1  5220 74 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2  5590 29 ROLE OF THE BICARBONATE-RESPONSIVE SOLUBLE ADENYLYL CYCLASE IN CHOLANGIOCYTE APOPTOSIS IN PRIMARY BILIARY CHOLANGITIS; A NEW HYPOTHESIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC FIBROSING CHOLANGIOPATHY CHARACTERIZED BY AN AUTOIMMUNE STEREOTYPE AND DEFECTIVE BILIARY BICARBONATE SECRETION DUE TO DOWN-REGULATION OF ANION EXCHANGER 2 (AE2). DESPITE THE AUTOIMMUNE FEATURES, IMMUNOSUPPRESSANTS ARE INEFFECTIVE WHILE TWO BILE ACID-BASED THERAPIES (URSODEOXYCHOLIC ACID AND OBETICHOLIC ACID) HAVE BEEN SHOWN TO IMPROVE BIOCHEMICAL AND HISTOLOGICAL FEATURES OF CHOLESTASIS AND LONG-TERM PROGNOSIS. HOWEVER, THE ETIOLOGY AND PATHOGENESIS OF PBC IS LARGELY UNKNOWN. RECENTLY, IT HAS BEEN SHOWN THAT MICRORNA-506 (MIR-506) ON CHROMOSOME X IS UP-REGULATED IN PBC CHOLANGIOCYTES AND SUPPRESSES AE2 EXPRESSION, WHICH SENSITIZES CHOLANGIOCYTES TO BILE SALT-INDUCED APOPTOSIS BY ACTIVATING SOLUBLE ADENYLYL CYCLASE (SAC), AN EVOLUTIONARILY CONSERVED BICARBONATE SENSOR. IN THIS REVIEW, WE DISCUSS THE EXPERIMENTAL EVIDENCE FOR THE EMERGING ROLE OF THE MIR-506-AE2-SAC AXIS IN PBC PATHOGENESIS. WE FURTHER HYPOTHESIZE THAT THE INITIAL DISEASE TRIGGER INDUCES AN X-LINKED EPIGENETIC CHANGE, LEADING TO A FEMALE-BIASED ACTIVATION OF THE MIR-506-AE2-SAC AXIS. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: CHOLANGIOCYTES IN HEALTH AND DISEASEEDITED BY JESUS BANALES, MARCO MARZIONI AND PETER JANSEN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  3012 37 GENETICS AND EPIGENETICS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC, SLOWLY PROGRESSIVE CHOLESTATIC AUTOIMMUNE LIVER DISEASE PREDOMINANTLY AFFLICTING WOMEN. PBC IS CHARACTERIZED BY THE PRESENCE OF DISEASE-SPECIFIC ANTIMITOCHONDRIAL ANTIBODIES AND THE HISTOLOGICAL DESTRUCTION OF INTRAHEPATIC BILE DUCTS, WHICH EVENTUALLY LEAD TO CIRRHOSIS AND HEPATIC FAILURE. FORTUNATELY, URSODEOXYCHOLIC ACID THERAPY HAS IMPROVED THE OUTCOME OF THE VAST MAJORITY OF PBC CASES. ALTHOUGH THE ETIOLOGY OF PBC HAS NOT YET BEEN ELUCIDATED, HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II ALLELES HAVE BEEN CONSISTENTLY ASSOCIATED WITH DISEASE ONSET FOR DECADES. PBC PATIENTS MAY ALSO HAVE GENETICALLY DETERMINED RISK FACTORS IN NON-HLA REGIONS. MEANWHILE, EXPOSURE TO ENVIRONMENTAL FACTORS, SUCH AS INFECTIOUS DISEASES AND HARMFUL CHEMICALS, CAN PRODUCE EPIGENETIC ALTERATIONS IN SOME INDIVIDUALS AND SUBSEQUENT PBC ONSET. IN THIS REVIEW, WE DESCRIBE THE INFLUENCE OF HLA ALLELES AND OTHER GENE POLYMORPHISMS ON PBC ALONG WITH THE RESULTS OF GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE AND ITS FUTURE PROSPECTS IN TERMS OF EPIGENETICS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4  2936 32 GENETIC AND EPIGENETIC ABNORMALITIES IN PRIMARY SCLEROSING CHOLANGITIS-ASSOCIATED CHOLANGIOCARCINOMA. PRIMARY SCLEROSING CHOLANGITIS (PSC) IS A CHOLESTATIC LIVER DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE BILIARY TREE WITH SUBSEQUENT FIBROSIS AND CIRRHOSIS OF THE LIVER. PATIENTS WITH PSC ARE AT INCREASED RISK FOR THE DEVELOPMENT OF CHOLANGIOCARCINOMA (CCA), A HIGHLY MALIGNANT EPITHELIAL TUMOR ARISING FROM THE INTRAHEPATIC AND EXTRAHEPATIC BILE DUCTS. CURRENTLY, ORTHOTOPIC LIVER TRANSPLANTATION IS THE ONLY CURATIVE TREATMENT. THE LACK OF EFFICIENT DIAGNOSTIC METHODS FOR EARLY DETECTION AND THE LIMITED THERAPEUTIC OPTIONS FOR CCA ARE MAJOR PROBLEMS AND ARE ASSOCIATED WITH POOR SURVIVAL. THE PATHOGENESIS OF PSC-ASSOCIATED CCA IS COMPLEX AND POORLY UNDERSTOOD. IT SEEMS THAT PRO-INFLAMMATORY CYTOKINES PLAY AN IMPORTANT ROLE IN GENETIC AND EPIGENETIC CHANGES THAT CONTRIBUTE TO THE CARCINOGENIC PROCESS. THE MAPPING OF GENETIC ALTERATIONS MAY ELUCIDATE MOLECULAR TARGETS THAT MAY BE APPLIED AS BIOMARKERS TO FACILITATE EARLY DIAGNOSIS OF MALIGNANT DEGENERATION TO IMPROVE PATIENT OUTCOME. IN THE LAST DECADE, THE INTRODUCTION OF SEVERAL NOVEL MOLECULAR TECHNIQUES AVAILABLE FOR GENOME-WIDE SCREENING HAS ADVANCED OUR KNOWLEDGE ON MANY OF THE GENETIC ABNORMALITIES THAT ARE PREVALENT IN CCA AND PSC-ASSOCIATED CCA. THIS REVIEW SUMMARIZES GENETIC AND EPIGENETIC ABNORMALITIES, WHICH HAVE IMPORTANT POTENTIAL FOR CLINICAL APPLICATION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5   852 31 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  1978 26 EPIGENETIC ALTERATIONS IN CHOLANGIOCARCINOMA-SUSTAINED IL-6/STAT3 SIGNALING IN CHOLANGIO- CARCINOMA DUE TO SOCS3 EPIGENETIC SILENCING. CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM, CHARACTERIZED BY ITS TYPICALLY LATE CLINICAL PRESENTATION AND LACK OF EFFECTIVE THERAPEUTIC MODALITIES. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION AND HEPATOLITHIASIS, ARE LISTED IN THE RISK FACTORS, BUT FOR MOST CASES OF CCA THE CAUSE IS UNKNOWN. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION IN ADDITION TO GENETIC CHANGES IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES HYPERMETHYLATED IN CCA TO DATE AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. AMONG GENES HYPERMETHYLATED, WE FOUND THE CPG ISLAND HYPERMETHYLATION IN SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3) GENE PROMOTER IN CCA. INTERLEUKIN-6 (IL-6)-MEDIATED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION ARE ABERRANTLY SUSTAINED IN CCA CELLS, RESULTING IN RESISTANCE TO APOPTOSIS. SOCS3 CONTROLS THE IL-6/STAT3 SIGNALING PATHWAY BY A CLASSIC FEEDBACK LOOP. INDEED, SOCS3 EPIGENETIC SILENCING IS RESPONSIBLE FOR SUSTAINED IL-6/STAT3 SIGNALING IN CCA. THESE FINDINGS PROVIDE NEW PERSPECTIVES FOR EPIGENETIC THERAPY TO RESTORE SOCS3 IN THIS CANCER.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7  4951 25 PATHOGENESIS OF CHOLANGIOCARCINOMA: FROM GENETICS TO SIGNALLING PATHWAYS. CHOLANGIOCARCINOMA (CCA) IS A MALIGNANT TUMOUR OF BILE DUCT EPITHELIAL CELLS WITH DISMAL PROGNOSIS AND RISING INCIDENCE. CHRONIC INFLAMMATION RESULTING FROM LIVER FLUKE INFECTION, HEPATITIS AND OTHER INFLAMMATORY BOWEL DISEASES IS A MAJOR CONTRIBUTING FACTOR TO CHOLANGIOCARCINOGENESIS, LIKELY THROUGH ACCUMULATION OF SERIAL GENETIC AND EPIGENETIC ALTERATIONS RESULTING IN ABERRATION OF ONCOGENES AND TUMOUR SUPPRESSORS. RECENT STUDIES MAKING USE OF ADVANCES IN HIGH-THROUGHPUT GENOMICS HAVE REVEALED THE GENETIC LANDSCAPE OF CCA, GREATLY INCREASING OUR UNDERSTANDING OF ITS UNDERLYING BIOLOGY. A SERIES OF HIGHLY RECURRENT MUTATIONS IN GENES SUCH AS TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 AND BAP1, WHICH ARE KNOWN TO BE INVOLVED IN CELL CYCLE CONTROL, CELL SIGNALLING PATHWAYS AND CHROMATIN DYNAMICS, HAVE LED TO INVESTIGATIONS OF THEIR ROLES, THROUGH MOLECULAR TO MOUSE MODELLING STUDIES, IN CHOLANGIOCARCINOGENESIS. THIS REVIEW FOCUSES ON THE LANDSCAPE GENETIC ALTERATIONS IN CCA AND ITS FUNCTIONAL RELEVANCE TO THE FORMATION AND PROGRESSION OF CCA.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8  5506 33 RHEUMATOID ARTHRITIS AND PRIMARY BILIARY CIRRHOSIS: CAUSE, CONSEQUENCE, OR COINCIDENCE? PRIMARY BILIARY CIRRHOSIS (PBC) IS A PROGRESSIVE CHOLESTATIC LIVER DISEASE CHARACTERIZED SEROLOGICALLY BY CHOLESTASIS AND THE PRESENCE OF HIGH-TITRE ANTIMITOCHONDRIAL ANTIBODIES AND HISTOLOGICALLY BY CHRONIC NONSUPPURATIVE CHOLANGITIS AND GRANULOMATA. PBC PATIENTS OFTEN HAVE CONCOMITANT AUTOIMMUNE DISEASES, INCLUDING ARTHROPATHIES. THIS RAISES THE QUESTION AS TO WHETHER THERE ARE SHARED FEATURES IN THE PATHOGENESIS OF THOSE DISEASES WITH THE PATHOGENESIS OF PBC. EPIDEMIOLOGICAL AND LARGE CASE STUDIES HAVE INDICATED THAT ALTHOUGH THE INCIDENCE OF RHEUMATOID ARTHRITIS (RA) IS NOT SIGNIFICANTLY RAISED IN PBC PATIENTS, THERE APPEARS TO BE A HIGHER RATE OF RA IN PBC PATIENTS AND THEIR RELATIVES. GENETIC STUDIES HAVE DEMONSTRATED THAT SEVERAL GENES IMPLICATED IN PBC HAVE ALSO BEEN IMPLICATED IN RA. EPIGENETIC STUDIES PROVIDED A WEALTH OF DATA REGARDING RA, BUT THE FINDINGS ON EPIGENETIC CHANGES IN PBC ARE VERY LIMITED. AS WELL, CERTAIN INFECTIOUS AGENTS IDENTIFIED IN THE PATHOGENESIS OF PBC MAY ALSO PLAY A ROLE IN THE PATHOGENESIS OF RA. THESE DATA SUGGEST THAT ALTHOUGH RA IS NOT SIGNIFICANTLY PRESENT IN PBC, SOME INDIVIDUALS WITH CERTAIN GENETIC TRAITS AND ENVIRONMENTAL EXPOSURES MAY DEVELOP BOTH CONDITIONS. THIS CONCEPT MAY ALSO APPLY TO OTHER CONCOMITANT DISEASES FOUND IN PBC PATIENTS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  6650 32 UPDATE ON ETIOLOGY AND PATHOGENESIS OF BILIARY ATRESIA. BILIARY ATRESIA IS A RARE INFLAMMATORY SCLEROSING OBSTRUCTIVE CHOLANGIOPATHY THAT INITIATES IN INFANCY AS COMPLETE CHOLEDOCHAL BLOCKAGE AND PROGRESSES TO THE INVOLVEMENT OF INTRAHEPATIC BILIARY EPITHELIUM. GROWING EVIDENCE SHOWS THAT BILIARY ATRESIA IS NOT A SINGLE ENTITY WITH A SINGLE ETIOLOGY BUT A PHENOTYPE RESULTING FROM MULTIFACTORIAL EVENTS WHOSE COMMON PATH IS OBLITERATIVE CHOLANGIOPATHY. THE ETIOLOGY OF BILIARY ATRESIA HAS BEEN EXPLAINED AS RESULTING FROM GENETIC VARIANTS, TOXINS, VIRAL INFECTION, CHRONIC INFLAMMATION OR BILE DUCT LESIONS MEDIATED BY AUTOIMMUNITY, ABNORMALITIES IN THE DEVELOPMENT OF THE BILE DUCTS, AND DEFECTS IN EMBRYOGENESIS, ABNORMAL FETAL OR PRENATAL CIRCULATION AND SUSCEPTIBILITY FACTORS. IT IS INCREASINGLY EVIDENT THAT THE GENETIC AND EPIGENETIC PREDISPOSITION COMBINED WITH THE ENVIRONMENTAL FACTORS TO WHICH THE MOTHER IS EXPOSED ARE POTENTIAL TRIGGERS FOR BILIARY ATRESIA. THERE IS ALSO AN INDICATION THAT A PROGRESSIVE THICKENING OF THE ARTERIAL MIDDLE LAYER OCCURS IN THIS DISEASE, SUGGESTIVE OF VASCULAR REMODELING AND DISAPPEARANCE OF THE INTERLOBULAR BILE DUCTS. IT IS SUGGESTED THAT THE HYPOXIA/ISCHEMIA PROCESS CAN AFFECT PORTAL STRUCTURES IN BILIARY ATRESIA AND IS ASSOCIATED WITH BOTH THE EXTENT OF BILIARY PROLIFERATION AND THE THICKENING OF THE MEDIAL LAYER.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  1972 31 EPIGENETIC ALTERATIONS ASSOCIATED WITH CHOLANGIOCARCINOMA (REVIEW). CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION, AND HEPATOLITHIASIS, ARE CONSIDERED RISK FACTORS, BUT THE CAUSE IS STILL UNKNOWN IN MOST CASES. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS, INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION, IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. MORE RECENTLY, RESEARCH INTEREST HAS BEEN FOCUSING ON MICRORNA (MIR), A MAJOR SUBTYPE OF NON-CODING RNA. MIR IS HIGHLY CONSERVED AMONG SPECIES AND REGULATES THE EXPRESSION OF SPECIFIC TARGET GENES BY BINDING TO THE 3'-UNTRANSLATED REGIONS OF MESSENGER RNA. THE NUMBER OF STUDIES ON A POSSIBLE LINK BETWEEN MIR AND VARIOUS CANCERS IS GROWING. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES CURRENTLY KNOWN TO BE HYPERMETHYLATED IN CCA AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. THE EPIGENETIC ROLE OF MIR IN THE PATHOGENESIS OF CCA IS ALSO DISCUSSED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  4472 33 MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA. BACKGROUND: CHOLANGIOCARCINOMAS ARE A HETEROGENEOUS GROUP OF MALIGNANCIES ARISING FROM A NUMBER OF CELLS OF ORIGIN ALONG THE BILIARY TREE. ALTHOUGH MOST CASES IN WESTERN COUNTRIES ARE SPORADIC, LARGE POPULATION-BASED STUDIES HAVE IDENTIFIED A NUMBER OF RISK FACTORS. THIS REVIEW SUMMARISES THE EVIDENCE BEHIND REPORTED RISK FACTORS AND CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA, WITH A FOCUS ON INFLAMMATION AND CHOLESTASIS AS THE DRIVING FORCES IN CHOLANGIOCARCINOMA DEVELOPMENT. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: CHOLESTATIC LIVER DISEASES (E.G. PRIMARY SCLEROSING CHOLANGITIS AND FIBROPOLYCYSTIC LIVER DISEASES), LIVER CIRRHOSIS, AND BILIARY STONE DISEASE ALL INCREASE THE RISK OF CHOLANGIOCARCINOMA. CERTAIN BACTERIAL, VIRAL OR PARASITIC INFECTIONS SUCH AS HEPATITIS B AND C AND LIVER FLUKES ALSO INCREASE CHOLANGIOCARCINOMA RISK. OTHER RISK FACTORS INCLUDE INFLAMMATORY DISORDERS (SUCH AS INFLAMMATORY BOWEL DISEASE AND CHRONIC PANCREATITIS), TOXINS (E.G. ALCOHOL AND TOBACCO), METABOLIC CONDITIONS (DIABETES, OBESITY AND NON-ALCOHOLIC FATTY LIVER DISEASE) AND A NUMBER OF GENETIC DISORDERS. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS CAUSE CHRONIC INFLAMMATION OR CHOLESTASIS. CHRONIC INFLAMMATION LEADS TO INCREASED EXPOSURE OF CHOLANGIOCYTES TO THE INFLAMMATORY MEDIATORS INTERLEUKIN-6, TUMOUR NECROSIS FACTOR-A, CYCLO-OXYGENASE-2 AND WNT, RESULTING IN PROGRESSIVE MUTATIONS IN TUMOUR SUPPRESSOR GENES, PROTO-ONCOGENES AND DNA MISMATCH-REPAIR GENES. ACCUMULATING BILE ACIDS FROM CHOLESTASIS LEAD TO REDUCED PH, INCREASED APOPTOSIS AND ACTIVATION OF ERK1/2, AKT AND NF-KAPPAB PATHWAYS THAT ENCOURAGE CELL PROLIFERATION, MIGRATION AND SURVIVAL. OTHER MEDIATORS UPREGULATED IN CHOLANGIOCARCINOMA INCLUDE TRANSFORMING GROWTH FACTOR-BETA, VASCULAR ENDOTHELIAL GROWTH FACTOR, HEPATOCYTE GROWTH FACTOR AND SEVERAL MICRORNAS. INCREASED EXPRESSION OF THE CELL SURFACE RECEPTOR C-MET, THE GLUCOSE TRANSPORTER GLUT-1 AND THE SODIUM IODIDE SYMPORTER LEAD TO TUMOUR GROWTH, ANGIOGENESIS AND CELL MIGRATION. STROMAL CHANGES ARE ALSO OBSERVED, RESULTING IN ALTERATIONS TO THE EXTRACELLULAR MATRIX COMPOSITION AND RECRUITMENT OF FIBROBLASTS AND MACROPHAGES THAT CREATE A MICROENVIRONMENT PROMOTING CELL SURVIVAL, INVASION AND METASTASIS. CONCLUSION: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS FOR CHOLANGIOCARCINOMA CAUSE CHRONIC INFLAMMATION AND/OR CHOLESTASIS, LEADING TO THE ACTIVATION OF COMMON INTRACELLULAR PATHWAYS THAT RESULT IN REACTIVE CELL PROLIFERATION, GENETIC/EPIGENETIC MUTATIONS AND CHOLANGIOCARCINOGENESIS. AN UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA IS VITAL WHEN DEVELOPING NEW DIAGNOSTIC BIOMARKERS AND TARGETED THERAPIES FOR THIS DISEASE.	2019	

12  2588 33 EPIGENETICS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE WITH NON-SUPPURATIVE DESTRUCTION OF THE INTRAHEPATIC BILE DUCTS. THE INTERPLAY OF GENETICS AND ENVIRONMENTAL TRIGGERS CONTRIBUTES TO THE ONSET OF THE DISEASE AND SUBSEQUENTLY RESULTS IN CHOLESTASIS AND PROGRESSIVE FIBROSIS. RECENTLY, GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED MULTIPLE GENES INFLUENCING THE SUSCEPTIBILITY TO PBC IN HLA AND NON-HLA LOCI. HOWEVER, IT IS ESTIMATED THAT THE KNOWN RISK VARIANTS MERELY ACCOUNT FOR NO MORE THAN 20% OF THE HERITABILITY OF PBC AND CAUSES OF THE REMAINING HERITABILITY REMAIN UNCERTAIN. INCREASING EVIDENCE SUGGESTS THAT THE PRESENCE OF EPIGENETIC ABNORMALITIES MAY EXPLAIN THE "MISSING HERITABILITY" THAT CANNOT BE CAPTURED BY GWAS. AMONG THESE EPIGENETIC MECHANISMS, DNA METHYLATION, HISTONE MODIFICATION, AND NONCODING RNAS (I.E. MIRNA AND LNCRNA) ARE INVOLVED IN THE PATHOGENESIS OF PBC. ADDITIONALLY, TELOMERE DYSREGULATION IN BILIARY EPITHELIAL CELLS (BECS) MAY PLAY A ROLE IN DISEASE ONSET, WHEREAS A DEFICIENCY IN SEX CHROMOSOME AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY TO SOME EXTENT EXPLAIN THE FEMALE DOMINANCE IN PBC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13  4175 21 MELATONIN PROTECTS CHOLANGIOCYTES FROM OXIDATIVE STRESS-INDUCED PROAPOPTOTIC AND PROINFLAMMATORY STIMULI VIA MIR-132 AND MIR-34. BIOSYNTHESIS OF MELATONIN BY CHOLANGIOCYTES IS ESSENTIAL FOR MAINTAINING THE FUNCTION OF BILIARY EPITHELIUM. HOWEVER, THIS CYTOPROTECTIVE MECHANISM APPEARS TO BE IMPAIRED IN PRIMARY BILIARY CHOLANGITIS (PBC). MIR-132 HAS EMERGED AS A MEDIATOR OF INFLAMMATION IN CHRONIC LIVER DISEASES. THE EFFECT OF MELATONIN ON OXIDATIVE STRESS AND BILE ACID-INDUCED APOPTOSIS WAS ALSO EXAMINED IN CHOLANGIOCYES OVEREXPRESSING MIR506, AS A PBC-LIKE CELLULAR MODEL. IN PBC PATIENTS THE SERUM LEVELS OF MELATONIN WERE FOUND INCREASED IN COMPARISON TO HEALTHY CONTROLS. WHEREAS, IN CHOLANGIOCYTES WITHIN CIRRHOTIC PBC LIVERS THE MELATONIN BIOSYNTHETIC PATHWAY WAS SUBSTANTIALLY SUPPRESSED EVEN THOUGH THE EXPRESSIONS OF MELATONIN RATE-LIMITING ENZYME ARALKYLAMINE N-ACETYLTRANSFERASE (AANAT), AND CK-19 (MARKER OF CHOLANGIOCYTES) WERE ENHANCED. IN CHOLANGIOCYTES EXPOSED TO MITOCHONDRIAL OXIDATIVE STRESS MELATONIN DECREASED THE EXPRESSION OF PROAPOPTOTIC STIMULI (PTEN, BAX, MIR-34), WHICH WAS ACCOMPANIED BY THE INHIBITION OF A PIVOTAL MEDIATOR OF INFLAMMATORY RESPONSE NF-KAPPAB-P65 AND THE ACTIVATION OF ANTIAPOPTOTIC SIGNALING (MIR-132, BCL2). SIMILARLY, MELATONIN REDUCED BILE ACID-INDUCED PROAPOPTOTIC CASPASE 3 AND BIM LEVELS. IN SUMMARY, THE INSUFFICIENT HEPATIC EXPRESSION OF MELATONIN IN PBC PATIENTS MAY PREDISPOSE CHOLANGIOCYTES TO OXIDATIVE STRESS-RELATED DAMAGE. MELATONIN, VIA EPIGENETIC MODULATION, WAS ABLE TO SUPPRESS NF-KAPPAB SIGNALING ACTIVATION AND PROTECT AGAINST BILIARY CELLS APOPTOTIC SIGNALING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14  6778 21 [BILIARY TRACT CANCERS : MOLECULAR CHARACTERIZATION AND IDENTIFICATION OF NOVEL PROGNOSTIC MARKERS]. BACKGROUND: BILE DUCT CANCERS (BTCS) ARE HIGHLY AGGRESSIVE TUMORS WITH A DISMAL PROGNOSIS AND AN INCREASING INCIDENCE. BTC IS A TUMORBIOLOGICALLY AND CLINICALLY HETEROGENEOUS TUMOR GROUP AND CAN BE SUBDIVIDED ACCORDING TO ANATOMICAL ASPECTS INTO INTRAHEPATIC CHOLANGIOCARCINOMAS (ICCA), EXTRAHEPATIC CHOLANGIOCARCINOMAS (ECCA) AND GALLBLADDER CARCINOMAS (GBC). NEW THERAPY OPTIONS: CHRONIC INFLAMMATORY PROCESSES OF THE BILIARY SYSTEM SEEM TO PLAY A ROLE IN THE DEVELOPMENT OF THESE TUMORS. INSIGHTS INTO MOLECULAR CHOLANGIOCARCINOGENESIS COULD MAKE AN IMPORTANT CONTRIBUTION TO NOVEL AND MORE PRECISE CLASSIFICATION ATTEMPTS AND TO THE DEVELOPMENT OF NEW, TARGETED THERAPIES FOR BTC. EPIGENETIC AND GENETIC ALTERATIONS IN CHOLANGIOCARCINOMAS: THE FIRST DESCRIPTION OF GENOME-WIDE DNA METHYLATION PATTERNS IN CCA SHOWED DRASTIC GLOBAL METHYLATION DIFFERENCES BETWEEN CCA AND CORRESPONDING NON-NEOPLASTIC TISSUE (MATCHED-PAIR ANALYSES). MOREOVER, SIGNIFICANT METHYLATION DIFFERENCES BETWEEN THE CCA SUBTYPES (ECCA AND ICCA) COULD BE FOUND. USING IMMUNOHISTOCHEMISTRY AND SANGER SEQUENCING, IT WAS SHOWN THAT THE ACTUAL BRAF V600E MUTATION RATE SEEMS TO BE SIGNIFICANTLY LOWER (1.3%) THAN PREVIOUSLY DESCRIBED IN THE LITERATURE. IMMUNEPHENOTYPING IN BILIARY TRACT CANCERS: A COMPREHENSIVE, SUBTYPE-SPECIFIC CHARACTERIZATION OF TUMOR-INFILTRATING IMMUNE CELLS AS WELL AS AN EXPRESSION ANALYSIS OF MAJOR HISTOCOMPATIBILITY COMPLEX I WAS PERFORMED IN A LARGE AND WELL-CHARACTERIZED BTC COHORT. FOR FURTHER STUDIES ON THE EFFICACY OF IMMUNOMODULATORY THERAPY APPROACHES FOR BTC, THE PRESENTED RESULTS PROVIDE A SOLID BASIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  5221 26 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  4483 16 MOLECULAR REGULATION OF MAMMALIAN HEPATIC ARCHITECTURE. THE ESSENTIAL LIVER EXOCRINE AND ENDOCRINE FUNCTIONS REQUIRE A PRECISE SPATIAL ARRANGEMENT OF THE HEPATIC LOBULE CONSISTING OF THE CENTRAL VEIN, PORTAL VEIN, HEPATIC ARTERY, INTRAHEPATIC BILE DUCT SYSTEM, AND HEPATOCYTE ZONATION. THIS ALLOWS BLOOD TO BE CARRIED THROUGH THE LIVER PARENCHYMA SAMPLED BY ALL HEPATOCYTES AND BILE PRODUCED BY THE HEPATOCYTES TO BE CARRIED OUT OF THE LIVER THROUGH THE INTRAHEPATIC BILE DUCT SYSTEM COMPOSED OF CHOLANGIOCYTES. THE MOLECULAR ORCHESTRATION OF MULTIPLE SIGNALING PATHWAYS AND EPIGENETIC FACTORS IS REQUIRED TO SET UP LINEAGE RESTRICTION OF THE BIPOTENTIAL HEPATOBLAST PROGENITOR INTO THE HEPATOCYTE AND CHOLANGIOCYTE CELL LINEAGES, AND TO FURTHER REFINE CELL FATE HETEROGENEITY WITHIN EACH CELL LINEAGE REFLECTED IN THE FUNCTIONAL HETEROGENEITY OF HEPATOCYTES AND CHOLANGIOCYTES. IN ADDITION TO THE COMPLEX MOLECULAR REGULATION, THERE IS A COMPLICATED MORPHOGENETIC CHOREOGRAPHY OBSERVED IN BUILDING THE REFINED HEPATIC EPITHELIAL ARCHITECTURE. GIVEN THE MULTIFACETED MOLECULAR AND CELLULAR REGULATION, IT IS NOT SURPRISING THAT IMPAIRMENT OF ANY OF THESE PROCESSES CAN RESULT IN ACUTE AND CHRONIC HEPATOBILIARY DISEASES. TO ENLIGHTEN THE DEVELOPMENT OF POTENTIAL MOLECULAR AND CELLULAR TARGETS FOR THERAPEUTIC OPTIONS, AN UNDERSTANDING OF HOW THE INTRICATE HEPATIC MOLECULAR AND CELLULAR INTERACTIONS ARE REGULATED IS IMPERATIVE. HERE, WE REVIEW THE SIGNALING PATHWAYS AND EPIGENETIC FACTORS REGULATING HEPATIC CELL LINEAGES, FATES, AND EPITHELIAL ARCHITECTURE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  3112 34 GEOEPIDEMIOLOGY AND (EPI-)GENETICS IN PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A RARE FEMALE PREPONDERANT CHRONIC AUTOIMMUNE CHOLESTATIC LIVER DISEASE, CHARACTERIZED BY INTRAHEPATIC DUCTOPENIA AND PROGRESSIVE FIBROSIS. DURING LAST DECADES INCIDENCE AND PREVALENCE SHOWED AN INCREASING RATE WHICH VARY WIDELY WORLDWIDE DEMONSTRATING AN IMPORTANT INTERACTION BETWEEN ENVIRONMENTAL AND GENETIC FACTORS. HERITABILITY SUGGESTED BY FAMILIAL OCCURRENCE AND MONOZYGOTIC TWINS CONCORDANCE HAVE BEEN CONFIRMED IN MORE STUDIES. EPIGENETICS MECHANISMS SUCH AS HISTONE MODIFICATION AND DNA METHYLATION CAN PARTIALLY EXPLAIN PREDISPOSITION AND INHERITANCE OF THIS DISEASE. NEVERTHELESS, AN ASSOCIATION WITH SPECIFIC CLASS II HUMAN LEUKOCYTE ANTIGEN (HLA) VARIANTS HAVE BEEN REPORTED, SHOWING AN INCREASE RISK IN SUSCEPTIBILITY. MORE RECENTLY, DATA REGARDING A STRONG PROTECTIVE ASSOCIATION BETWEEN PBC AND HLA ALLELES CONFIRMED THIS ASSOCIATION. AFTER RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS), A MORE INTRICATE INTERACTION BETWEEN PBC AND THE HLA REGION HAS BEEN SHOWN. FURTHERMORE, GWAS ALSO IDENTIFIED SEVERAL IMMUNE-RELATED-GENES IMPLICATED. MORE GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE ARE NEEDED TO REACH A COMPLETE AND SYSTEMATIC KNOWLEDGE OF THIS DISEASE. IN THIS REVIEW WE DISCUSS MORE RECENT ISSUED DATA ON GEOEPIDEMIOLOGY OF PBC AND THE ROLE OF (EPI-)GENETIC MECHANISMS IN ITS PATHOGENESIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18  6269 23 THE NEXT CHALLENGE IN PEDIATRIC CHOLESTASIS: DECIPHERING THE PATHOGENESIS OF BILIARY ATRESIA. CHOLESTASIS IS A COMMON PRESENTING SYMPTOM OF LIVER DISEASE IN INFANTS. CHIEF AMONG DISEASES PRESENTING AS NEONATAL CHOLESTASIS IS BILIARY ATRESIA, THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN CHILDREN, BUT LITTLE IS KNOWN ABOUT THE PATHOGENESIS OF THIS DISEASE. IN SEARCH FOR THE MOLECULAR BASIS OF BILIARY ATRESIA, WE BEGAN TWO AREAS OF INVESTIGATION. IN THE FIRST, WE INTERROGATED THE HEPATIC TRANSCRIPTOME OF CHILDREN WITH BILIARY ATRESIA AND FOUND AN INTERFERON-GAMMA (IFNGAMMA)-RICH PROINFLAMMATORY FOOTPRINT AT THE TIME OF DIAGNOSIS. TO DIRECTLY EXPLORE IF IFNGAMMA PLAYS AN IMPORTANT ROLE IN BILIARY INJURY AND OBSTRUCTION, WE USED A MOUSE MODEL OF EXPERIMENTAL BILIARY ATRESIA AND FOUND THAT INACTIVATION OF THE MURINE IFNGAMMA GENE DECREASES THE TROPISM OF LYMPHOCYTES TO NEONATAL BILE DUCTS AND PREVENTS THE INFLAMMATORY OBSTRUCTION OF THE DUCT LUMEN. FURTHER ANALYSIS OF THE EXTRAHEPATIC BILIARY TRACT ALSO OUTLINED A BROADER NETWORK OF PROINFLAMMATORY GENES AT THE ONSET AND DURING PROGRESSION TO DUCT OBSTRUCTION, WITH THE TIME-SPECIFIC ACTIVATION OF IFNGAMMA-, APOPTOSIS-, AND COMPLEMENT-DRIVEN NETWORKS. IN THE SECOND APPROACH, WE SEARCHED FOR MOLECULAR PROFILES THAT DIFFERENTIATE CLINICAL FORMS OF BILIARY ATRESIA BY ANALYZING THE HEPATIC TRANSCRIPTOME OF AGE-MATCHED SUBJECTS AT THE TIME OF DIAGNOSIS. WE FOUND A PRELIMINARY PROFILE THAT DIFFERENTIATES THE EMBRYONIC FROM THE PERINATAL FORMS OF BILIARY ATRESIA. THE PROFILE CONTAINED THE DIFFERENTIAL ACTIVATION OF GENES INVOLVED IN EPIGENETIC MECHANISMS OF DISEASE. COLLECTIVELY, THESE STUDIES PROVIDE NEW INSIGHT INTO PATHOGENESIS OF BILIARY ATRESIA AND IDENTIFY POTENTIAL THERAPEUTIC TARGETS TO FOSTER LONG-TERM OUTCOME WITH THE NATIVE LIVER.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  5222 28 PRIMARY BILIARY CIRRHOSIS: FAMILY STORIES. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC IMMUNE-MEDIATED CHOLESTATIC LIVER DISEASE OF UNKNOWN AETIOLOGY WHICH AFFECTS MOSTLY WOMEN IN MIDDLE AGE. FAMILIAL PBC IS WHEN PBC AFFECTS MORE THAN ONE MEMBER OF THE SAME FAMILY, AND DATA SUGGEST THAT FIRST-DEGREE RELATIVES OF PBC PATIENTS HAVE AN INCREASED RISK OF DEVELOPING THE DISEASE. MOST OFTEN, THESE FAMILIAL CLUSTERS INVOLVE MOTHER-DAUGHTER PAIRS, WHICH IS CONSISTENT WITH THE FEMALE PREPONDERANCE OF THE DISEASE. THESE CLUSTERS PROVIDE EVIDENCE TOWARDS A GENETIC BASIS UNDERLYING PBC. HOWEVER, CLUSTERS OF NONRELATED INDIVIDUALS HAVE ALSO BEEN REPORTED, GIVING STRENGTH TO AN ENVIRONMENTAL COMPONENT. TWIN STUDIES HAVE DEMONSTRATED A HIGH CONCORDANCE FOR PBC IN MONOZYGOTIC TWINS AND A LOW CONCORDANCE AMONG DIZYGOTIC TWINS. IN CONCLUSION, STUDIES OF PBC IN FAMILIES CLEARLY DEMONSTRATE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF THE DISEASE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  5146 35 POTENTIAL ROLES FOR INFECTIOUS AGENTS IN THE PATHOPHYSIOLOGY OF PRIMARY BILIARY CIRRHOSIS: WHAT'S NEW? PRIMARY BILIARY CIRRHOSIS (PBC) IS A PROGRESSIVE CHOLESTATIC LIVER DISEASE SEROLOGICALLY CHARACTERIZED BY THE PRESENCE OF HIGH-TITER ANTIMITOCHONDRIAL ANTIBODIES AND, HISTOLOGICALLY BY CHRONIC NONSUPPURATIVE CHOLANGITIS AND GRANULOMATA. THE AETIOLOGY OF THE DISEASE REMAINS ELUSIVE, ALTHOUGH GENETIC, EPIGENETIC, ENVIRONMENTAL, AND INFECTIOUS FACTORS HAVE BEEN CONSIDERED IMPORTANT FOR THE INDUCTION OF THE DISEASE IN GENETICALLY PRONE INDIVIDUALS. THE DISEASE SHOWS A STRIKING FEMALE PREDOMINANCE AND BECOMES CLINICALLY OVERT AT THE FOURTH TO SIXTH DECADE. THESE CHARACTERISTICS HAVE PROMPTED INVESTIGATORS TO CONSIDER INFECTIONS THAT PREDOMINATE IN WOMEN AT THESE AGES AS THE LIKELY CANDIDATES FOR TRIGGERING THE DISEASE. RECURRENT URINARY TRACT INFECTIONS DUE TO ESCHERICHIA COLI WERE THE FIRST INFECTIONS TO BE CONSIDERED PATHOGENETICALLY RELEVANT. OVER THE YEARS, SEVERAL OTHER MICROORGANISMS HAVE BEEN LINKED TO THE PATHOGENESIS OF PBC OWING TO EPIDEMIOLOGICAL, IMMUNOLOGICAL, MICROBIOLOGICAL, OR EXPERIMENTAL FINDINGS IN ANIMAL MODELS. RECENT STUDIES HAVE PROVIDED DATA SUPPORTING THE PATHOGENIC ROLE OF NOVOSPHINGOBIUM AROMATICIVORANS AND BETARETROVIRUSES. SEVERAL REPORTS HAVE LINKED OTHER ORGANISMS TO THE INDUCTION OF THE DISEASE AND/OR THE MAINTENANCE OF THE AUTO-AGGRESSIVE RESPONSES THAT ARE PERPETUATED OVER THE COURSE OF THE DISEASE. THIS REVIEW HIGHLIGHTS THE FINDINGS OF THE MOST RECENT STUDIES INVESTIGATING THE LINK BETWEEN INFECTIONS AND PBC. WE ALSO DISCUSS THE CLOSE INTERPLAY OF THE INFECTIOUS AGENTS WITH OTHER ENVIRONMENTAL AND GENETIC FACTORS, WHICH MAY EXPLAIN THE MULTIFACETED NATURE OF THIS PUZZLING DISEASE.	2013