ABSTRACT
CONTEXT: Incidence of periampullary carcinoma is low, approximately 0.5-2% of all gastrointestinal malignancies. Histologic subtyping has a prognostic bearing. The purpose of this study is to differentiate periampullary carcinomas based on immunohistochemistry (IHC) by using cytokeratin 7 (CK7), cytokeratin 20 (CK20), caudal type homeobox 2 (CDX2). AIMS: To analyze the usefulness of IHC as single/panel of markers that included CK7, CK20, and CDX2. SETTINGS AND DESIGN: This was a prospective study done from January 2017 to September 2018. SUBJECTS AND METHODS: A total 50 pancreaticoduodenectomy specimens were evaluated and classified as intestinal (INT) and pancreaticobiliary (PB) types based on their morphological and immunohistochemical features, respectively. The morphologic subtypes, expression of IHC markers were correlated with different histologic parameters. STATISTICAL ANALYSIS: Chi-square test was used to study the association between different IHC markers with histologic parameters. Probability (P) values <0.05 were regarded as statistically significant. RESULTS: The expression of CK7, CK20, CDX2 were studied in 50 cases to classify them as INT and pancreatobiliary subtypes. CK7 has high sensitivity (88.2%), CDX2 has high specificity (96.4%), CK20+/CDX2+ has both high sensitivity (94.2 percent) and specificity (89.2 percent) in differentiating INT from pancreatobiliary subtypes. The morphologic subtypes showed correlation with two variables (tumor grade, pathologic T stage). CK20 and CK20/CDX2 expression showed a positive correlation with tumor grade, pathologic T staging, and lymphovascular invasion. CONCLUSIONS: In conclusion, morphological classification can significantly discriminate histologic types, IHC plays a moderate role. However, the combined expression of CK20 and CDX2 is helpful in subtyping.
Subject(s)
Bile Duct Diseases/genetics , CDX2 Transcription Factor/genetics , Duodenal Neoplasms/genetics , Gene Expression , Intestines/pathology , Keratin-7/genetics , Pancreas/pathology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Bile Duct Diseases/pathology , Biomarkers, Tumor/genetics , Duodenal Neoplasms/diagnosis , Female , Humans , Immunohistochemistry/methods , Keratin-20/genetics , Male , Prognosis , Prospective StudiesABSTRACT
Objective: To investigate the relationship between V444A mutation of the ABCB11 gene and primary intrahepatic stone (PIS). Methods: A total of 164 patients (including 91 males and 73 females, with an average age of (46.0±13.0) years) with PIS and 164 healthy (including 99 males and 65 females, with an average age of (43.8±16.7) years) volunteers were enrolled in this case-control study between October 2017 and June 2019. TaqMan-MGB was used for detecting the V444A polymorphism site of the ABCB11 gene. All the genotypes and allele frequencies were calculated. Pearson chi-squared test was performed to detect the differences in allele and genotype distribution between the two groups. Logistic regression analysis was used to identify genotypes associated with PIS. Results: There was no significant difference in age and gender between the two groups(both P>0.05). The distributions of V444A allele and genotype accorded with Hardy-Weinberg equilibrium law (P=0.161), which indicated that the selected control group represented statistically acceptable sample. Two alleles of T and C, and three genotypes of TT, TC and CC were detected in the locus of V444A. The T and C allele frequencies in the PIS group and the control group were 28.4% vs 35.4%, and 71.6% vs 64.6%, respectively. The frequencies of the T and C alleles were not different between the two groups (P=0.054). The frequencies of TT, TC and CC genotypes in the two groups were 5.5%, 45.7%, 48.8%, and 14.6%, 41.5%, 43.9%, respectively, with significant difference between the two groups (P=0.023). Logistic regression analysis revealed the V444A polymorphism (TC heterozygous mutation) was associated with PIS. Conclusion: ABCB11 gene polymorphism at the site of V444A may be related to the susceptibility of PIS.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics , Bile Duct Diseases/genetics , Calculi/genetics , Polymorphism, Single Nucleotide , Adult , Alleles , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , MutationABSTRACT
To investigate the pathogenesis of a congenital form of hepatic fibrosis, human hepatic organoids were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD). Here we show that these hepatic organoids develop the key features of ARPKD liver pathology (abnormal bile ducts and fibrosis) in only 21 days. The ARPKD mutation increases collagen abundance and thick collagen fiber production in hepatic organoids, which mirrors ARPKD liver tissue pathology. Transcriptomic and other analyses indicate that the ARPKD mutation generates cholangiocytes with increased TGFß pathway activation, which are actively involved stimulating myofibroblasts to form collagen fibers. There is also an expansion of collagen-producing myofibroblasts with markedly increased PDGFRB protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resemble those present in commonly occurring forms of liver fibrosis. PDGFRB pathway involvement was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. Besides providing insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.
Subject(s)
Liver Cirrhosis/pathology , Models, Biological , Organoids/pathology , Bile Duct Diseases/genetics , Bile Duct Diseases/metabolism , Bile Duct Diseases/pathology , Collagen/metabolism , Epithelial Cells/pathology , Humans , Induced Pluripotent Stem Cells/cytology , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Cirrhosis/drug therapy , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Mutation , Myofibroblasts/metabolism , Myofibroblasts/pathology , Organoids/drug effects , Organoids/metabolism , Polycystic Kidney, Autosomal Recessive/drug therapy , Polycystic Kidney, Autosomal Recessive/genetics , Polycystic Kidney, Autosomal Recessive/metabolism , Polycystic Kidney, Autosomal Recessive/pathology , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolismABSTRACT
PURPOSE OF REVIEW: Indeterminate biliary strictures (IDBS) continue to be an area of frustration for clinicians. Standard endoscopic retrograde cholangiopancreatography (ERCP) with conventional brush cytology and/or forceps biopsy has a low sensitivity for distinguishing benign from malignant biliary strictures. A delay in diagnosis of malignancy has consequences for subsequent therapy or surgery. In this article, we review current and emerging technologies that may aid in this diagnostic dilemma. RECENT FINDINGS: Several technologies have been utilized in IDBS to establish a diagnosis which include peroral cholangioscopy, confocal laser endomicroscopy, endoscopic ultrasound with fine needle aspiration, intraductal ultrasound, optical coherence tomography, fluorescence in situ hybridization, next generation sequencing, integrated molecular pathology, and DNA-image cytometry. While cholangioscopy and confocal laser endomicroscopy have become standards of care in expert centers for the evaluation of patients with IDBS, there are several endoscopic and molecular modalities that may also aid in establishing a diagnosis. Further head-to-head prospective diagnostic studies as well as cost-efficacy studies are needed.
Subject(s)
Bile Duct Diseases/diagnostic imaging , Constriction, Pathologic/diagnostic imaging , Diagnostic Techniques, Digestive System , Bile Duct Diseases/genetics , Bile Duct Diseases/pathology , Diagnostic Imaging , Genetic Techniques , HumansABSTRACT
ATP-binding cassette (ABC) subfamily B member 4 (ABCB4), also known as multidrug resistance protein 3 (MDR3), encoded by ABCB4, is involved in biliary phospholipid secretion, protecting hepatobiliary system from deleterious detergent and lithogenic properties of the bile. ABCB4 mutations altering canalicular ABCB4 protein function and expression may have variable clinical presentation and predispose to several human liver diseases. Well-established phenotypes of ABCB4 deficit are: progressive familial intrahepatic cholestasis type 3, gallbladder disease 1 (syn. low phospholipid associated cholelithiasis syndrome), high ɣ-glutamyl transferase intrahepatic cholestasis of pregnancy, chronic cholangiopathy, and adult biliary fibrosis/cirrhosis. Moreover, ABCB4 aberrations may be involved in some cases of drug induced cholestasis, transient neonatal cholestasis, and parenteral nutrition-associated liver disease. Recently, genome-wide association studies have documented occurrence of malignant tumours, predominantly hepatobiliary malignancies, in patients with ABCB4/MDR3 deficit. The patient's age at the time of the first presentation of cholestatic disease, as well as the severity of liver disorder and response to treatment are related to the ABCB4 allelic status. Mutational analysis of ABCB4 in patients and their families should be considered in all individuals with cholestasis of unknown aetiology, regardless of age and/or time of onset of the first symptoms.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/deficiency , Chemical and Drug Induced Liver Injury/genetics , Cholelithiasis/genetics , Cholestasis, Intrahepatic/genetics , Liver Cirrhosis, Biliary/genetics , Pregnancy Complications/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Age of Onset , Alleles , Bile Duct Diseases/genetics , Cholagogues and Choleretics/therapeutic use , Cholestasis/genetics , Gallbladder Diseases/genetics , Humans , Liver Diseases/etiology , Liver Diseases/genetics , Parenteral Nutrition/adverse effects , Ursodeoxycholic Acid/therapeutic useABSTRACT
Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases ß-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1ß and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.
Subject(s)
Bile Duct Diseases/genetics , Alagille Syndrome/physiopathology , Bile Duct Diseases/drug therapy , Bile Duct Diseases/etiology , Bile Duct Diseases/physiopathology , Cystic Fibrosis/complications , Cystic Fibrosis/physiopathology , Cysts/genetics , Cysts/physiopathology , Gastrointestinal Microbiome/physiology , Humans , Liver Diseases/genetics , Liver Diseases/physiopathology , Molecular Targeted Therapy/methods , Receptors, Notch/physiology , Signal Transduction/physiologyABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct epithelial cell lining. The misdiagnosis of CCA and other biliary diseases may occur due to the similarity of clinical manifestations and blood tests resulting in inappropriate or delayed treatment. Thus, an accurate and less-invasive method for differentiating CCA from other biliary diseases is inevitable. METHODS: We quantified methylation of OPCML, HOXA9, and HOXD9 in serum cell-free DNA (cfDNA) of CCA patients and other biliary diseases using methylation-sensitive high-resolution melting (MS-HRM). Their potency as differential biomarkers between CCA and other biliary diseases was also evaluated by using receiver operating characteristic (ROC) curves. RESULTS: The significant difference of methylation levels of OPCML and HOXD9 was observed in serum cfDNA of CCA compared to other biliary diseases. Assessment of serum cfDNA methylation of OPCML and HOXD9 as differential biomarkers of CCA and other biliary diseases showed the area under curve (AUC) of 0.850 (0.759-0.941) for OPCML which sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 80.00%, 90.00%, 88.88%, 81.81%, and 85.00%, respectively. The AUC of HOXD9 was 0.789 (0.686-0.892) with sensitivity, specificity, PPV, NPV, and accuracy of 67.50%, 90.00%, 87.09%, 73.46%, and 78.75%, respectively. The combined marker between OPCML and HOXD9 showed sensitivity, specificity, PPV, and NPV of 62.50%, 100%, 100%, and 72.72%, respectively, which may be helpful to prevent a misdiagnosis between CCA and other biliary diseases. CONCLUSIONS: Our findings suggest the application of serum cfDNA methylation of OPCML and HOXD9 for differential diagnosis of CCA and other biliary diseases due to its less invasiveness and clinically practical method which may benefit the patients by preventing the misdiagnosis of CCA and avoiding unnecessary surgical intervention.
Subject(s)
Bile Duct Neoplasms/diagnosis , Biomarkers, Tumor/genetics , Cell Adhesion Molecules/genetics , Cholangiocarcinoma/diagnosis , DNA Methylation , Homeodomain Proteins/genetics , Neoplasm Proteins/genetics , Area Under Curve , Bile Duct Diseases/diagnosis , Bile Duct Diseases/genetics , Bile Duct Neoplasms/genetics , Cell-Free Nucleic Acids , Cholangiocarcinoma/genetics , Diagnosis, Differential , Female , GPI-Linked Proteins/genetics , Humans , Male , Sensitivity and SpecificityABSTRACT
In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre-ert2-nlacz , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-ß6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) ß activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.
Subject(s)
AC133 Antigen/genetics , Bile Duct Diseases/genetics , Bile Duct Diseases/pathology , Biliary Atresia/genetics , Rotavirus/pathogenicity , Animals , Animals, Newborn , Biliary Atresia/pathology , Biopsy, Needle , Cells, Cultured , Disease Models, Animal , Fibrosis/pathology , Gene Expression Regulation , Humans , Immunohistochemistry , Mice , Mice, Knockout , Mutation/genetics , Random Allocation , Risk Assessment , Rotavirus Infections/pathology , Sensitivity and Specificity , Transcription Factors/metabolismABSTRACT
BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in many acute and chronic inflammatory diseases. However, its role in intrahepatic bile duct (IBD) cell damage associated with severe acute pancreatitis (SAP) remains unclear. AIMS: This study was aimed to identify the role of MIF and its underlying mechanisms in SAP complicated by IBD cell damage. METHODS: Forty-eight specific-pathogen-free male Wistar rats were randomly divided into four groups (N = 12): a sham operation group (SO group) and three SAP model groups (SAP-3h, SAP-6h, and SAP-12h). Immunohistochemistry was used to detect the expression of MIF and P38 in IBD cells. MIF mRNA expression in IBD cells was observed using real-time fluorescent quantitative polymerase chain reaction (real-time PCR). In addition, Western blotting was performed to detect the protein expression of P38, phosphorylated P38 (P-P38), nuclear factor-κB (NF-κB p65), and tumor necrosis factor alpha (TNF-α). Enzyme-linked immunosorbent assays were used to analyze the levels of TNF-α, IL-1ß, and IL-6 in the IBD of rats. RESULTS: Compared with the SO group, the expression of MIF in the IBD was significantly upregulated both at mRNA and at protein levels in the SAP group. Besides, the protein expression levels of P38, P-P38, NF-κB, p65, TNF-α, IL-1ß, and IL-6 in the IBD in rats were also significantly increased in the SAP group and the levels increased gradually as acute pancreatitis progressed (all P < 0.05). CONCLUSIONS: MIF may promote the IBD injury and inflammatory reaction in SAP via activating the P38-MAPK and NF-κB signaling pathways.
Subject(s)
Bile Duct Diseases/etiology , Bile Ducts, Intrahepatic/metabolism , Intramolecular Oxidoreductases/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Pancreatitis/complications , Acute Disease , Animals , Bile Duct Diseases/genetics , Bile Duct Diseases/metabolism , Bile Duct Diseases/pathology , Bile Ducts, Intrahepatic/pathology , Disease Models, Animal , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Male , Pancreatitis/genetics , Pancreatitis/metabolism , Pancreatitis/pathology , Phosphorylation , Rats, Wistar , Severity of Illness Index , Signal Transduction , Transcription Factor RelA/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Liver diseases constitute an important medical problem, and a number of these diseases, termed cholangiopathies, affect the biliary system of the liver. In this review, we describe the current understanding of the causes of cholangiopathies, which can be genetic, viral or environmental, and the few treatment options that are currently available beyond liver transplantation. We then discuss recent rapid progress in a number of areas relevant for decoding the disease mechanisms for cholangiopathies. This includes novel data from analysis of transgenic mouse models and organoid systems, and we outline how this information can be used for disease modeling and potential development of novel therapy concepts. We also describe recent advances in genomic and transcriptomic analyses and the importance of such studies for improving diagnosis and determining whether certain cholangiopathies should be viewed as distinct or overlapping disease entities.
Subject(s)
Bile Duct Diseases/genetics , Animals , Bile Duct Diseases/diagnosis , Bile Duct Diseases/therapy , Cell Polarity , Disease Models, Animal , Humans , Liver/embryology , Liver/pathology , Models, BiologicalABSTRACT
Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC], and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression, and functional studies and applied network-based analytics in the search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential and hub genes. In addition to disease-specific modules, we found a substantial overlap of disease neighborhoods and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing signal transduction and activator of transcription 3, interleukin-6, tumor necrosis factor, and forkhead box P3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the advanced glycation endproduct/receptor for advanced glycation endproducts (RAGE) pathway and showed that RAGE activation induced cholangiocyte proliferation. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC, and PSC. (Hepatology 2018;67:676-689).
Subject(s)
Bile Duct Diseases/genetics , Connectome , Animals , Bile Duct Diseases/etiology , Bile Duct Diseases/immunology , Biliary Atresia/genetics , Cholangitis, Sclerosing/genetics , Databases, Genetic , Forkhead Transcription Factors/physiology , Gene Regulatory Networks , Glycation End Products, Advanced/physiology , Humans , Interleukin-6/physiology , Mice , MicroRNAs/physiology , Receptor for Advanced Glycation End Products/physiology , STAT3 Transcription Factor/physiologyABSTRACT
BackgroundBiliary atresia (BA) is an etiologically perplexing disease, manifested by neonatal cholestasis, repeated cholangitis, and progressive biliary fibrosis. MiR-155 has been implicated to modulate the immune response, which contributes to biliary injury. However, its potential role in the pathogenesis of BA has not been addressed so far.MethodsThe microRNA changes from BA patients and controls were identified via microarray. The immunomodulatory function of miR-155 was investigated via cell transfection and reporter assay. The lentiviral vector pL-miR-155 inhibitor was transfected into a mouse model to investigate its role in BA.ResultsThe expression of miR-155 in livers of BA patients was significantly increased, and an inverse correlation between miR-155 and suppressor of cytokine signaling 1 (SOCS1) was detected. MiR-155 overexpression promoted expressions of major histocompatibility complex (MHC) I, MHC II, Chemokine (C-X-C motif) ligand (CXCL) 9, CXCL10, monocyte chemotactic protein 1, and CXCL1 after IFN-γ stimulation, which could be suppressed by SOCS1 overexpression. Moreover, miR-155 overexpression activated JAK2/STAT3, thus enhancing the pro-inflammatory effect. Downregulating miR-155 reduced the incidence of BA in a rhesus monkey rotavirus-induced BA model.ConclusionOur results reveal a vital contribution of miR-155 upregulation and consequent SOCS1 downregulation to an immune response triggered via IFN-γ in BA.
Subject(s)
Bile Duct Diseases/genetics , Biliary Atresia/genetics , Inflammation/genetics , MicroRNAs/genetics , Suppressor of Cytokine Signaling 1 Protein/metabolism , Animals , Animals, Newborn , Bile Duct Diseases/metabolism , Bile Duct Diseases/pathology , Biliary Atresia/metabolism , Biliary Atresia/pathology , Case-Control Studies , Cell Line , Disease Models, Animal , Female , Humans , Infant , Infant, Newborn , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/metabolism , Mice , Mice, Inbred BALB C , PregnancyABSTRACT
Vanishing bile duct syndrome (VBDS) has been described in different pathologic conditions including infection, ischemia, adverse drug reactions, autoimmune diseases, allograft rejection, and humoral factors associated with malignancy. It is an acquired condition characterized by progressive destruction and loss of the intra-hepatic bile ducts leading to cholestasis. Prognosis is variable and partially dependent upon the etiology of bile duct injury. Irreversible bile duct loss leads to significant ductopenia, biliary cirrhosis, liver failure, and death. If biliary epithelial regeneration occurs, clinical recovery may occur over a period of months to years. VBDS has been described in a number of cases of patients with Hodgkin's lymphoma (HL) where it is thought to be a paraneoplastic phenomenon. This case describes a 25-year-old man found on liver biopsy to have VBDS. Given poor response to medical treatment, the patient underwent transplant evaluation at that time and was found to have classical stage IIB HL. Early recognition of this underlying cause or association of VBDS, including laboratory screening, and physical exam for lymphadenopathy are paramount to identifying potential underlying VBDS-associated malignancy. Here we review the literature of HL-associated VBDS and report a case of diagnosed HL with biopsy proven VBDS.
Subject(s)
Bile Duct Diseases/complications , Bile Duct Diseases/genetics , Bile Ducts, Intrahepatic/pathology , Hepatocyte Growth Factor/genetics , Hodgkin Disease/complications , Hodgkin Disease/diagnosis , Proto-Oncogene Proteins/genetics , Adult , Antineoplastic Agents/therapeutic use , Bile Duct Diseases/blood , Bile Duct Diseases/pathology , Biopsy , Cholangiopancreatography, Magnetic Resonance , Cholestasis/etiology , Exome/genetics , High-Throughput Nucleotide Sequencing , Hodgkin Disease/drug therapy , Hodgkin Disease/therapy , Humans , Hyperbilirubinemia/blood , Hypertension, Portal/diagnosis , Hypertension, Portal/etiology , Jaundice/etiology , Liver/pathology , Liver Function Tests , Male , Neoplasm Staging , Syndrome , Tomography, X-Ray ComputedABSTRACT
Cholangiopathies are the group of diseases targeting the bile duct epithelial cells (i.e. cholangiocytes). These disorders arise from different etiologies and represent a current diagnostic, prognostic and therapeutic challenge. Different molecular mechanisms participate in the development and progression of each type of biliary disease. However, microRNA deregulation is a common central event occurring in all of them that plays a key role in their pathogenesis. MicroRNAs are highly stable small non-coding RNAs present in cells, extracellular microvesicles and biofluids, representing valuable diagnostic tools and potential targets for therapy. In the following sections, the most novel and significant discoveries in this field are summarized and their potential clinical value is highlighted.
Subject(s)
Bile Duct Diseases/genetics , MicroRNAs , Bile Duct Diseases/diagnosis , Bile Duct Diseases/therapy , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/therapy , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/genetics , Cholangiocarcinoma/therapy , Cholangitis/diagnosis , Cholangitis/genetics , Cholangitis/therapy , HumansABSTRACT
UNLABELLED: Haploinsufficiency for the Notch ligand JAG1 in humans results in an autosomal-dominant, multisystem disorder known as Alagille syndrome, which is characterized by a congenital cholangiopathy of variable severity. Here, we show that on a C57BL/6 background, jagged1 heterozygous mice (Jag1(+/-) ) exhibit impaired intrahepatic bile duct (IHBD) development, decreased SOX9 expression, and thinning of the periportal vascular smooth muscle cell (VSMC) layer, which are apparent at embryonic day 18 and the first postnatal week. In contrast, mice double heterozygous for Jag1 and the glycosyltransferase, Poglut1 (Rumi), start showing a significant improvement in IHBD development and VSMC differentiation during the first week. At P30, Jag1(+/-) mice show widespread ductular reactions and ductopenia in liver and a mild, but statistically, significant bilirubinemia. In contrast, P30 Jag1/Rumi double-heterozygous mice show well-developed portal triads around most portal veins, with no elevation of serum bilirubin. Conditional deletion of Rumi in VSMCs results in progressive arborization of the IHBD tree, whereas deletion of Rumi in hepatoblasts frequently results in an increase in the number of hepatic arteries without affecting bile duct formation. Nevertheless, removing one copy of Rumi from either VSMCs or hepatoblasts is sufficient to partially suppress the Jag1(+/-) bile duct defects. Finally, all Rumi target sites of the human JAG1 are efficiently glucosylated, and loss of Rumi in VSMCs results in increased levels of full-length JAG1 and a shorter fragment of JAG1 without affecting Jag1 messenger RNA levels. CONCLUSIONS: On a C57BL/6 background, Jag1 haploinsufficiency results in bile duct paucity in mice. Removing one copy of Rumi suppresses the Jag1(+/-) bile duct phenotype, indicating that Rumi opposes JAG1 function in the liver.
Subject(s)
Bile Duct Diseases/congenital , Bile Duct Diseases/genetics , Calcium-Binding Proteins/genetics , Gene Deletion , Glucosyltransferases/genetics , Heterozygote , Intercellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Animals , Humans , Jagged-1 Protein , Mice , Mice, Inbred C57BL , Serrate-Jagged ProteinsABSTRACT
Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter- and intra-familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra-familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well-known disease-associated genes, using reverse phenotyping.
Subject(s)
Bile Duct Diseases/genetics , Bile Ducts, Intrahepatic/abnormalities , Mutation/genetics , Polycystic Kidney, Autosomal Recessive/genetics , Receptors, Cell Surface/genetics , Adult , Bile Duct Diseases/pathology , Bile Ducts, Intrahepatic/embryology , Bile Ducts, Intrahepatic/pathology , Child , Exome/genetics , Female , Genetic Predisposition to Disease , Heterozygote , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Pedigree , Phenotype , Polycystic Kidney, Autosomal Recessive/pathology , Prognosis , Young AdultABSTRACT
BACKGROUND: In qualitative diagnosis of bile duct stenosis, single diagnostic measure is difficult to make a correct diagnosis, to combine several diagnostic techniques may be helpful to make an accurate diagnosis. The aim of this study was to evaluate the value of intraductal ultrasonography (IDUS), endoscopic brush cytology and K-ras, P53 gene mutation in the early diagnosis of malignant biliary stricture. METHODS: From February 2012 to February 2013, 84 patients with suspected malignant biliary stricture were performed IDUS firstly, then endoscopic brush cytology and finally K-ras, P53 gene mutation detection, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of all above ways were evaluated and compared. RESULTS: Of 84 patients, 52 cases were ultimately diagnosed malignant biliary stenosis; of which, 9 cases had no recurrence or metastasis to other organs after radical operation during the follow-up period. IDUS combined with brush cytology and K-ras + P53 gene mutation detection had obvious advantage in the sensitivity, accuracy and negative predictive value than any other joint detection and single detection (the advantage was more significant compared with IDUS + brush cytology or any single detection P < 0.01). There were obvious statistical significance in the sensitivity and accuracy between IDUS + brush cytology + P53 or IDUS + brush cytology + K-ras and IDUS + brush cytology or IDUS (P < 0.05). There was no statistical significance in the sensitivity, specificity, positive predictive value, negative predictive value and accuracy between IDUS + brush cytology + P53 and IDUS + brush cytology + K-ras (P > 0.05). CONCLUSIONS: IDUS combined with brush cytology and K-ras, P53 gene mutation detection is better than the separate detection and contribute to the early diagnosis of malignant biliary stricture. Its more widespread use is recommended.
Subject(s)
Bile Duct Diseases/diagnosis , Bile Duct Diseases/genetics , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/genetics , Bile Ducts/pathology , Genes, p53/genetics , Genes, ras/genetics , Aged , Aged, 80 and over , Constriction, Pathologic/diagnosis , Constriction, Pathologic/genetics , Female , Humans , Male , Middle Aged , MutationABSTRACT
Biliary cysts in adult patients affected by polycystic liver disease are lined by cholangiocytes that proliferate, suggesting that initiation of cyst formation depends on proliferation. Here, we challenge this view by analyzing cyst-lining cell proliferation and differentiation in Cpk mouse embryos and in livers from human fetuses affected by Autosomal Recessive Polycystic Kidney Disease (ARPKD), at early stages of cyst formation. Proliferation of fetal cholangiocyte precursors, measured by immunostaining in human and mouse livers, was low and did not differ between normal and ARPKD or Cpk livers, excluding excessive proliferation as an initiating cause of liver cysts. Instead, our analyses provide evidence that the polycystic livers exhibit increased and accelerated differentiation of hepatoblasts into cholangiocyte precursors, eventually coalescing into large biliary cysts. Lineage tracing experiments, performed in mouse embryos, indicated that the cholangiocyte precursors in Cpk mice generate cholangiocytes and periportal hepatocytes, like in wild-type animals. Therefore, contrary to current belief, cyst formation in polycystic liver disease does not necessarily depend on overproliferation. Combining our prenatal data with available data from adult livers, we propose that polycystic liver can be initiated by proliferation-independent mechanisms at a fetal stage, followed by postnatal proliferation-dependent cyst expansion.