Paucity Of Bile Ducts Research Articles

Clinical, pathological and genetic characteristics of 17 unrelated children with Alagille Syndrome

BackgroundAlagille syndrome (ALGS) is a multisystem genetic disorder frequently characterized by hepatic manifestations. This study analyzed the clinical, pathological, and molecular genetic features of ALGS to improve the efficiency of clinical diagnosis.MethodsWe retrospectively analyzed the clinical manifestations, pathological examination findings, and genetic testing results of 17 children diagnosed with ALGS based on the revised criteria and hospitalized at our center from January 2012 to January 2022.ResultsThe clinical manifestations are as follows: Cholestasis (16/17, 94%), characteristic facies (15/17, 88%), heart disease (12/16, 75%), butterfly vertebrae (12/17, 71%) and posterior embryotoxon (7/12, 58%). Among the 15 patients who underwent liver pathology examination, 13 (87%) were found to have varying degrees of bile duct paucity. Genetic testing was performed on 15 children, and pathogenic variants of the jagged canonical Notch ligand 1 (JAG1) gene were identified in 13 individuals, including 4 novel variants. No pathogenic variant in the notch homolog 2 (NOTCH2) gene were identified, and 2 children exhibited none of the aforementioned gene pathogenic variants. The median follow-up duration was 7 years. Of the remaining 15 patients (excluding 2 lost to follow-up), 11 remained stable, 4 deteriorated, and no patient died during the follow-up period.ConclusionsAmong children diagnosed with ALGS, cholestasis stands as the most common feature. To minimize the risk of misdiagnosis, genetic testing should be performed on children exhibiting cholestasis, followed by the application of the revised diagnostic criteria for ALGS. While pharmacological therapy has shown effectiveness for ALGS patients, liver transplantation may be considered in instances of severe pruritus.

Liver Mitochondrial Morphology and Gene Expression as Markers of Liver Reserve: Prognostic Implications for Native Liver Survival in Biliary Atresia

PurposeHepatocyte mitochondrial morphology and gene expression were compared between biliary atresia (BA), infantile cholestasis (IC), and normal liver (NL) as prognostic indicators. MethodsSpecimens of liver at portoenterostomy (PE) for BA, from intrahepatic bile duct paucity patients for IC, and from choledochal cyst or hepatoblastoma patients for NL were collected prospectively (P) beginning in 2021 (P-BA = 11, P-IC = 9, P-NL = 7) and retrospectively (R) from paraffin-embedded tissue going back to 1981 (R-BA = 25, R-IC = 9, R-NL = 4). The P-cohort had transmission electron microscopy (TEM) to image mitochondria, immunoblotting for heat shock protein 60 (HSP60), and quantitative PCR (qPCR) for HSP60 and mitochondrial functional genes. Both cohorts had immunofluorescence for HSP60 quantified as a ratio to albumin-positive hepatocytes (ALB) with HSP60/ALB<1.0 as a cutoff limit using ImageJ. ResultsHSP60 was significantly lower in BA/IC than NL on qPCR (BA: p < 0.01, IC: p < 0.05) and lower in BA than IC/NL on immunoblotting (p < 0.05). HSP60/ALB was significantly lower in BA than NL/IC (p < 0.001). Despite BA subjects being matched for types of BA and ages at PE, HSP60/ALB did not correlate with jaundice clearance (JC; T-Bil<1.2 mg/dL) but was significantly higher in native liver survivors (NLS) after PE compared with liver transplant (LTx) cases (p < 0.05) and significantly lower in LTx cases achieving JC than NLS achieving JC (p < 0.05). TEM showed BA had significantly more mitochondrial inclusion bodies (p < 0.05) and significantly larger cristae (p < 0.01) than IC/NL. qPCR in BA showed significant repression of mitochondrial functional genes for mRNA stabilization and energy facilitation. ConclusionHSP60/ALB correlates with NLS after PE for BA. Level of evidenceII

Spatially segregated defects and IGF1-responsiveness of hilar and peripheral biliary organoids from a model of Alagille syndrome.

Alagille syndrome (ALGS) manifests with peripheral intrahepatic bile duct (IHBD) paucity, which can spontaneously resolve. In a model for ALGS, Jag1Ndr/Ndr mice, this occurs with distinct architectural mechanisms in hilar and peripheral IHBDs. Here, we investigated region-specific IHBD characteristics and addressed whether IGF1, a cholangiocyte mitogen that is downregulated in ALGS and in Jag1Ndr/Ndr mice, can improve biliary outcomes. Intrahepatic cholangiocyte organoids (ICOs) were derived from hilar and peripheral adult Jag1+/+ and Jag1Ndr/Ndr livers (hICOs and pICOs, respectively). ICOs were grown in Matrigel or microwell arrays, and characterized using bulk RNA sequencing, immunofluorescence, and high throughput analyses of nuclear sizes. ICOs were treated with IGF1, followed by analyses of growth, proliferation, and death. CellProfiler and Python scripts were custom written for image analyses. Key results were validated invivo by immunostaining. Cell growth assays and transcriptomics demonstrated that Jag1Ndr/Ndr ICOs were less proliferative than Jag1+/+ ICOs. IGF1 specifically rescued survival and growth of Jag1Ndr/Ndr pICOs. Jag1Ndr/Ndr hICOs were the least proliferative, with lower Notch signalling and an enrichment of hepatocyte signatures and IGF uptake/transport pathways. Invitro (Jag1Ndr/Ndr hICOs) and invivo (Jag1Ndr/Ndr hilar portal tracts) analyses revealed ectopic HNF4a+ hepatocytes. Hilar and peripheral Jag1Ndr/Ndr ICOs exhibit differences in Notch signalling status, proliferation, and cholangiocyte commitment which may result in cholangiocyte-to-hepatocyte transdifferentiation. While Jag1Ndr/Ndr pICOs can be rescued by IGF1, hICOs are unresponsive, perhaps due to their hepatocyte-like state and/or expression of IGF transport components. IGF1 represents a potential therapeutic for peripheral bile ducts.

Alagille syndrome and liver: an adult case report

BackgroundAlagille syndrome is a rare autosomal-dominant disorder, representing 10 to 15% of the causes of neonatal cholestasis with no gender predominance. The diagnosis is based on the association of liver, heart, eye, skeleton abnormalities, and characteristic facial appearance.Case presentationAn 18-year-old male patient, with a family history of benign recurrent intrahepatic cholestasis in a brother, was diagnosed at birth with bile duct paucity. He consulted in adulthood for cholestatic jaundice and pruritus. Physical exam found cutaneous jaundice, particular face, skeletal abnormality of fingers, posterior embryotoxon, and splenomegaly. An echocardiogram found cardiovascular abnormalities. The diagnosis of Alagille syndrome was made in front of five major criteria. A liver biopsy revealed a cirrhosis liver. Upper gastrointestinal endoscopy revealed grade II esophageal varices of portal hypertension. Laboratory tests revealed bicytopenia related to hypersplenism, hypoferritinemia, cytolysis with cholestasis, high bilirubin levels, low prothrombin time, hypoalbuminemia, decreased factor V activity, and hypocholesterolemia. The patient had vitamin K supplementation and was put on ursodeoxycholic acid, propranolol for the liver disease, a high protein hypercaloric diet for malnutrition, vitamin D supplementation and bisphosphonate for the osteoporosis, therapeutic abstention with monitoring for the asymptomatic cardiac disease. After a year of treatment, the patient had an overall health status improvement. Abdominal ultrasound found liver nodules. A biliary MRI showed a multinodular liver. The complement by CT hepatic angiography did not show any nodules while the MRI angiography revealed multiple dysplastic nodules. A liver biopsy was performed and found regenerative nodules.ConclusionThe treatment of Alagille syndrome is based on managing the cholestasis and its complications, especially pruritus because it can have a significant impact on quality of life. Due to the complexity of presentation and multi-organ involvement, management of cases with Alagille syndrome should be done by a multidisciplinary team. Liver disease is responsible for morbidity while cardiac disease is a mortality risk factor in this population.

The Curious Case of Alagille Syndrome: A Case Report With NANDA-I Classification, NIC, and NOC Linkage to the Patient Care Plan.

Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%-2%) genes located on the short arm of chromosome 20. This case is reported as per the CAse REports (CARE) guidelines (2013). A 14-year-old boy who is a known case of chronic cholestatic liver disease of neonatal onset, was diagnosed with Alagille syndrome as evident from a NOTCH 2 mutation in genetic analysis and paucity of intrahepatic bile ducts on biopsy. He presented with portal hypertension, growth failure, and persistent hyperbilirubinemia. This case highlights the gamut of multisystem dysfunctions faced by this child. He is currently on conservative management and worked up for liver transplantation. The condition is often rare and challenging due to the multisystem pathogenesis. Thus, the nursing care is also multifaceted. This case study identified relevant North American Nursing Diagnosis Association (NANDA) Classification, Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC) concepts to describe care of children with Alagille syndrome based on actual patient data.

Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease.

Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the JAG1 or NOTCH2 gene. The variable expressivity of the clinical phenotype and the lack of genotype-phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the JAG1 and NOTCH2 genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases-one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the JAG1 gene-eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with NOTCH2 variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.

Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5’-untranslated region of UNC45A

Lymphedema cholestasis syndrome 1 or Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. The genetic background of this autosomal recessive disease was unknown up to now. A total of 26 patients with Aagenaes syndrome and 17 parents were investigated with whole-genome sequencing and/or Sanger sequencing. PCR and western blot analyses were used to assess levels of mRNA and protein, respectively. CRISPR/Cas9 was used to generate the variant in HEK293T cells. Light microscopy, transmission electron microscopy and immunohistochemistry for biliary transport proteins were performed in liver biopsies. One specific variant (c.-98G>T) in the 5'-untranslated region of Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome. Nineteen were homozygous for the c.-98G>T variant and seven were compound heterozygous for the variant in the 5'-untranslated region and an exonic loss-of-function variant in UNC45A. Patients with Aagenaes syndrome exhibited lower expression of UNC45A mRNA and protein than controls, and this was reproduced in a CRISPR/Cas9-created cell model. Liver biopsies from the neonatal period demonstrated cholestasis, paucity of bile ducts and pronounced formation of multinucleated giant cells. Immunohistochemistry revealed mislocalization of the hepatobiliary transport proteins BSEP (bile salt export pump) and MRP2 (multidrug resistance-associated protein 2). c.-98G>T in the 5'-untranslated region of UNC45A is the causative genetic variant in Aagenaes syndrome. The genetic background of Aagenaes syndrome, a disease presenting with cholestasis and lymphedema in childhood, was unknown until now. A variant in the 5'-untranslated region of the Unc-45 myosin chaperone A (UNC45A) was identified in all tested patients with Aagenaes syndrome, providing evidence of the genetic background of the disease. Identification of the genetic background provides a tool for diagnosis of patients with Aagenaes syndrome before lymphedema is evident.

Alagille-like syndrome with surprising karyotype: a case report

BackgroundChromosome 5p partial monosomy (5p-syndrome) and chromosome 6p partial trisomy are chromosomal abnormalities that result in a variety of symptoms, but liver dysfunction is not normally one of them. Alagille syndrome (OMIM #118450) is a multisystem disorder that is defined clinically by hepatic bile duct paucity and cholestasis, in association with cardiac, skeletal, and ophthalmologic manifestations, and characteristic facial features. Alagille syndrome is caused by mutations in JAG1 on chromosome 20 or NOTCH2 on chromosome 1. Here, we report a preterm infant with karyotype 46,XX,der(5)t(5,6)(p15.2;p22.3) and hepatic dysfunction, who was diagnosed as having incomplete Alagille syndrome.Case presentationThe Japanese infant was diagnosed based on the cardiac abnormalities, ocular abnormalities, characteristic facial features, and liver pathological findings. Analysis of the JAG1 and NOTCH sequences failed to detect any mutations in these genes.ConclusionsThese results suggest that, besides the genes that are known to be responsible for Alagille syndrome, other genetic mutations also may cause Alagille syndrome.

Premature senescence of the liver in Alagille patients.

Alagille syndrome (ALGS) is an autosomal dominant disease characterized by a multisystem involvement including bile duct paucity and cholestasis, caused by JAG1 or NOTCH2 mutations in most of the cases. Jagged1-Notch2 interactions are known to be crucial for intrahepatic biliary tract development, but the Notch signaling pathway is also involved in the juxtacrine transmission of senescence and in the induction and modulation of the senescence-associated secretory phenotype (SASP). Our aim was to investigate premature senescence and SASP in ALGS livers. Liver tissue from ALGS patients was prospectively obtained at the time of liver transplantation (n = 5) and compared to control livers (n = 5). We evidenced advanced premature senescence in the livers of five JAG1 mutated ALGS pediatric patients through increased senescence-associated beta-galactosidase activity (p<0.05), increased p16 and p21 gene expression (p<0.01), and increased p16 and γH2AX protein expression (p<0.01). Senescence was located in hepatocytes of the whole liver parenchyma as well as in remaining bile ducts. The classical SASP markers TGF-β1, IL-6, and IL-8 were not overexpressed in the livers of our patients. We demonstrate for the first time that ALGS livers display important premature senescence despite Jagged1 mutation, underlying the complexity of senescence and SASP development pathways.

ASO silencing of a glycosyltransferase, Poglut1 , improves the liver phenotypes in mouse models of Alagille syndrome.

Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in several mouse models generated by removing one copy of Jag1 in the germline with or without reducing the gene dosage of sex-determining region Y-box 9 in the liver. Using an ASO established in this study, we show that reducing Poglut1 levels in postnatal livers of ALGS mouse models with moderate to profound biliary abnormalities can significantly improve BD development and biliary tree formation. Importantly, ASO injections prevent liver damage in these models without adverse effects. Furthermore, ASO-mediated Poglut1 knockdown improves biliary tree formation in a different mouse model with no Jag1 mutations. Cell-based signaling assays indicate that reducing POGLUT1 levels or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein level and JAG1-mediated signaling, suggesting a likely mechanism for the observed in vivo rescue. Our preclinical studies establish ASO-mediated POGLUT1 knockdown as a potential therapeutic strategy for ALGS liver disease and possibly other diseases associated with BD paucity.

Alagille Syndrome: Challenging Diagnosis and Prognostic Factors, A Case Report

Alagille syndrome (AS) commonly presents with cholestasis, much like other liver diseases, making the diagnosis challenging. We report a case of a patient with AS mimicking biliary atresia (BA) with a poor outcome. The infant, a product of a non-consanguineous marriage, presented with jaundice, clay stools, peripheral pulmonary stenosis, atrial septal defect, and butterfly vertebrae. Cholescintigraphy showed an absence of radiotracer excretion. Surgical exploration revealed the presence of a hypoplastic hepatic duct but a normal gallbladder, cystic, and common bile ducts. Intraoperative cholangiogram favored BA, and a Kasai procedure was performed. The liver biopsy demonstrated focal areas of ductular proliferation and periportal ballooning degeneration without bile duct paucity. The patient exhibited worsening cardiac and liver conditions, growth failure, and developmental delay. She died suddenly at home at the age of 34 months. The cholangiographic and histological abnormalities found in our patient were suggestive of BA. At the same time, she displayed four out of five diagnostic criteria for AS. Based on our experience with this case, we suggest expeditious genetic testing should be considered for any case of neonatal cholestasis with diagnostic uncertainty. This may help avoid unwarranted surgical interventions, potentially associated with worse outcomes.

Clinical, Laboratory, Radiological, and Genetic Characteristics of Pediatric Patients with Alagille Syndrome.

Alagille syndrome (ALGS) is an autosomal dominant disease caused by JAG1 or NOTCH2 mutation. It is diagnosed by the presence of three out of five features: characteristic facies, posterior embryotoxon, peripheral pulmonary stenosis, vertebral defects, and interlobular bile duct paucity. This study aimed to review the prevalence, clinical presentations, diagnosis, treatment, and outcome of patients with ALGS. This is a retrospective review of patients with ALGS at the Pediatric Department, Salmaniya Medical Complex, Bahrain, between August 1994 and October 2022. The diagnosis was based on clinical, laboratory, radiological, histopathological, and genetic findings. Five patients were found to have ALGS. The prevalence of ALGS in Bahrain was 1.04 patients per 100,000 (0.001%). Four were Bahraini and three were females. Median birth weight was 2.3 (2.3-2.5) kg. All patients presented at the time of birth with low birth weight, cholestatic jaundice, clay-colored stool, heart murmur, and dysmorphic facial features. All had congenital heart diseases, two had butterfly vertebrae, and one had posterior embryotoxon. All had elevated liver enzymes and normal abdominal ultrasound. Three had positive hepatobiliary iminodiacetic acid scan and one had bile duct paucity in liver biopsy. Three had intraoperative cholangiogram. Four were positive for JAG1 mutation. All received ursodeoxycholic acid and fat-soluble vitamins. Two required liver transplantation. ALGS is a rare disorder in Bahrain. Diagnosis is challenging as the disease can be associated with or misdiagnosed as biliary atresia. Patients with ALGS are at high risk of morbidity either by unnecessary intraoperative cholangiogram or unavoidable liver transplantation.

526 ALAGILLE SYNDROME, A CASE REPORT

Abstract Alagille syndrome (AGS) is a dominantly inherited multisystem disorder caused by heterozygous mutations of genes that are components of the Notch signaling pathway. The main clinical manifestations of AGS are intrahepatic bile duct paucity, congenital heart defects involving primarily the pulmonary arteries, butterfly vertebrae, anterior chamber defects of the eye and facial dysmorphism. A male patient of 39 years old came to our observation due to the worsening of dyspnea, cyanosis, dizziness, heartbeat and asthenia for about two years. His cardiological history includes percutaneous pulmonary artery angioplasty in both left and right main pulmonary artery in 1994. In 2012, finding of pulmonary hypertension and diagnosis of Alagille syndrome confirmed by genetic analysis (JAG1 gene), and vasoreactivity testing of the pulmonary circulation was positive. Intrastent restenosis of the right lobar pulmonary artery treated with POBA in 2016. Patient therapy includes, diltiazem 60 mg OD, macitentan 10 mg OD, sildenafil 40 mg TID. Echocardiogram showed: preserved global and segmental systolic function. Minimal mitral valve insufficiency. Dilated right ventricle (RV / LV&amp;gt; 1), ipokinetic. Right atrium of increased size. Mild tricuspid valve insufficiency (VD-AD 20 mmHg). reduced systolic flow acceleration time (80 msec). Inferior vena cava of normal caliber with preserved inspiratory collapse. Indirect signs of pulmonary hypertension. The six minutes walking test showed severe desaturation after only one hundred meters. Right catheterization showed severe pulmonary hypertension (PAPm 63 mmHg). blood gas analysis showed oxygen saturation of 83% in the pulmonary artery. Angiography of the pulmonary arteries showed intrastent restenosis on the left pulmonary artery and fracture of the stent on the right pulmonary artery. For which was performed angioplasty with stent intrastent implantation in the right pulmonary artery. After the procedure there was immediate reduction in pulmonary mean arterial pressure (53 mmHg), a progressive improvement in 02 saturation (88% at discharge) while the echocardiogram after the procedure results unchanged except for the increasing of the systolic flow acceleration time (100 msec). Right catheterization showed a gradient trans-stenosis of 96 mmHg. We performed angioplasty with stent intrastent implantation in the right pulmonary artery. After that we saw a drop in the gradient trans-stenosis (63 mmHg) and a raise in the systolic pressure of the left pulmonary artery. In Conclusion, in this particular population of patients with pulmonary hypertension even if on maximal therapy, the worsening of symptoms should in our opinion be an indication for right cardiac catheterization and angiography of the pulmonary arteries.

S3098 Vanishing Bile Duct Syndrome in the Setting of Newly Diagnosed Hodgkin Lymphoma

Introduction: Vanishing bile duct syndrome (VBDS) is characterized by cholestatic liver disease in the setting of disappearing intra-hepatic bile ducts. It can resemble other forms of cholestatic liver disease; however, imaging and biochemical tests will be unrevealing. We describe a case of a woman with Hodgkin lymphoma (HL) who developed cholestatic hepatitis with loss of intra-hepatic bile ducts. Case Description/Methods: A 23-year-old woman with a history of HL who presented for evaluation and treatment of HL. Two months prior she had been treated for CMV-associated gastroenteritis and sepsis. Initial examination revealed jaundice and bilateral conjunctival icterus. Lab results showed total bilirubin of 18.1 mg/dL, ALT 363 U/L, AST 149 U/L, alkaline phosphatase (ALP) of 2392 U/L, direct bilirubin of 15.5 mg/dL, INR of 2.07, and cytomegalovirus (CMV) PCR at 670 IU/mL. Other acute viral hepatitis studies, tests for intrinsic liver disease, and autoimmune markers were negative. Computerized tomography (CT) of the abdomen and pelvis showed extensive lymphadenopathy, sclerotic changes throughout the skeleton, splenomegaly, and hepatomegaly without focal liver lesions. Magnetic resonance cholangiopancreatography (MRCP) of the abdomen showed no evidence of biliary ductal dilatation. Treatment for her HL was initiated, as well as foscarnet for her CMV viremia. Liver biopsy showed benign liver parenchyma with marked cholestasis and paucity of bile ducts, no cirrhosis, and no viral inclusions. The patient was initiated on ursodeoxycholic acid (UDCA) at 15 mg/kg/d without resolution of symptoms or cholestasis. Given no improvement in her cholestasis, the prospects of liver transplantation (LT) were discussed, but the patient was not a candidate (Figure 1). Discussion: Liver involvement in HL typically manifests as parenchymal invasion, external compression, or paraneoplastic destruction of bile ducts (VBDS). VBDS tends to signify a poor prognosis with patients frequently progressing to liver failure. The pathogenesis of VBDS in HL is not yet defined with current evidence suggesting an immune-mediated response. Typically, viral causes should be excluded. In this case, the patient did have CMV viremia. Given her prior treatment, low viral load, and absence of viral inclusions on liver biopsy, CMV was excluded as a cause. Treatment for VBDS revolves around treating the underlying cause. UDCA can be used as a temporizing measure, but, if no improvement is observed over time, patients are referred for liver transplant.Figure 1.: Parenchymal liver biopsy: (A) and (B) Lobular cholestasis. The hepatic lobules show cholestasis within the hepatocytes and bile canaliculi. (C) Paucity of intrahepatic bile duct. No bile duct is seen in the portal tract. (D) CK-7 positive hepatocytes in chronic cholestasis. The hepatocytes in this case stain positive for CK-7.

Non-syndromic bile duct paucity and non-IgE cow’s milk allergy: a case report of challenging nutritional management and maltodextrin intolerance

BackgroundCholestasis in extremely premature infants (EPI) constitutes a nutritional challenge and maltodextrins have been reported as a possible strategy for hypoglycaemia. We aim to describe the nutritional management of an EPI with non-syndromic bile duct paucity (NSBDP) and feeding intolerance.Case presentationA patient, born at 27 weeks of gestational age, presented cholestatic jaundice at 20 days of life with a clinical picture of NSBDP. Patient’s growth was insufficient with formula rich in medium-chain triglyceride (MCT) and branched-chain amino acids (BCAA). Due to frequent fasting hypoglicemic episodes, maltodextrins supplements were provided. He subsequently presented severe abdominal distension and painful crises, which required hospital admission and withdrawal of maltodextrins. Hypercaloric extensively hydrolysed formula provided weight gain, glycemic control, and parallel improvement in cholestasis.ConclusionsOur case suggests caution with the use of maltodextrins in infants, especially if premature. Commercial preparations for hepatopatic patients contain higher concentrations of MCTs and BCAAs, but personalized strategies must be tailored to each patient.

Case report: Unusual and extremely severe lipoprotein X-mediated hypercholesterolemia in extrahepatic pediatric cholestasis

BackgroundLipoprotein X (LpX) - mediated extremely severe hyperlipidemia is a possible feature detectable in children with syndromic paucity of intralobular bile ducts (Alagille syndrome) but rarely in other types of intra- and/or extrahepatic infantile cholestasis.Case presentationHere we report on a previously well 18-month child admitted for cholestatic jaundice and moderate hepatomegaly. Laboratory tests at entry showed conjugated hyperbilirubinemia, elevated values of serum aminotransferases, gamma-glutamyl transpeptidase (GGT) and bile acids (100 folds upper normal values). Extremely severe and ever-increasing hypercholesterolemia (total cholesterol up to 1,730 mg/dl) prompted an extensive search for causes of high GGT and/or hyperlipidemic cholestasis, including an extensive genetic liver panel (negative) and a liver biopsy showing a picture of obstructive cholangitis, biliary fibrosis, and bile duct proliferation with normal MDR3 protein expression. Results of a lipid study showed elevated values of unesterified cholesterol, phospholipids, and borderline/low apolipoprotein B, and low high-density lipoprotein-cholesterol. Chromatographic analysis of plasma lipoproteins fractions isolated by analytical ultracentrifugation revealed the presence of the anomalous lipoprotein (LpX). Magnetic resonance cholangiopancreatography and percutaneous transhepatic cholangiography showed stenosis of the confluence of the bile ducts with dilation of the intrahepatic biliary tract and failure to visualize the extrahepatic biliary tract. Surgery revealed focal fibroinflammatory stenosis of the left and right bile ducts confluence, treated with resection and bilioenteric anastomosis, followed by the rapid disappearance of LpX, paralleling the normalization of serum lipids, bilirubin, and bile acids, with a progressive reduction of hepatobiliary enzymes.ConclusionWe have described a unique case of focal non-neoplastic extrahepatic biliary stenosis of uncertain etiology, presenting with unusual extremely high levels of LpX-mediated hypercholesterolemia, a condition which is frequently mistaken for LDL on routine clinical tests.

The Liver Biopsy in Neonatal Cholestasis: Just a Cherry on Top?

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Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct.

Paucity of interlobular bile ducts (PILBD) is a heterogeneous disorder classified into two categories, syndromic and non-syndromic bile duct paucity. Syndromic PILBD is characterized by the presence of clinical manifestations of Alagille syndrome. Non-syndromic PILBD is caused by multiple diseases, such as metabolic and genetic disorders, infectious diseases, and inflammatory and immune disorders. We evaluated a family with a dominantly inherited PILBD, who presented with cholestasis at 1-2 months of age but spontaneously improved by 1 year of age. Next-generation sequencing analysis revealed a heterozygous CACYBP/SIP p.E177Q pathogenic variant. Calcyclin-binding protein and Siah1 interacting protein (CACYBP/SIP) form a ubiquitin ligase complex and induce proteasomal degradation of non-phosphorylated β-catenin. Immunohistochemical analysis revealed a slight decrease in CACYBP and β-catenin levels in the liver of patients in early infancy, which almost normalized by 13 months of age. The CACYBP/SIP p.E177Q pathogenic variant may form a more active or stable ubiquitin ligase complex that enhances the degradation of β-catenin and delays the maturation of intrahepatic bile ducts. Our findings indicate that accurate regulation of the β-catenin concentration is essential for the development of intrahepatic bile ducts and CACYBP/SIP pathogenic variant is a novel cause of PILDB.

Management of intractable pruritus in a child with cholestatic liver disorder

BackgroundChildhood cholestatic hepatobiliary disorders present with pruritus which is bothersome and difficult to manage. The pathogenesis of pruritus in cholestasis is unknown but several hypotheses have been proposed, including bile acid accumulation, increased opioidergic tone and elevations in lysophosphatidic acid levels. Pruritus can have a profound effect on the patient’s quality of life resulting in sleep deprivation and emotional disturbances. Treatment of the primary cause of cholestasis is important to address the pruritus. However, symptomatic treatment is often necessary especially in cases where the underlying hepatobiliary disease cannot be corrected.&#x0D; Case Description&#x0D; Currently, 19-month-old male was first seen at the gastroenterology clinic at age of 5 months. He was referred as a case of prolonged conjugated hyperbilirubinaemia. He was born at term with birth-weight (BW) of 2kg. He had a history of jaundice for 2 weeks. There was no pale stools or dark urine and has doubled his BW.&#x0D; On examination, he was jaundiced, had no dysmorphic features, but developed the typical facies of Alagille syndrome over time. Investigations showed conjugated hyperbilirubinemia with raised ALP, GGT and transaminases. A liver biopsy showed severe paucity of bile ducts in 12 portal areas.&#x0D; 2 weeks after the initial visit he presented with severe generalized itching associated with bleeding upon scratching, irritability and poor sleep. A presumptive diagnosis of cholestasis-associated pruritus was made after any possible dermatologic disorder associated with pruritus were ruled out.&#x0D; Ursodeoxycholic acid was started with no improvement even at a maximum dose of the medication. Phenobarbitone and rifampicin were added in a stepwise manner which improved pruritus, but there were challenges with obtaining rifampicin after 9 months of treatment hence cholestyramine was added to the ursodeoxycholic acid and phenobarbital, but the child’s pruritus worsened. Though clear instructions were given to the mother regarding administration of cholestyramine we thought the worsening of the child’s pruritus was still possibly due to chelation of the other medications by cholestyramine, hence it was suspended.&#x0D; An antihistamine, cetirizine was added to child’s treatment and his mother reported some improvement in pruritus but this was short-lived. Finally parenteral infusion of naloxone, an opioid antagonist, was administered over 24 hours with significant improvement in child’s symptoms like scratching, irritability and sleeplessness.&#x0D; Child is currently on oral ursodeoxycholic acid, natrelxone, phenobarbitone and cetirizine with continued remarkable response.&#x0D; Conclusion&#x0D; Pharmacologic treatment with recommended medications in a stepwise approach is essential for symptomatic relief of the pruritus.

Etiology and outcome of neonatal cholestasis: an experience in a tertiary center of Bangladesh

BackgroundNeonatal cholestasis (NC) is a major cause of morbidity and mortality in young infants. This study examines the etiology of NC and its outcome during 2 years of follow-up at a tertiary referral center in Bangladesh.ResultsOut of 80 cholestatic infants, 60% had intrahepatic cholestasis with a mean age of onset of 12.4±2.8 days and a mean age of admission of 82.4±29.0 days. The remaining 40% were extrahepatic with a mean age of onset of 6.7±2.3 days and a mean age of admission of 94.6±50.4 days. Biliary atresia (BA), idiopathic neonatal hepatitis (INH), and TORCH (Toxoplasma, rubella, cytomegalovirus, and herpes simplex) infection except rubella were the most common causes. After receiving treatment, 46.2% of the cases improved, 23.8% deteriorated with morbidity, and 30% died. The majority of the children with INH, TORCH, choledochal cyst, hypothyroidism, galactosemia, and urinary tract infection (UTI) with sepsis were improved. Significant mortality was found in BA (56.6%), intrahepatic bile duct paucity (PIBD) (100%), and progressive familial intrahepatic cholestasis (PFIC) (100%) whereas the rest of BA (43.4%) live with persistent morbidity. Significant clinical improvement was observed in 37 (46.2%) cases of cholestasis evidenced by decreasing jaundice, change of color of urine from dark to normal color, change of stool color from pale to yellow, and gradual decrease in liver size from hepatomegaly state. In addition, decreasing median total bilirubin, direct bilirubin, alanine transaminase, gamma-glutamyl transferase, and alkaline phosphatase showed biochemical improvement at 2 years follow-up. The age of admission, etiology, and presence of ascites are the predictors of outcomes.ConclusionBA was the most common cause of extrahepatic while INH and TORCH infection were the most common cause of intrahepatic cholestasis. Majority of children with intrahepatic cholestasis improved but deteriorated with BA and genetic causes. Prompt referral and early diagnosis as well as the etiology of NC were the main determinants of the favorable outcome.