Progressive Intrahepatic Cholestasis Research Articles

Adverse outcomes associated with progressive intrahepatic cholestasis of pregnancy.

To assess the association between increasing bile acid levels in pregnancies with cholestasis and adverse outcomes. This is a retrospective cohort study of singleton, non-anomalous gestations complicated by cholestasis delivering at a single academic medical center from 2005-2019. We compared rates of adverse outcomes in pregnancies complicated by mild cholestasis (initial total bile acid (TBA) < 40 μmol/L and peak TBA < 40 μmol/L), progressive cholestasis (initial TBA < 40 μmol/L and peak TBA ≥ 40 μmol/L), and severe cholestasis (initial TBA ≥ 40 μmol/L). Our primary outcome was a composite adverse outcome including spontaneous preterm labor and delivery, umbilical artery pH < 7.20, 5-min Apgar < 7, cesarean delivery for non-reassuring fetal heart rate tracing, meconium-stained amniotic fluid, and neonatal ICU admission. Analyses were performed using mild cholestasis as the base comparator and a second analysis using severe cholestasis as the base comparator. Of the 1182 pregnancies complicated by cholestasis, 732 (61.9%) had mild cholestasis, 78 (6.6%) had progressive cholestasis, and 372 (31.5%) had severe cholestasis. After adjusting for confounders including gestational age at diagnosis and using mild cholestasis as the base comparator, both progressive and severe cholestasis were associated with the composite adverse outcome (progressive ICP OR 1.70; 95% CI 1.04-2.78 and severe ICP OR 1.60; 95% CI 1.24-2.06). When using progressive cholestasis as the base comparator, there were no statistically significant differences in the primary or secondary outcomes between progressive cholestasis and severe cholestasis. This study highlights the significance of monitoring peak bile acid levels and that some cases of cholestasis may progress in pregnancy and the adverse associations are better reflected by the peak total bile acid level and not the cholestasis severity at initial diagnosis.

Case series of progressive familial intrahepatic cholestasis type 3: Characterization of variants in ABCB4 in China.

To improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, https://www.omim.org/entry/602347). Between September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (ABCB4), https://www.omim.org/entry/171060] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed. Four patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, γ-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of ABCB4 (c.1560 + 2T > A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant ABCB4 pathogenesis. MDR3 immunohistochemistry and molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3.

Disordered farnesoid X receptor signaling is associated with liver carcinogenesis in Abcb11-deficient mice.

ABCB11 encodes the bile salt export pump (BSEP), a key regulator in maintaining bile acid (BA) homeostasis. Although inherited ABCB11 mutations have previously been linked to primary liver cancer, whether ABCB11 deficiency leads to liver cancer remains unknown. Here, we analyzed ABCB11 mRNA expression levels in liver tumor specimens [29 with hepatocellular carcinoma (HCC), one with intrahepatic cholangiocarcinoma (ICC), and one with mixed HCC/ICC] with adjacent normal specimens and published human datasets. Liver tissues obtained from Abcb11-deficient (Abcb11-/- ) mice and wild-type mice at different ages were compared by histologic, RNA-sequencing, and BA analyses. ABCB11 was significantly downregulated in human liver tumors compared with normal controls. Abcb11-/- mice demonstrated progressive intrahepatic cholestasis and liver fibrosis, and spontaneously developed HCC and ICC over 12 months of age. Abcb11 deficiency increased BAs in the liver and serum in mice, most of which are farnesoid X receptor (FXR) antagonists/non-agonists. Accordingly, the hepatic expression and transcriptional activity of FXR were downregulated in Abcb11-/- mouse livers. Administration of the FXR agonist obeticholic acid reduced liver injury and tumor incidence in Abcb11-/- mice. In conclusion, ABCB11 is aberrantly downregulated and plays a vital role in liver carcinogenesis. The cholestatic liver injury and liver tumors developed in Abcb11-/- mice are associated with increased FXR antagonist BAs and thereby decreased activation of FXR. FXR activation might be a therapeutic strategy in ABCB11 deficiency diseases. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Molecular Mechanism of Intrahepatic Cholestasis in Sickle Cell Disease

Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects over three million people worldwide. Sickle Cell Anemia, the most common form of SCD is caused by the substitution of hydrophilic glutamic acid with hydrophobic valine at the sixth position in β-globin chain. The mutated hemoglobin (HbS) polymerizes under hypoxic conditions to promote erythrocyte sickling. Sickling promotes vaso-occlusion (ischemia) and hemolysis, which are two major pathophysiological events contributing to end organ damage. SCD patients can develop Sickle Cell Intrahepatic Cholestasis (SCIC), which is a rare but lethal form of hepatopathy. Besides SCIC, cholethiasis (gallstone formation), viral hepatitis and choledocholithiasis (stones in bile duct) have also been reported in SCD patients. The morbidity associated with sickle hepatopathy is expected to rise with growing life expectancy of SCD patients. Rescue therapies to halt the progression of sickle hepatopathy will be highly beneficial, however, development of such therapies is stalled by the lack of understanding of the molecular mechanism underlying sickle hepatopathy.We assessed the liver pathophysiology in a humanized mouse model of SCD in Townes SS mice homozygous for Hbatm1(HBA)Tow and homozygous for Hbbtm2(HBG1,HBB*)Tow). Littermate sickle cell trait mice (Townes AS mice homozygous for Hbatm1(HBA)Tow and compound heterozygous for Hbbtm2(HBG1,HBB*)Tow/Hbbtm3(HBG1,HBB)Tow) were used as control mice. Our findings reveal that SCD but not control mice developed progressive intrahepatic cholestasis with age characterized by increased level of serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and cholesterol. Immunohistochemical analysis of SCD mice liver revealed increased ductular reaction, inflammation, and fibrosis, which is hallmark of cholestatic liver disease. Immunoelectron microscopy revealed damage to bile canalicular structure and loss of several bile transporters from hepatocyte membrane. Remarkably, biochemical analysis revealed that intrahepatic cholestasis in SCD mice was associated with loss of Wnt signaling in hepatocytes. Our preliminary findings suggest that further studies are needed to elucidate the molecular mechanism underlying progressive cholestasis in SCD mice. Profound understanding of the regulation of cholestasis and hepatobiliary injury in SCD could potentially benefit the development of new therapies to attenuate sickle hepatopathy in SCD patients. DisclosuresNo relevant conflicts of interest to declare.

Successful treatment of infantile oxysterol 7\u03b1-hydroxylase deficiency with oral chenodeoxycholic acid

BackgroundDeficiency of oxysterol 7α-hydroxylase, encoded by CYP7B1, is associated with fatal infantile progressive intrahepatic cholestasis and hereditary spastic paraplegia type 5. Most reported patients with CYP7B1 mutations presenting with liver disease in infancy have died of liver failure. However, it was recently reported that two patients treated with chenodeoxycholic acid survived. Correlations between the phenotype and genotype of CYP7B1 deficiency have not been clearly established.Case presentationA 5-month-7-day-old Chinese baby from non-consanguineous parents was referred for progressive cholestasis and prolonged prothrombin time from one month of age. Genetic testing revealed compound heterozygous mutations c.187C > T(p.R63X)/c.334C > T(p.R112X) in CYP7B1, and fast atom bombardment mass spectrometry analysis of the urinary bile acid confirmed the presence of atypical hepatotoxic 3β-hydroxy-Δ5-bile acids. While awaiting liver transplantation she was orally administered chenodeoxycholic acid. Her liver function rapidly improved, urine atypical bile acids normalized, and she thrived well until the last follow-up at 23 months of age. Her 15-year-old brother, with no history of infantile cholestasis but harboring the same mutations in CYP7B1, had gait abnormality from 13 years of age. Neurological examination revealed hyper-reflexia and spasticity of the lower limbs. Brain MRI revealed enlarged perivascular space in the bilateral basal ganglia and white matter of frontal parietal.ConclusionsIn summary, these findings highlight that the phenotype of CYP7B1 deficiency varies widely, even in siblings and that early administration of chenodeoxycholic acid may improve prognosis.

Dual β-Catenin and γ-Catenin Loss in Hepatocytes Impacts Their Polarity through Altered Transforming Growth Factor-β and Hepatocyte Nuclear Factor 4α Signaling

Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood. Loss of β-catenin at adherens junctions is compensated by γ-catenin and dual loss of both catenins in double knockouts (DKOs) in mice liver leads to progressive intrahepatic cholestasis. However, the clinical relevance of this observation, and further phenotypic characterization of the phenotype, is important. Herein, simultaneous loss of β-catenin and γ-catenin was identified in a subset of liver samples from patients of progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. Hepatocytes in DKO mice exhibited defects in apical-basolateral localization of polarity proteins, impaired bile canaliculi formation, and loss of microvilli. Loss of polarity in DKO livers manifested as epithelial-mesenchymal transition, increased hepatocyte proliferation, and suppression of hepatocyte differentiation, which was associated with up-regulation of transforming growth factor-β signaling and repression of hepatocyte nuclear factor 4α expression and activity. In conclusion, concomitant loss of the two catenins in the liver may play a pathogenic role in subsets of cholangiopathies. The findings also support a previously unknown role of β-catenin and γ-catenin in the maintenance of hepatocyte polarity. Improved understanding of the regulation of hepatocyte polarization processes by β-catenin and γ-catenin may potentially benefit development of new therapies for cholestasis.

Split liver transplantation in two recipients for urgent indications: an example and logistics of interregional cooperation

Aim. To report a rare case of split liver transplantation in two urgent recipients treated in hospitals that are very far from each other. Material and methods. Partial liver grafts were obtained by controlled full-right/full-left in situ splitting. The left lobe was transplanted in a 7-year-old child with severe hepatic failure (PELD score 39) resulting, probably from an progressive intrahepatic familial cholestasis in Novosibirsk. The right lobe was used for re-transplantation in a 28-year-old patient with hepatic artery thrombosis (UNOS status 1A) after living donor right lobe liver transplantation in Moscow. Results. The course of the early post-operative period in recipient 1 was complicated by infected total pancreatonecrosis with the development of limited biliary leakage and the formation of a stricture, which required reconstructive cholangiojejunostomy 12 months after transplantation. Recipient 2 consistently underwent biliary leakage, arrosive arterial bleeding, graft artery thrombosis, all of which could become fatal. Complications were successfully eliminated by the consistent use of surgical and endovascular interventions. Conclusion. The presented observation is, firstly, an example of effective inter-center cooperation, and secondly, a demonstration of the existing problems of postmortem organ donation, which determine the need for such extreme surgery in critical situations.

Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies.

Cholestatic liver diseases are a significant cause of morbidity and mortality and the leading indication for pediatric liver transplant. These include diseases such as biliary atresia, Alagille syndrome, progressive intrahepatic cholestasis entities, ductal plate abnormalities including Caroli syndrome and congenital hepatic fibrosis, primary sclerosing cholangitis, bile acid synthesis defects, and certain metabolic disease. Medical management of these patients typically includes supportive care for complications of chronic cholestasis including malnutrition, pruritus, and portal hypertension. However, there are limited effective interventions to prevent progressive liver damage in these diseases, leaving clinicians to ultimately rely on liver transplantation in many cases. Agents such as ursodeoxycholic acid, bile acid sequestrants, and rifampicin have been mainstays of treatment for years with the understanding that they may decrease or alter the composition of the bile acid pool, though clinical response to these medications is frequently insufficient and their effects on disease progression remain limited. Recently, animal and human studies have identified potential new therapeutic targets which may disrupt the enterohepatic circulation of bile acids, alter the expression of bile acid transporters or decrease the production of bile acids. In this article, we will review bile formation, bile acid signaling, and the relevance for current and newer therapies for pediatric cholestasis. We will also highlight further areas of potential targets for medical intervention for pediatric cholestatic liver diseases.

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

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. 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. 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. 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.

Summary and Considerations in the Nursing Care of Patients with Progressive Familial Intrahepatic Cholestasis

Background: Progressive familiar intrahepatic cholestasis (PFIC) is a group of rare cholestatic liver diseases whose main features are itching, jaundice and even liver failure. Many studies have been reported in clinical reports, but the care of PFIC is rarely described. Purpose: To provide a summary and recommendations for the setup of strategies for PFIC patient care. Material and methods: A non-systematic review of PFIC nursing research until July 12, 2020. Use online search engines (PubMed, Medline, Embase, Web of Science, and CINAHL) to find PFIC nursing-related content, sort and summarize nursing-related content. Results: As a rare disease, there is limited research in PFIC nursing. The main care measures of PFIC including nursing interventions and evaluation tools. Nursing intervention is divided into general symptom care and nursing care of postoperative complications. Evaluation tools mainly focus on quality of life assessment and evaluation of itching. Conclusions: Nurses should pay attention to the use of scales when caring for PFIC patients, and observe whether specific nursing measures can help improve patients’ quality of life. PFIC nursing interventions and evaluation tools should be tailored according to PFIC clinical manifestation. A multidisciplinary collaborative approach is encouraged for proper management and tailoring therapy according to clinical manifestation.

FRI-444-VTX-803 AAV-mediated correction of progressive familiar intrahepatic cholestasis type 3 in a clinically relevant mouse model

FRI-444-VTX-803 AAV-mediated correction of progressive familiar intrahepatic cholestasis type 3 in a clinically relevant mouse model

Immunological abnormalities in patients with primary biliary cholangitis.

Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.

Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges

To test the application of a target enrichment next-generation sequencing (NGS) jaundice panel in genetic diagnosis of pediatric liver diseases. We developed a capture-based target enrichment NGS jaundice panel containing 42 known disease-causing genes associated with jaundice or cholestasis and 10 pathway-related genes. During 2015-2017, 102 pediatric patients with various forms of cholestasis or idiopathic liver diseases were tested, including patients with initial diagnosis of cholestasis in infancy, progressive familial intrahepatic cholestasis, syndromic cholestasis, Wilson disease, and others. Of the 102 patients, 137 mutations/variants in 44 different genes were identified in 84 patients. The genetic disease diagnosis rate was 33 of 102 (32.4%). A total of 79 of 102 (77.5%) of patients had at least 1 heterozygous genetic variation. Those with progressive intrahepatic cholestasis or syndromic cholestasis in infancy had a diagnostic rate of 62.5%. Disease-causing mutations, including ATP8B1, ABCB11, ABCB4, ABCC2, TJP2, NR1H4 (FXR), JAG1, AKR1D1, CYP7B1, PKHD1, ATP7B, and SLC25A13, were identified. Nine patients had unpredicted genetic diagnosis with atypical phenotype or novel mutations in the investigational genes. We propose an NGS diagnosis classification categorizing patients into high (n = 24), moderate (n = 9), or weak (n = 25) levels of genotype-phenotype correlations to facilitate patient management. This panel enabled high-throughput detection of genetic variants and disease diagnosis in patients with a long list of candidate causative genes. A NGS report with diagnosis classification may aid clinicians in data interpretation and patient management.

Double Heterozygous Mutation Causing PFIC2 with Synchronic Hepatocellular Carcinomas before Two Years of Age

Introduction Bile salts are exclusively synthesized in the liver. The bile salt export pump (BSEP), an adenosine triphosphate (ATP)-dependent transporter, is exclusively located in the hepatic canalicular membrane, and exports the bile salts into the canaliculus against a concentration gradient. Mutations in the ABCB11 gene alter BSEP and cause progressive intrahepatic familial cholestasis (PFIC2) type 2. This disease is characterized by low GGT hepatitis and early onset of cholestasis and pruritus; these patients are at increased risk of developing hepatocellular carcinoma (HCC) or cholangiocarcinoma. Aim To communicate a case or PFIC 2 with early development of synchronic HCC, with two ABCB11 heterozygous mutations, one of them not described before. Case Report This is a female referred to this center at 3 months of age due to cholestasis and coagulopathy. Coagulation corrected after vitamin K administration; hepatocellular enzymes and bilirubin persisted elevated with normal GGT. Further workup was done, ruling out viral hepatitis, biliary atresia and cystic fibrosis. Alpha-fetoprotein and bile serum salts were markedly elevated. A percutaneous liver biopsy was remarkable for giant cell hepatitis with moderate activity, portal and periportal fibrosis with incomplete bridges. PFIC was suspected and a molecular analysis was requested. Two heterozygous mutations were identified: p.Glu297Gly already reported in association to PFIC2 and p.Arg303Met previously not identified as related with this disease. The patient remained clinically stable, with progression of cholestasis and pruritus that was managed medically. At 17 months of age she presented sustained increase of Alpha-fetoprotein. A liver ultrasound showed a 7 mm nodule that was confirmed by CT hepatic angiography. She was promptly evaluated for liver transplant; extra hepatic lesions were excluded. Three weeks later the patient was transplanted with a split liver. The transplant was uneventful and she was discharged home 10 days after the surgery. The explanted liver showed cirrhosis and 4 nodules of poorly differentiated HCC measuring less than 1 cm each. The Alpha-fetoprotein decreased to normal values three weeks after TX and it has remained normal. The patient is now 14 months post TX with a functioning graft and showing no lesions of HCC. Conclusion PFIC type 2 is one of the few entities that might present HCC at a very early age. It is important to perform an adequate follow up in order to make the appropriate diagnosis and to perform a timely adequate liver transplant. It is of great interest for the medical community that newly identified mutations are reported, in order to enrich the medical knowledge.

Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis.

We report partially redundant function of catenins at AJ in regulating TJ and contributing to the blood-biliary barrier. Furthermore, concomitant hepatic loss of β- and γ-catenin disrupts structural and functional integrity of AJ and TJ via transcriptional and posttranslational mechanisms. Mice with dual catenin loss develop progressive intrahepatic cholestasis, providing a unique model to study diseases such as PFIC. (Hepatology 2018;67:2320-2337).

Splicing analysis of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ‐glutamyltransferase

The aim of this study was to analyze the pathogenicity of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ-glutamyltransferase. The enrolled variants were identified in ABCB11 between October 2009 and June 2016. The effects on pre-RNA splicing were analyzed by in silico tools and minigene splicing assay. There were three intronic (c.908 + 5G > A, c.2815-8A > G, and c.612-15_-6del10bp) and two synonymous (c.1809G > A, p.K603K and c.2418C > T, p.G806G) variants with unknown significance identified in ABCB11 of five ABCB11 heterozygotes. Parental studies were carried out for four patients, and revealed that the variants with unknown significance were compound heterozygous with other pathogenic variants. The five variants with unknown significance had minor allele frequency <0.1% or were absent from controls, and had positive prediction results by in silico tools. The effects on pre-RNA splicing were further confirmed by minigene splicing assay. c.908 + 5A caused abnormal splicing in at least 78.5 ± 3.8% of products using a cryptic splice site (ss) 22nucleotides (nt) upstream of the wild-type (WT) 5'ss. Seven nucleotides of intron 22 upstream of the WT 3'ss was retained for all products from c.2815-8G. c.612-15_-6del caused exon 8 skipping in 24.8 ± 7.7% of products, and 55nt of exon 8 downstream of the WT 3'ss removal in remaining products. c.1809A led to exon 15 skipping. c.2418T removed exon 20 and 62nt of exon 21 downstream of the WT 3'ss by using a cryptic ss. We successfully identified five pathogenic synonymous or intronic variants with some common features. These features might help to choose the right variant for further functional assay.

Lower Plasma Levels of IL-35 in Patients with Primary Biliary Cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Its histological characteristics, such as progressive intrahepatic bile duct destruction, cholestasis, and liver cirrhosis, are caused by the body's autoimmune disorders. Interleukin (IL)-35 has two subunits (p35 and Ebi3) and is a member of the IL-12 family of heterodimeric cytokines. IL-35 has immunosuppressive functions and plays an important role in many autoimmune diseases. In this study, we compared plasma levels of IL-35 and relative mRNA expression levels of p35 and Ebi3 in peripheral blood mononuclear cells (PBMCs) from 70 PBC patients and 70 healthy individuals. The results showed that the relative expression levels of Ebi3 mRNA were lower in PBMCs from PBC patients than in PBMCs from healthy individuals, whereas the levels of p35 mRNA were similar in both groups. Plasma IL-35 concentrations were lower in patients with PBC than in healthy individuals. Plasma levels were higher in PBC patients at an advanced stage compared to patients at an early stage. Variable plasma levels with different stages were also found in transforming growth factor beta (TGF-β), which is mainly produced by regulatory T cells (Tregs). IL-35 and TGF-β levels were positively correlated with each other, and IL-35 was capable of promoting the inhibitory functions of Tregs in PBC patients at both the early and late stages of disease. Lower plasma IL-35 levels were accompanied by higher levels of typical clinical parameters, such as alkaline phosphatase, or of proinflammatory cytokines, such as interferon-gamma (IFN-γ), in PBC patients (P < 0.05 for each). We propose that IL-35 may be involved in the pathogenesis of PBC and could be a potential biomarker for diagnosing this disease.

Molecular characterization of exons 6, 8 and 9 of ABCB4 gene in children with Progressive Familial Intrahepatic Cholestasis type 3

Aim of work: To estimate the frequency of mutations involving exons 6, 8 and 9 of Adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene among children with progressive intrahepatic cholestasis with high γ-GT activity (PFIC3).Subjects and methods: Cross sectional study was conducted on 30 children with PFIC3. Genotyping was performed by sequencing analysis of exons 6, 8 and exon 9 of ABCB4 gene.Results: Heterozygous synonymous polymorphic variant was detected in exon 6 (rs 1202283) and in exon 8 (rs 2109505). No mutations in studied exons were detected.Conclusion: Exons 6, 8 and 9 mutations of ABCB4 gene are not common among Egyptian children with PFIC3.

Progressive Familial Intrahepatic Cholestasis: A Rare Cause of Cirrhosis in Young Adult Patients.

Hepatic cirrhosis is an important cause of morbidity and mortality. An unusual case of cirrhosis and portal hypertension in an 18-year-old patient secondary to Progressive Intrahepatic Cholestasis is discussed. The clinical and biochemical findings are discussed and a clinical approach to determining the underlying etiology of cirrhosis is outlined. Significant complications of portal hypertension include ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, varices, and hepatic encephalopathy. A clinical approach to these complications of cirrhosis is presented. Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare congenital metabolic abnormality. There are 3 subtypes and Type 3 PFIC commonly presents in late adolescence and early adulthood. Clinical and laboratory findings as well as management for the condition are described.

Resolution of biliary stricture after living donor liver transplantation in a child by percutaneous trans-hepatic cholangiography and drainage: a case report

IntroductionIntra-hepatic cholestasis arising from biliary strictures is a frequent complication in pediatric patients after liver transplantation. Minimally invasive procedures such as percutaneous drainage placement and balloon dilation are the preferred diagnostic and therapeutic modalities.Case presentationWe report the case of a 12-month-old Caucasian boy with biliary atresia who was initially treated with hepatoportoenterostomy. In the following months, he developed biliary cirrhosis, accompanied by cystic bile retention, recurrent bile duct infections and malabsorption. Six months after the initial surgical intervention, he underwent living donor liver transplantation. Within two months, the hepatico-jejunostomy became occluded leading to progressive intra-hepatic cholestasis. Under sonographic guidance, external drainage of bile was accomplished by percutaneous trans-hepatic cholangiography and drainage. In total, our patient underwent 12 interventions under general anesthesia until balloon dilatation of the hepatico-jejunostomy was successfully performed. Finally, our patient’s general condition improved and he gained weight.ConclusionsMinimally invasive techniques are preferred to surgical revisions and justify even multiple attempts. Interventions under general anesthesia, though not without risks, are still reasonable. Co-operation with parents and multidisciplinary approach to complication management by the involved surgeon, radiologist, pediatrician and anesthesiologist are important.