency may coexist with systemic vasculitis, vascular aneurysm, many other diseases, as well as with the development of aplastic processes of various localization. In addition to clinical manifestations, diagnosis of inherited AAT deficiency includes screening programs, instrumental (X-ray, spirometry, ECG, ultrasound), laboratory (liver function, coagulation profile, immunogram, serum AAT concentration), genetic investigations, exclusion testing for cystic fibrosis, viral hepatitis, and other diseases. Treatment of patients with inherited AAT deficiency consists in adequate nutrition and physical activity; treatment of pre-existing conditions; prevention and timely therapy for respiratory infections; pathogenetic therapy. Pathogenetic therapy for AAT deficiency is a replacement (augmentation) therapy with exogenous α1-antitrypsin concentrate. Replacement therapy is indicated only in patients >18 years of age with the PiZZ phenotype or other rare AAT phenotypes. No conflict of interest was declared by the author. Key words: children, inherited α1-antitrypsin deficiency, diagnosis, therapy.

Background Congenital biliary atresia is a type of obstruction of the bile ducts inside and outside the liver, which can lead to cholestatic liver cirrhosis and eventually liver failure. The preduodenal portal vein (PD-PV) is a rare developmental malformation of the PV. The PV courses in front of the duodenum. However, very few cases of neonatal biliary atresia combined with PD-PV have been reported in the scientific literature. Case summary A 1-mo-and-4-d-old child was admitted to the hospital in January because of yellowish skin. After surgical consultation, surgical intervention was recommended. The child underwent Hilar-jejunal anastomosis, duodenal rhomboid anastomosis, and abdominal drainage under general anesthesia. During the operation, the PV was located at the anterior edge of the duodenum. Conclusion Diagnoses: (1) Congenital biliary atresia; (2) PD-PV; and (3) Congenital cardiovascular malformations. Outcomes: Recommendation for liver transplantation. Lessons: The choice of treatment options for neonatal biliary atresia combined with PD-PV.

Successful portoenterostomy (SPE) improves the short-term outcome of patients with biliary atresia (BA) by relieving cholestasis and extending survival with native liver. Despite SPE, hepatic fibrosis progresses in most patients, leading to cirrhosis and a deterioration of liver function. The goal of this study was to characterize the effects of SPE on the BA liver transcriptome. We used messenger RNA sequencing to analyze global gene-expression patterns in liver biopsies obtained at the time of portoenterostomy (n = 13) and 1 year after SPE (n = 8). Biopsies from pediatric (n = 2) and adult (n = 2) organ donors and other neonatal cholestatic conditions (n = 5) served as controls. SPE was accompanied by attenuation of inflammation and concomitant up-regulation of key extracellular matrix (ECM) genes. Highly overexpressed genes promoting biliary fibrosis and bile duct integrity, such as integrin subunit beta 6 and previously unreported laminin subunit alpha 3, emerged as candidates to control liver fibrosis after SPE. At a cellular level, the relative abundance of activated hepatic stellate cells and liver macrophages decreased following SPE, whereas portal fibroblasts (PFs) and cholangiocytes persisted. Conclusion: The attenuation of inflammation following SPE coincides with emergence of an ECM molecular fingerprint, a set of profibrotic molecules mechanistically connected to biliary fibrosis. The persistence of activated PFs and cholangiocytes after SPE suggests a central role for these cell types in the progression of biliary fibrosis.

Background: : Pediatric patients sometimes develop graft fibrosis after living donor liver transplant (LDLT). Autotaxin is a recently developed serum marker for hepatic fibrosis. We studied the relationship between serum autotaxin levels and histological findings in patients after LDLT for biliary atresia (BA). Methods: Information on patients aged

Objective: This study aimed to use transient elastography (TE) to evaluate the correlation between liver stiffness measure (LSM) and functional status of native liver in longterm follow-up of pediatric patients with biliary atresia (BA). Methods: Twenty cases of BA who had undergone hepatic portoenterostomy and had good initial outcome (total bilirubin < 2 mg/dL) were enrolled for a transient elastography. The LSMs derived from the study were analyzed with clinical and radiological parameters and endoscopic findings of esophageal varices. Results: The median age at enrollment of the 20 cases was 8.4 years. Of the 20 cases, 15 were diagnosed as cirrhosis by ultrasonography and 9 had esophageal varices detected by an endoscopy. Parameters that were significantly associated with LSM were history of cholangitis, splenomegaly, cirrhosis and esophageal varices. Significantly higher LSM was found to be correlated with hyperbilirubinemia, transaminitis, alkaline phosphatasemia, thrombocytopenia and prolonged INR. On linear regression, LSM was significantly correlated with pediatric end-stage liver disease score at the r2 of 0.32 and correlated with the aspartate transaminase to platelet ratio index at the r2 of 0.70. The area under the receiver operating characteristic curve that reflected the performance of LSM in predicting esophageal varices was 0.97. At the cut-off value of 10.2 kPa, the sensitivity and specificity of LSM in predicting esophageal varices were 100% and 72.7%, respectively. Conclusion: TE can be useful as a non-invasive, point-of-care evaluation of liver fibrosis in long term follow-up of BA. A high LSM indicates surveillance for esophageal varices in these patients.

Publisher Copyright: © 2021 The Author(s) Portoenterostomy (PE) has remained as the generally accepted first line surgical treatment for biliary atresia (BA) for over 50 years. Currently, close to half of BA patients survive beyond 10 years with their native livers, and most of them reach adulthood without liver transplantation (LT). Despite normalization of serum bilirubin by PE, ductular reaction and portal fibrosis persist in the native liver. The chronic cholangiopathy progresses to cirrhosis, complications of portal hypertension, recurrent cholangitis or hepatobiliary tumors necessitating LT later in life. Other common related health problems include impaired bone health, neuromotor development and quality of life. Only few high-quality trials are available for evidence-based guidance of post-PE adjuvant medical therapy or management of the disease complications. Better understanding of the pathophysiological mechanisms connecting native liver injury to clinical outcomes is critical for development of accurate follow-up tools and novel therapies designed to improve native liver function and survival.

Aim To determine factors associated with severe hospitalized Respiratory syncytial virus (RSV)‐associated LRTI and to describe management in tertiary care center. Methods Retrospective medical record review was conducted among children under 5 years old hospitalized with RSV‐associated LRTI at King Chulalongkorn Memorial Hospital. Severe RSV‐associated LRTI was defined as death, mechanical ventilator, or positive pressure ventilation use, prolonged hospitalization >7 days. Factors associated with severe RSV were analyzed using univariate and multivariate logistic regression. Results From January 2011 to December 2016, 427 children were hospitalized. Median age was 10 months (IQR 4.2‐23.0). One hundred seventy‐four (41%) patients had severe RSV (11 deaths, 56 mechanical ventilators, 19 positive pressure ventilation, and 88 prolonged hospitalization). Factors associated with severe RSV were chronic lung disease (aOR 15.16 [4.26‐53.91]), cirrhosis/biliary atresia (aOR 15.01 [3.21‐70.32]), congenital heart disease (aOR 5.11 [1.97‐13.23]), chemotherapy (aOR 4.7 [1.34‐16.56]), and pre‐term (aOR 2.03 [1.13‐3.67]). Oxygen therapy was mainly low flow oxygen delivery. 88% of cases received bronchodilator. Parenteral antibiotics were prescribed in 37.9% of cases. Conclusions Children with co‐morbidities have higher risk of severe RSV‐associated LRTI. More than two‐third of patients received bronchodilator, of which was not recommended by American Academy of Pediatrics. The specific treatment and prevention for RSV are urgently needed.

La atresia de vías biliares es una alteración con gran importancia clínica, más frecuente en la primera infancia, secaracteriza por la obliteración proliferativa de los conductos biliares que progresa a fibrosis hepática, cirrosis einsuficiencia hepática en etapa terminal.El objetivo es presentar un caso clínico inusual y conocer la forma de actuar ante un caso similar. Se trata depaciente femenino de 4 meses de edad, con piel y mucosas ictéricas – verdosas, con hígado palpable debajodel reborde costal derecho, bazo palpable debajo del reborde costal izquierdo. Serología para Citomegaloviruspositivo. La ecografía abdominal reporto: Atresia de vías biliares.Se indicó una portoenterostomia de Kasai, sin embargo por la edad de la paciente, el procedimiento quirúrgicono se realizó.La atresia de vías biliares es una patología poco frecuente, su etiología es desconocida, pero es importante saberreconocerla durante los primeros 2 meses de vida, para evitar complicaciones.

BACKGROUND Untreated neonatal cholestasis can progress to liver cirrhosis and end stage liver disease in infancy due to prolonged hepatocyte and biliary tree injury and may require liver transplantation. Therefore, non-invasive evaluation of hepatic fibrosis is important in infants with cholestasis. AIM To investigate the usefulness of periportal thickening (PT) measured on liver magnetic resonance imaging (MRI) for the assessment of hepatic fibrosis in infants with cholestasis including biliary atresia (BA). METHODS This retrospective study included infants less than 6 mo who underwent liver MRI and biopsy for the evaluation of infantile cholestasis. PT and spleen size were measured on MRI. Serologic assessment was based on aspartate transaminase to platelet ratio index (APRI). The grade of histopathologic fibrosis was assessed by the METAVIR grading system. Correlation and diagnostic performance of PT, normalized spleen size ratio (SR, using the upper normal size limit), and APRI for diagnosing hepatic fibrosis were obtained by receiver-operating characteristic (ROC) curve analysis. RESULTS A total of 155 patients were included, 110 of which were diagnosed with BA. Mean age at the time of MRI was 57.6 ± 34.4 d. There were positive correlations between fibrosis grade and PT and SR, even after adjusting age (all, P < 0.001). For the diagnosis of significant fibrosis (METAVIR grade F2-F4), the area under the ROC curve was 0.899 (95%CI: 0.840–0.941) for PT (cutoff, 4.2 mm), which was higher than 0.741 (95%CI: 0.664–0.808) for SR and 0.712 (95%CI: 0.634–0.782) for APRI (both, P < 0.001). For the diagnosis of cirrhosis (F4), the area under the ROC curve was the highest with SR as 0.790 (95%CI: 0.718–0.852). CONCLUSION Liver MRI findings of PT and SR are useful to assess clinically significant hepatic fibrosis (F2 and higher) in infants with cholestasis including BA.

Atresia of the biliary tract, or biliary atresia (BA), is a destructive, inflammatory disease in which progressive biliary tree fibrosis in an infant leads to obstruction of the bile ducts and, as a result, to cirrhosis of the liver. If untreated, progressive cirrhosis leads to death by 2 years. Biliary atresia can be divided into 3 types, each of which depends on the level closest to biliary obstruction. Type I (obstruction of the common bile duct), type II (patency of the bile ducts to the level of the common hepatic duct), type III (obstruction at the level of the gates of the liver). It is very important to distinguish between types of BA and conduct differential diagnosis with other cholestatic diseases. There are nonsyndromic, syndromic, and BA, combined with other malformations. In diagnostics, in addition to clinical manifestations and specific changes in blood biochemical parameters characterizing cholestasis, an ultrasound examination of the abdominal cavity organs, gepatobiliscintigraphy, magnetic resonance cholecystopancreatocholangiography, according to indications, a puncture biopsy of the liver and histological examination are performed. The main method of treatment is hepatoportoenterostomy according to Kasai, which must be performed no later than 3 months, and with liver cirrhosis and hepatic insufficiency, liver transplantation. Additional methods of treatment include the use of ursodeoxycholic acid, fat-soluble vitamins.

Background: To understand the changing demands and recent trends in the indications for living donor liver transplantation (LDLT), the present study aimed to analyze the indications for LDLT performed in a high-volume transplantation center over 10 years. Methods: The liver transplantation database at our institution was searched to identify patients who underwent LDLT during a 10-year period from January 2008 to December 2017. The study subjects (n=3,145) were divided into two groups: adult patients (n=3,019, 92.7%) and pediatric patients (n=126, 3.9%). Results: In the adult recipients, the primary diagnoses were hepatitis B virus (HBV)-associated liver cirrhosis (n=1,898, 62.9%), alcoholic liver disease (n=482, 16.0%), hepatitis C virus-associated cirrhosis (n=203, 6.7%), acute liver failure (n=127, n=4.2%), and other diseases (n=157, 5.2%). The mean Model for End-Stage Liver Disease score was 15.6±8.8 (range, 6-40). The proportion of patients with HBV-associated liver disease gradually decreased, but the proportion of those with alcoholic liver disease increased. Hepatocellular carcinoma (HCC) was diagnosed in 1,467 patients (48.6%). The mean proportion of patients with HCC was 63.1% among those with HBV-associated liver disease. In pediatric recipients, the primary diagnoses were biliary atresia (n=51, 40.5%), liver failure of various causes (n=37, 29.4%), metabolic disease (n=22, 17.5%), hepatoblastoma (n=12, 9.5%), and infectious diseases (n=4, 3.2%). Conclusions: Our results showed that there were some significant changes in the indications of LDLT. We believe that our results may reflect the real changes in the indications of LDLT and they will be useful for predicting further changes in the future.

Background/rationale Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy (KPE), BA leads to death or liver transplant (LTx). Early-onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver prognostication. Results We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be girls with a significantly different mean bilirubin (P = 0.002), albumin (P = 0.001), and alanine aminotransferase (P = 0.03) at 3 months post-KPE. By 1 year post-KPE, 50% of patients in the high CHP intensity group required LTx versus 27% in the low CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than 3 times the risk of requiring LTx by 4 years of age (hazard ratio 3.6, 95% confidence interval 1.15-10.93, P = 0.03). When controlling for sex and total bilirubin >2 mg/dL and albumin at 3 months post-KPE, it predicted nearly 7 times the risk of LTx (hazard ratio 6.89, 95% confidence interval 1.38-34.32, P = 0.02). Conclusion Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.

Background: Biliary Atresia (BA) is congenital condition, where infant intra- and extrahepatic bile ducts become obliterated, leading to cholestasis, and cirrhosis if untreated. This study aims to assess the predictive measure of absent gallbladder on ultrasounds (US) performed in infants with cholestasis for diagnosing BA.Method: After Institutional Review Board approval, retrospective chart reviews of 61 infants with cholestasis found 43 (70.5%) were diagnosed with BA. A pediatric radiologist provided interpretations of all ultrasounds in a blinded fashion. Statistical analysis was used to assess the utility of absence of gallbladder on US in predicting BA, confirmed intraoperatively.Results: Absent gallbladder on US predicts absent gallbladder with 77% accuracy, 92% sensitivity, 73% specificity, PPV 43%, and NPV 97% (P < 0.001, Fisher exact test). To diagnose BA, absent gallbladder on US has 66% accuracy, 53% sensitivity, 94% specificity, 96% PPV, and 46% NPV (P < 0.001, Fisher exact test).Conclusion: Sonographic gallbladder absence has high specificity and PPV, indicating utility for BA diagnosis; however, it is not useful for ruling out BA given its low sensitivity.

Background: Biliary atresia (BA) is a neonatal cholangiopathy characterized by progressive destruction of the biliary system resulting in liver cirrhosis. Residual bile drainage can temporarily be achieved through Kasai portoenterostomy (KPE) and some children show long-term survival with their native liver. However, most children eventually require liver transplantation (LTX). As several growth factors (GF) and chemokines have been shown to promote fibrogenesis in the liver, we assessed whether GF are predictive for the course of disease. Material and Methods: Liver and sera samples were collected from 49 infants with BA during KPE. Levels of 13 different GF were measured by multiplex immunoassay. Patient outcomes were stratified into favorable (bilirubin &lt, 20 µmol/L at 2-year follow-up) and unfavorable (LTX). GF levels were compared between groups by a t-test, correlation coefficients were calculated, and principal component analyses performed. Results: Twenty-two patients showed a favorable and 27 an unfavorable disease course. No relation of GF and outcome could be established. In both groups, high levels of SDF-1alpha/CXCL12 (1473.0 ± 497.5 pg/mL), FGF2 (301.2 ± 207.8 pg/mL), and VEGF-a (209.0 ± 146.4 pg/mL) levels were measured within the liver, followed (in descending order) by PDGF-bb, LIF, GM-CSF, BDNF, VEGF-d, beta-NGF, IL-7, SCF, PIGF-1, and EGF. Serum marker levels showed much higher mean variation compared to hepatic values and no correlation to the protein microenvironment in the liver. Conclusions: Our study demonstrates high amounts of GF in livers from infants with BA at KPE, but no correlation to the outcome or serum values could be established. Our data suggest that local or systemic GF levels are unsuitable for prediction of the disease course. Collectively, we conclude that in BA the degree of proliferative activity caused by GF is a dismissible factor for the further course of disease.

Günümüzde alıcı ve vericinin özel anatomik bir varyasyonunun yokluğunda kullanılan transplantasyon prosedürü; pediatrik yaş grubu için sol lateral segmentin alınması, erişkin yaş grubunda ise sağ lobun kullanılmasıdır. Çocuklarda biliyer atrezi, erişkinlerde ise metabolik olaylar gibi çeşitli karaciğer hastalıkları karaciğer transplantasyonu için başlıca nedenlerdir. Karaciğer transplantasyonu, konjenital damar anomalisi olan hastalar için oldukça zor bir işlemdir. İnferior vena cavadaki, infrahepatik kesinti %0,6 ile %2 oranında gerçekleşen oldukça nadir bir konjetinal anomalidir ve genellikle konjenital kalp hastalığı ile birlikte görülür. Biz bu çalışmada, hepatit B virüsü (HBV) zemininde gelişen dekompanse karaciğer yetmezliği tanısı olan ve canlı vericiden karaciğer nakli için ilk kez hastaneye yatışı yapılan 58 yaşındaki erkek hastayı takdim etmek istedik.

Introduction: Liver biopsy contributes greatly to the understanding of liver diseases & is considered gold standard for evaluating liver disorders, providing information regarding diagnosis, disease progression and response to therapy. Objectives: 1). To study histomorphological features of liver biopsies and to correlate them with presenting co mplaints & radiological findings. 2). To document the pattern of various hepatic lesions. Results/Observations: A retrospective study of 66 liver biopsies during the period January 2013 to May 2015 was done. Sections were stained with H & E and examined under light microscope. Special stains were done in specific cases. Among these, 45 cases were males and 21 cases were females. Out of 66 cases, 24(36.3%) cases were hepatocellular carcinoma, 13(19.69 %) cases of glycogen storage disorder, 3(4.54%) cases each of fatty liver, hepatitis, cirrhosis & degenerative liver disease. 2(3.03%) cases of liver cell dysplasia and 1(1.51%) case each of biliary atresia , amyloidosis, miliary tuberculosis and liver abscess. Liver biopsy was non specific in 4(6.06%) cases & inadequate in 7(10.6%)cases. Conclusion: Microscopic examination of liver biopsy yields a diverse range of pathological findings and helps to uncover diseases for which specific management is indicated. Keywords: Hepatocellular carcinoma, Glycogen Storage Disorder, Liver biopsy.

Introduction: Biliary atresia (BA) is the leading cause of liver fibrosis and failure in neonates with surgical jaundice, leading to poor outcome. Clinical and animal studies showing that granulocyte colony-stimulating factor (GCSF) treatment could improve liver fibrosis and cirrhosis suggest that GCSF may be offered as a low-cost intervention to improve the course of BA. This study aims to test the hypothesis that 10 µg/kg/day x 5 days of GCSF could improve liver function, reduce molecular pro-fibrotic markers and decrease liver fibrosis in a mouse model of bile duct ligation (BDL). Methods: Balb/c mice underwent Sham surgery, or BDL for seven days followed by subcutaneous GCSF administration at 10 µg/kg/day for five consecutive days. Twelve days post-operation, blood samples were taken from the facial vein for leukocyte/neutrophil count and for measurement of serum enzymatic activities. The median lobe of the liver was acquired for total RNA and protein extraction. Moreover, the median liver lobe was used for hematoxylin-eosin staining, sirius red staining, and for visualization by immunohistochemistry (IHC). Results: Twelve days post-operation, GCSF-treated bile duct-ligated (BDL) mice had a higher survival rate than that of placebo-treated mice (hazard ratio=1.88, p=0.084). The GCSF-treated mice had diminished liver serum transaminase activities (AST: 228.92 ± 222.67 vs. 313.46 ± 164.80 IU/L; ALP: 573.24 ± 177.89 IU/L vs. 471.75 ± 117.92 IU/L). GCSF treatment also reduced fibrosis with down-regulation of expression of pro-fibrotic markers including TGF-β1 (-2.61-fold mRNA), α-SMA (-2.46-fold mRNA; -1.88-fold protein, p

We investigated noninvasive follow‐up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin 11 µmol/L in the youngest tertile (AUROC, 0.91; P < 0.001), bile acids was >80 µmol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.

Background Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT. Methods A retrospective single-center study including all BA children listed for LT in 2008–2016. Clinical, endoscopical, and biochemical data were analyzed. Results Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1–37.9 years] vs 11.2 years [range, 5.1–43 years]; P = .03 vs 10.7 years [range, 6.9–39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0–17.7 months] vs 2.2 months [0–17.9 months], respectively; P = .89). After 45.5 months (range, 13.7–105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16). Conclusions Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation.

Purpose Biliary atresia (BA) is a rare disease of unknown pathogenesis in infants characterized by an inflammatory, progressive destruction of the biliary system and deterioration of liver function. The standard treatment for BA is a Kasai-hepatoportoenterostomy (KPE). However, liver transplantation (LTX) becomes necessary in about 50–80% of cases. Therefore, some authors advocate for primary LTX in BA, but this would require early markers to predict which children would benefit from KPE or to show rapid progression to liver cirrhosis (RLC) instead. Methods Snap-frozen liver biopsies and sera samples of 57 infants with BA were collected during KPE. Clinical and follow-up data were assessed via the biliary atresia and related diseases registry ( BARD-online.com ). Protein-levels of 25 pro- and anti-inflammatory mediators of 49 infants were assessed via multiplex protein-immunoassay and analyzed by t-test as well as multidimensional principal component analysis. Results 22 different immunomodulatory mediators were detectable in livers of children with BA, while serum protein levels were very low to undetectable. Following KPE, 33 BA patients showed RLC that required early LTX, while 24 had favorable course of disease with long-term survival with native liver (SNL). There were no significant differences between RLC and SNL in terms of local (from liver samples) nor systemic (from sera) immunomodulatory mediators. Protein levels were much lower in sera than in livers without statistical correlation. Conclusion Our data suggest that local or systemic immunomodulatory mediators are unsuitable for predicting the disease course of BA. Thus, no deduction for optimal treatment strategy can be drawn. Collectively, we conclude that in BA, the degree of inflammation and protein microenvironment in the liver at the time-point of KPE are dismissible factors for the future course of disease.

To evaluate the accuracy of biomarkers for the early diagnosis of biliary atresia (BA) and prognostic stratification after Kasai portoenterostomy (KPE). We conducted a systematic review of PubMed, Web of Science, Embase, Scopus and OVID for English literature reporting BA biomarkers published before August 2020. Screening, data extraction, and quality assessment were performed in duplicate. A total of 51 eligible studies were included in the systematic review, and data from 12 (4182 subjects) were extracted for meta-analysis regarding the following 2 domains: (1) serum matrix metallopeptidase-7 (MMP-7), interleukin33 (IL-33) and γ-glutamyl transferase (GGT) to differentiate BA from non-BA; (2) the aspartate aminotransferase to platelet ratio index (APRi) to predict post-KPE liver fibrosis/cirrhosis. The summary sensitivity, specificity and area under the curve (AUC) of MMP-7 for diagnosing BA were 96%, 91% and 0.9847, respectively, and those of GGT were 80%, 79% and 0.9645, respectively. The summary sensitivity and specificity of IL-33 for diagnosing BA were 77% and 85%, respectively. The summary sensitivity and specificity of APRi for predicting post-KPE liver fibrosis were 61% and 80%, respectively, and the summary sensitivity, specificity and AUC of APRi for predicting post-KPE cirrhosis were 78%, 83% and 0.8729, respectively. Moreover, good evidence was shown in investigations of serum IL-18 and IL-33 in distinguishing BA from healthy controls, serum IL-18 for prognosis of post-KPE persistent jaundice, and serum hyaluronic acid and MMP-7 for prognosis of post-KPE significant liver fibrosis. MMP-7, IL-33 and GGT are useful biomarkers to assist in the diagnosis of BA. APRi might be used to predict post-KPE significant liver fibrosis and cirrhosis. These noninvasive biomarkers can be integrated into the management protocol of BA.

Background and objectives: In patients with biliary atresia (BA), hepatoportoenterostomy (HPE) is still a valuable therapeutic tool for prolonged survival or a safer transition to liver transplantation. The main focus today is towards efficient screening programs, a faster diagnostic, and prompt treatment. However, the limited information on BA pathophysiology makes valuable any experience in disease management. This study aimed to analyze the evolution and survival of patients with BA referred for HPE (Kasai operation) in our department. Materials and Methods: A retrospective analysis was performed on fourteen patients with BA, diagnosed in the pediatric department and further referred for HPE in our surgical department between 2010 and 2016. After HPE, the need for transplantation was assessed according to patients cytomegalovirus (CMV) status, and histological and biochemical analysis. Follow-up results at 1&ndash, 4 years and long term survival were assessed. Results: Mean age at surgery was 70 days. Surgery in patients younger than 60 days was correlated with survival. Jaundice&rsquo, s clearance rate at three months was 36%. Total and direct bilirubin values had a significant variation between patients with liver transplants and native liver (p = 0.02). CMV was positive in eight patients, half with transplant need and half with native liver survival. Smooth muscle actin (SMA) positivity was proof of advanced fibrosis. The overall survival rate was 79%, with 75% for native liver patients and an 83% survival rate for those with liver transplantation. Transplantation was performed in six patients (43%), with a mean of 10 months between HPE and transplantation. Transplanted patients had better survival. Complications were diagnosed in 63% of patients. The mean follow-up period was six years. Conclusions: HPE, even performed in advanced cirrhosis, allows a significant survival, and ensures an essential time gain for patients requiring liver transplantation. A younger age at surgery is correlated with a better outcome, despite early CMV infection.

Purpose There is no consensus regarding adjuvant therapies following Kasai portoenterostomy (KP) for biliary atresia (BA). This study aimed to analyze the effect of extended perioperative intravenous antibiotics (PI-Abx) and adjuvant corticosteroid on cholangitis and jaundice clearance rates in the 3 years post-KP in children with BA. Methods Data of patients who underwent KP between 1999-2018 at a single center were retrospectively analyzed. Group A (1999-2010) received PI-Abx for 5 days, Group B (2010-2012) received PI-Abx for 5 days plus low-dose prednisolone (2 mg/kg), and Group C (2012-2017) received PI-Abx for 14 days plus high-dose prednisolone (5 mg/kg). Results Fifty-four patients were included with groups A, B, and C comprising 25, 9, and 20 patients, respectively. The number of episodes of cholangitis was 1.0, 1.6, and 1.3 per patient (p=NS) within the first year and 1.8, 2.3, and 1.7 (p=NS) over 3 years in Groups A, B, and C, respectively. The jaundice clearance rate at 6 months was 52%, 78%, and 50% (p=NS), and the 3-year native liver survival (NLS) rate was 76%, 100%, and 80% (p=NS) in Groups A, B, and C, respectively. A near-significant association was observed between the incidence of cholangitis within the first year and decompensated liver cirrhosis/death at 3 years post KP (p=0.09). Persistence of jaundice at 6 months was significantly associated with decompensated cirrhosis/death at 3 years (p

Background Biliary atresia in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants is rarely reported, and the optimal timing of Kasai portoenterostomy (KPE) in these cases remains unclear. Case presentation We report a case of biliary atresia in a preterm female infant of 24 weeks of gestation who weighed 824 g. She underwent exploratory laparotomy and intraoperative cholangiography at 58 days of age (weight, 1336 g). Despite the diagnosis of biliary atresia with a type I cyst, we could only perform gallbladder drainage at that time due to the unstable intraoperative condition. While we waited for her body weight to increase, KPE was performed at 122 days of age (corrected age: 16 days), when the patient weighed 2296 g. Although she initially became jaundice-free, her liver function deteriorated due to cholangitis, and she developed decompensated cholestatic liver cirrhosis. Living donor liver transplantation was successfully performed at 117 days after KPE, and the postoperative course was uneventful. The timing of KPE is difficult to determine and a review of the relevant literature revealed that a poor prognosis in VLBW and ELBW infants with BA. Conclusions Early KPE and careful postoperative follow-up, including liver transplantation is important for the improvement of outcomes.

Introducción: El trasplante hepático (TH), es una terapia establecida en el tratamiento de diversas enfermedades del hígado agudas y crónicas terminales y del carcinoma hepatocelular (CHC). Las principales indicaciones en nuestro medio son la cirrosis de diferentes etiologías, el CHC, la atresia de vías biliares en niños y la falla hepática fulminante (FHF). Menos del 10% corresponden a indicaciones inhabituales, que incluyen pacientes con una miscelánea de enfermedades entre las cuales están la enfermedad poliquística hepática (EPH), enfermedades metabólicas (Niemann – Pick, otras), el síndrome hepato/portopulmonar, metástasis de diferentes tumores, etc.Objetivo: Describir y evaluar los resultados obtenidos con el trasplante hepático en estas indicaciones.Material y Método: Estudio de cohorte no concurrente que incluyó los TH por indicaciones inhabituales realizados entre marzo de 1997 y diciembre de 2016. De 295 TH realizados, 34 (11,5%) fueron por estas indicaciones.Resultados: Las causas más frecuentes fueron el síndrome porto/hepatopulmonar en 11 (40,7%) pacientes y la EPH en 9 (26,5%). Las enfermedades metabólicas representaron la tercera indicación, con 5 (14,7%) casos. 7 (20,6%) pacientes eran menores de 18 años. Las complicaciones más frecuentes fueron biliares y la trombosis de arteria hepática en 6 (17,6%) y 4 (11,8%) casos respectivamente; estos últimos eran portadores de una EPH masiva. 4 (12,5%) pacientes requirieron retrasplante. La mortalidad a 90 días fue de 2 (5,9%) enfermos. Conclusión: El TH es una opción factible en este grupo de pacientes con resultados similares a los obtenidos en las indicaciones clásicas.

Fibropolycystic diseases of the liver comprise a spectrum of disorders affecting bile ducts of various sizes and arise due to an underlying ductal plate malformation (DPM). We encountered a previously unreported variant of DPM, the hilar fibropolycystic disease which we diagnosed in the explant liver. A 2-year-old boy was referred for liver transplantation with a diagnosis of biliary atresia (BA) and failed Kasai portoenterostomy (KPE). He had cirrhosis with portal hypertension along with synthetic failure indicated by coagulopathy and hypoalbuminemia. The child underwent liver transplant successfully. The explant liver had fibropolycystic disease confined to the perihilar liver and hilum. No pathogenic mutation was detected by whole exome sequencing. Fibropolycystic liver disease may represent a peculiar anatomical variant, which can be diagnosed by careful pathological examination of the explant liver. The neonatal presentation of hilar fibropolycystic liver disease can be misdiagnosed as BA.

Liver cirrhosis in infancy can be secondary to various etiologies such as biliary atresia, familial cholestatic and metabolic disorders. Wolman's disease (WD) is a lysosomal storage disorder caused by the absence of lysosomal acid lipase enzyme activity and a significant association with infantile cholestasis and cirrhosis. We encountered an infant presenting with advanced cirrhosis and decompensation having splenomegaly for which the underlying etiology was found to be WD and the diagnostic clue came from abdominal X-ray showing bilateral adrenal calcifications. The diagnosis was confirmed by genetic analysis. The outcome was poor and died before 6 months of age without enzyme replacement therapy or hematopoietic stem cell transplantation.

OBJECTIVE This study aimed to evaluate the role of preoperative two-dimensional (2D) shear wave elastography (SWE) in assessing the stages of liver fibrosis in patients with suspected biliary atresia (BA) and compared its diagnostic performance with those of serum fibrosis biomarkers. MATERIALS AND METHODS This study was approved by the ethical committee, and written informed parental consent was obtained. Two hundred and sixteen patients were prospectively enrolled between January 2012 and October 2018. The 2D SWE measurements of 69 patients have been previously reported. 2D SWE measurements, serum fibrosis biomarkers, including fibrotic markers and biochemical test results, and liver histology parameters were obtained. 2D SWE values, serum biomarkers including, aspartate aminotransferase to platelet ratio index (APRi), and other serum fibrotic markers were correlated with the stages of liver fibrosis by METAVIR. Receiver operating characteristic (ROC) curves and area under the ROC (AUROC) curve analyses were used. RESULTS The correlation coefficient of 2D SWE value in correlation with the stages of liver fibrosis was 0.789 (p < 0.001). The cut-off values of 2D SWE were calculated as 9.1 kPa for F1, 11.6 kPa for F2, 13.0 kPa for F3, and 15.7 kPa for F4. The AUROCs of 2D SWE in the determination of the stages of liver fibrosis ranged from 0.869 to 0.941. The sensitivity and negative predictive value of 2D SWE in the diagnosis of ≥ F3 was 93.4% and 96.0%, respectively. The diagnostic performance of 2D SWE was superior to that of APRi and other serum fibrotic markers in predicting severe fibrosis and cirrhosis (all p < 0.005) and other serum biomarkers. Multivariate analysis showed that the 2D SWE value was the only statistically significant parameter for predicting liver fibrosis. CONCLUSION 2D SWE is a more effective non-invasive tool for predicting the stage of liver fibrosis in patients with suspected BA, compared with serum fibrosis biomarkers.

Background Without early recognition and Kasai procedure, biliary atresia (BA) results in liver cirrhosis and leads to either transplantation or death at a young age. We aimed to characterize the liver histopathological findings for prediction of cirrhosis and survival in BA patients after Kasai surgery. Methods We retrospectively reviewed all histopathological results for BA patients who underwent liver biopsy during Kasai surgery from August 2012 to December 2018 in Dr. Sardjito Hospital, Yogyakarta, Indonesia. Results Fifty infants with BA were ascertained in our study, of whom 27 were males and 23 were females. The median age of Kasai procedure was 102.5 days (interquartile range (IQR), 75.75–142.25 days). There were 33 (66%) and 17 (34%) BA patients with and without liver cirrhosis, respectively, while the overall survival was 52%. The patients with a severe bile duct proliferation, severe cholestasis, and severe portal inflammation have a higher risk by 27-, 22-, and 19.3-fold, respectively, to develop liver cirrhosis compared with patients with a moderate/mild bile duct proliferation, moderate/mild/without cholestasis, and moderate/mild portal inflammation, respectively (p = 3.6 × 10− 6, 5.6 × 10− 4, and 1.6 × 10− 3, respectively), while the giant cell transformation was not associate with the development of liver cirrhosis (p = 0.77). The bile duct proliferation was strongly correlated with cholestasis and portal inflammation (p = 7.3 × 10− 5 and 2 × 10− 4, respectively), and cholestasis was also significantly correlated with portal inflammation (p = 0.016). Interestingly, the age at Kasai procedure was strongly associated with the development of liver cirrhosis (p = 0.02), but not with the patients’ survival (p = 0.33), while the degree of fibrosis and cholestasis were significantly correlated with the patients’ survival, with HR of 3.9 (95% CI = 1.7–9.0; p = 0.017) and 3.1 (95% CI = 1.4–7.0; p = 0.016), respectively. Conclusions Histopathological findings of bile duct proliferation, cholestasis, and portal inflammation can predict the liver cirrhosis development in patients with BA. Furthermore, degree of fibrosis and cholestasis affect the patients’ survival following the Kasai operation.

Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin‐1 (Prom1 or CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1‐expressing HPCs promote fibrogenesis in cholestatic liver injury. Using Prom1CreERT2‐nLacZ/+;Rosa26Lsl‐GFP/+ mice, we traced the fate of Prom1‐expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Prom1‐expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential toward both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1‐expressing HPCs gave rise to both PROM1(+) and PROM1(‐) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA‐sequencing analysis of GFP(+) Prom1‐expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor‐β pathway activation. When Prom1‐expressing cells were ablated with induced Diphtheria toxin in Prom1CreERT‐nLacZ/+;Rosa26DTA/+ mice, we observed a decrease in ductular reactions and biliary fibrosis typically present in BDL as well as decreased expression of numerous fibrogenic gene markers. Our data indicate that Prom1‐expressing HPCs promote biliary fibrosis associated with activation of myofibroblasts in cholestatic liver injury., In this study, we demonstrate that during cholestatic liver injury following bile duct ligation that cholangiocytes derived from Prominin‐1‐expressing hepatic progenitor cells promote biliary fibrosis; ablation of Prom1‐expressing cells decreases fibrosis.

Portal hypertension increases pressure in lymphatic ducts, which may lead to gastrointestinal (GI) protein loss. Reports have shown that adults with portal hypertension had resolution of protein-losing enteropathy after transplantation; but studies in children are very limited. We therefore aimed to evaluate GI protein loss in children with portal hypertension and defined changes after liver transplantation. Children aged 3 months to 18 years with portal hypertension and the age-matched healthy controls were enrolled during August 2018 to September 2019. Random fecal alpha-1 antitrypsin measurements were obtained at the initial visit, 3 months later, 1 week before, and 3 months after liver transplantation (if applicable). One or more positive test (> 0.795 mg/dL) was interpreted as a positive result. We enrolled 76 children (n = 38 in each group) with a median age of 15.5 months (interquartile range [IQR], 11.2–41.7), female 51%, and 92% with biliary atresia in the portal hypertension group. We noted GI protein loss in 4/38 children (10.5%) with portal hypertension, while none in the controls (p = 0.11). We found no significant differences on the markers of severity of liver disease and serum albumin between patients with vs. the ones without GI protein loss (p > 0.05). After liver transplantation, 2/4 patients with GI protein loss had undetectable loss. We found that, in a small group of children, 10.5% with portal hypertension had notable GI protein loss without significant relationships with the severity of liver disease.