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 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 3 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 4 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 5 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 6 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 7 2512 31 EPIGENETICS AND PRIMARY BILIARY CIRRHOSIS: A COMPREHENSIVE REVIEW AND IMPLICATIONS FOR AUTOIMMUNITY. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT DEVELOPS BASED UPON THE INTERACTION OF GENETIC AND ENVIRONMENTAL FACTORS. RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED DOZENS OF PREDISPOSING VARIANTS INCLUDING HLA, IL12A, AND CTLA4 BUT HAVE BEEN DISAPPOINTED IN IDENTIFYING A "SMOKING GUN." THESE DISCOVERIES HIGHLIGHT THE IMPORTANCE OF THE GENETIC BACKGROUND INVOLVED IN IMMUNOLOGICAL DYSREGULATION. ALTHOUGH CONCORDANCE RATE OF PBC IN MONOZYGOTIC (MZ) TWINS IS AMONG THE HIGHEST REPORTED IN AUTOIMMUNE DISORDERS, INCOMPLETE DISEASE CONCORDANCE IN TWINS ASSOCIATED WITH DIFFERENTIALLY EXPRESSED GENES HAS BEEN DEMONSTRATED. HOWEVER, LITTLE IS UNDERSTOOD ABOUT HOW ENVIRONMENTAL ASPECTS CONTRIBUTE TO THE DISEASE AND WHY MIDDLE-AGED WOMEN ARE MORE SUSCEPTIBLE. AS A RESULT, EPIGENETIC FACTORS, WHICH CONVERT SIGNALS INDICATING ENVIRONMENTAL CHANGES INTO DYNAMIC AND HERITABLE ALTERATIONS OF TRANSCRIPTIONAL POTENTIAL, ARE GETTING INCREASED ATTENTION BY RESEARCHERS IN BOTH BASIC AND CLINICAL STUDIES. AMONG EPIGENETIC MECHANISMS, THE INSTABILITY AND SKEWED GENE EXPRESSION IN THE X CHROMOSOME MAY ACCOUNT FOR THE FEMALE PREPONDERANCE IN PBC. IN ADDITION, TRANSCRIPTIONAL REGULATION OF HISTONE MODIFICATION AND DNA METHYLATION UNDERSCORES POTENTIAL INVOLVEMENT IN DISEASE PATHOGENESIS. HIGH-THROUGHPUT TECHNIQUES ARE BEING USED TO IDENTIFY EPIGENETIC REGULATORS. IN THIS REVIEW, WE ATTEMPT TO OUTLINE RECENT PROGRESS REGARDING EPIGENETICS IN PBC AND OTHER AUTOIMMUNE DISEASES. 2016 8 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 9 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 10 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 11 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 12 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 13 6178 21 THE HISTONE MODIFICATION CODE IN THE PATHOGENESIS OF AUTOIMMUNE DISEASES. AUTOIMMUNE DISEASES ARE CHRONIC INFLAMMATORY DISORDERS CAUSED BY A LOSS OF SELF-TOLERANCE, WHICH IS CHARACTERIZED BY THE APPEARANCE OF AUTOANTIBODIES AND/OR AUTOREACTIVE LYMPHOCYTES AND THE IMPAIRED SUPPRESSIVE FUNCTION OF REGULATORY T CELLS. THE PATHOGENESIS OF AUTOIMMUNE DISEASES IS EXTREMELY COMPLEX AND REMAINS LARGELY UNKNOWN. RECENT ADVANCES INDICATE THAT ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE DISEASES IN GENETICALLY PREDISPOSED INDIVIDUALS. IN ADDITION, ACCUMULATING RESULTS HAVE INDICATED A POTENTIAL ROLE OF EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. HISTONE MODIFICATIONS REGULATE THE CHROMATIN STATES AND GENE TRANSCRIPTION WITHOUT ANY CHANGE IN THE DNA SEQUENCE, POSSIBLY RESULTING IN PHENOTYPE ALTERATION IN SEVERAL DIFFERENT CELL TYPES. IN THIS PAPER, WE DISCUSS THE SIGNIFICANT ROLES OF HISTONE MODIFICATIONS INVOLVED IN THE PATHOGENESIS OF AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, PRIMARY BILIARY CIRRHOSIS, AND TYPE 1 DIABETES. 2017 14 3564 30 IMPACT OF GENETIC AND ENVIRONMENTAL FACTORS ON AUTOIMMUNE HEPATITIS. AUTOIMMUNE HEPATITIS (AIH) IS A CHRONIC NON-RESOLVING LIVER DISEASE CHARACTERIZED BY DIFFUSE HYPERGAMMAGLOBULINEMIA, THE PRESENCE OF AUTOANTIBODIES AND CHARACTERISTIC HISTOLOGICAL FINDINGS. THE DISEASE CAN HAVE CATASTROPHIC OUTCOME WITH THE DEVELOPMENT OF END-STAGE LIVER DISEASE IF MISDIAGNOSED/UNDIAGNOSED AND LEFT UNTREATED. AIH PATHOGENESIS REMAINS OBSCURE AND THE MAIN HYPOTHESIS SUPPORTS ITS DEVELOPMENT IN GENETICALLY PREDISPOSED INDIVIDUALS AFTER BEING EXPOSED TO CERTAIN ENVIRONMENTAL TRIGGERS. GENETIC PREDISPOSITION IS LINKED TO THE PRESENCE OF CERTAIN HLA ALLELES, MAINLY HLA-DR3 AND HLA-DR4. HOWEVER, A WIDE NUMBER OF NON-HLA EPITOPES HAVE ALSO BEEN ASSOCIATED WITH THE DISEASE ALTHOUGH DATA VARY SIGNIFICANTLY AMONG DIFFERENT ETHNIC GROUPS. THEREFORE, IT IS LIKELY THAT EPIGENETIC ALTERATIONS MAY ALSO PLAY A CRUCIAL ROLE IN DISEASE'S PATHOGENESIS, ALTHOUGH NOT YET EXTENSIVELY STUDIED. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE GENETIC AND ENVIRONMENTAL FACTORS THAT HAVE BEEN ASSOCIATED WITH AIH, BUT ALSO TO OPEN NEW INSIGHTS TOWARDS THE ROLE OF EPIGENETIC MODIFICATIONS IN THE ETIOLOGY OF THE DISEASE. 2021 15 4431 24 MOLECULAR CARCINOGENESIS OF HEPATOCELLULAR CARCINOMA AND INTRAHEPATIC CHOLANGIOCARCINOMA: ONE STEP CLOSER TO PERSONALIZED MEDICINE? HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICC) ARE THE TWO MAJOR FORMS OF PRIMARY LIVER CANCERS (PLC), ACCOUNTING FOR APPROXIMATELY 90% AND 5% RESPECTIVELY. THE INCIDENCE OF EACH IS INCREASING RAPIDLY IN THE WESTERN WORLD, HOWEVER OUR KNOWLEDGE OF THE UNDERLYING MECHANISMS REMAINS LIMITED AND THE OUTCOME, DISMAL. THE ETIOLOGIES OF EACH VARY GEOGRAPHICALLY; NEVERTHELESS, CHRONIC INFLAMMATION HAS BEEN IDENTIFIED IN MORE THAN 80% OF THE CASES AND APPEARS TO BE A KEY MEDIATOR IN ALTERING THE LIVER MICROENVIRONMENT, INCREASING THE RISK OF CARCINOGENESIS. HOWEVER, SINCE NOT ALL HCC AND ESPECIALLY ICC CASES HAVE A RECOGNIZED RISK FACTOR, THERE ARE CURRENTLY TWO PROPOSED MODELS FOR LIVER CARCINOGENESIS. THE CLONAL EVOLUTION MODEL DEMONSTRATES A MULTI-STEP PROCESS OF TUMOR DEVELOPMENT FROM PRECANCEROUS LESIONS TO METASTATIC CARCINOMA, ARISING FROM THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES IN A CELL IN THE SETTING OF CHRONIC INFLAMMATION. WHILE THE MAJORITY OF CASES DO OCCUR AS A CONSEQUENCE OF CHRONIC INFLAMMATION, MOST INDIVIDUALS WITH CHRONIC INFECTION DO NOT DEVELOP PLC, SUGGESTING THE INVOLVEMENT OF INDIVIDUAL GENETIC AND ENVIRONMENTAL FACTORS. FURTHER, SINCE HEPATOCYTES AND CHOLANGIOCYTES BOTH HAVE REGENERATIVE POTENTIAL AND ARISE FROM THE SAME BI-POTENTIAL PROGENITOR CELL, THE MORE RECENTLY PROPOSED CANCER STEM CELL MODEL IS GAINING ITS DUE ATTENTION. THE INTEGRATION OF THESE MODELS AND THE CONSTANT IMPROVEMENT IN MOLECULAR PROFILING PLATFORMS IS ENABLING A BROADER UNDERSTANDING OF THE MECHANISMS UNDERLYING THESE TWO DEVASTATING MALIGNANCIES, PERHAPS MOVING US CLOSER TO A NEW WORLD OF MOLECULARLY-INFORMED PERSONALIZED MEDICINE. 2011 16 6624 32 UNDERSTANDING PSORIASIS: ROLE OF MIRNAS. PSORIASIS IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY SKIN DISEASE, WITH A MULTIFACTORIAL ETIOLOGY AND IMPORTANT IMMUNOLOGIC, GENETIC AND ENVIRONMENTAL COMPONENTS. PSORIASIS VULGARIS REPRESENTS ITS MOST COMMON FORM, WITH A VARIABLE PREVALENCE ACROSS THE GLOBE. ALTHOUGH ITS PATHOGENESIS REMAINS TO BE FULLY ELUCIDATED, A LACK OF BALANCE IN THE EPIGENETIC NETWORK HAS BEEN SHOWN TO TRIGGER CERTAIN ELEMENTS OF THIS DISEASE, POSSIBLY ALTERING ITS OUTCOME. MICRORNAS ARE SMALL NON-CODING RNA MOLECULES INVOLVED IN RNA-SILENCING AND THE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, WHICH ALSO APPEAR TO MEDIATE THE IMMUNE DYSFUNCTION IN PSORIASIS. ALTHOUGH MICRORNA RESEARCH IS A NEW FIELD IN DERMATOLOGY AND PSORIASIS, THERE IS RAPIDLY ACCUMULATING EVIDENCE FOR ITS MAJOR CONTRIBUTION IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PSORIASIS AND OTHER DERMATOLOGICAL DISORDERS. FURTHERMORE, CIRCULATING MIRNAS IDENTIFIED IN PATIENTS' BLOOD SAMPLES HAVE BEEN IDENTIFIED AS PROMISING BIOMARKERS OF DIAGNOSIS, PROGNOSIS OR TREATMENT RESPONSE. EXTENDED INVESTIGATIONS IN THIS FIELD ARE REQUIRED, AS UNTIL NOW, THE EXACT INVOLVEMENT OF MIRNAS IN PSORIASIS HAVE REMAINED TO BE ENTIRELY ELUCIDATED. THIS SHORT REVIEW HIGHLIGHTS A NUMBER OF THE ROLES OF MIRNAS FOUND IN DIFFERENT STAGES OF PSORIASIS. 2018 17 398 29 AN UPDATE ON GENETIC SUSCEPTIBILITY IN LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY MULTIPLE SYSTEM INVOLVEMENT AND POSITIVE SERUM AUTOANTIBODIES. LUPUS NEPHRITIS (LN) IS THE MOST COMMON AND SERIOUS COMPLICATION OF SLE, AND IT IS THE MAIN CAUSE OF DEATH IN PATIENTS WITH SLE. ABNORMALITIES IN THE IMMUNE SYSTEM LEAD TO LN AND INVOLVE A VARIETY OF CELLS (T CELLS, B CELLS, MACROPHAGES, NK CELLS, ETC.), CYTOKINES (INTERLEUKIN, TUMOR NECROSIS FACTOR ALPHA, ETC.) AND THEIR RELATED PATHWAYS. PREVIOUS STUDIES HAVE SHOWN THAT THE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS CONTRIBUTE TO THE PATHOGENESIS AND DEVELOPMENT OF LN. IN RECENT YEARS, ONE GENOME-WIDE ASSOCIATION STUDY (GWAS) AND A NUMBER OF GENE ASSOCIATION STUDIES HAVE EXPLORED THE SUSCEPTIBILITY GENES OF LN, INCLUDING IMMUNIZATION-, INFLAMMATION-, ADHESION- AND OTHER PATHWAY-RELATED GENES. THESE GENES PARTICIPATE IN OR SUGGEST THE PATHOGENESIS AND PROGRESSION OF LN. IN THIS REVIEW, WE SUMMARIZE THE GENETIC SUSCEPTIBILITY OF LN AND DISCUSS THE POSSIBLE MECHANISM UNDERLYING THE SUSCEPTIBILITY GENES OF LN. 2020 18 2945 21 GENETIC AND EPIGENETIC BASIS OF PSORIASIS PATHOGENESIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WHOSE PREVALENCE VARIES AMONG DIFFERENT POPULATIONS WORLDWIDE. IT IS A COMPLEX MULTI-FACTORIAL DISEASE AND THE EXACT ETIOLOGY IS LARGELY UNKNOWN. FAMILY BASED STUDIES HAVE INDICATED A GENETIC PREDISPOSITION; HOWEVER THEY CANNOT FULLY EXPLAIN THE DISEASE PATHOGENESIS. IN ADDITION TO GENETIC SUSCEPTIBILITY, ENVIRONMENTAL AS WELL AS GENDER AND AGE RELATED FACTORS WERE ALSO BEEN FOUND TO BE ASSOCIATED. RECENTLY, IMBALANCES IN EPIGENETIC NETWORKS ARE INDICATED TO BE CAUSATIVE ELEMENTS IN PSORIASIS. THE PRESENT KNOWLEDGE OF EPIGENETIC INVOLVEMENT, MAINLY THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND MIRNA DEREGULATION IS SURVEYED HERE. AN INTEGRATED APPROACH CONSIDERING GENETIC AND EPIGENETIC ANOMALIES IN THE LIGHT OF IMMUNOLOGICAL NETWORK MAY EXPLORE THE PATHOGENESIS OF PSORIASIS. 2015 19 4980 24 PATHOPHYSIOLOGY OF LIVER FIBROSIS. PROGRESSIVE ACCUMULATION OF FIBRILLAR EXTRACELLULAR MATRIX (ECM) IN THE LIVER IS THE CONSEQUENCE OF REITERATED LIVER TISSUE DAMAGE DUE TO INFECTIVE (MOSTLY HEPATITIS B AND C VIRUSES), TOXIC/DRUG-INDUCED, METABOLIC AND AUTOIMMUNE CAUSES, AND THE RELATIVE CHRONIC ACTIVATION OF THE WOUND-HEALING REACTION. THE PROCESS MAY RESULT IN CLINICALLY EVIDENT LIVER CIRRHOSIS AND HEPATIC FAILURE. ALTHOUGH CIRRHOSIS IS THE COMMON RESULT OF PROGRESSIVE FIBROGENESIS, THERE ARE DISTINCT PATTERNS OF FIBROTIC DEVELOPMENT RELATED TO THE UNDERLYING DISORDERS CAUSING THE FIBROSIS. THESE DIFFERENT PATTERNS OF FIBROGENIC EVOLUTION ARE RELATED TO DIFFERENT FACTORS AND PARTICULARLY: (1) THE TOPOGRAPHIC LOCALIZATION OF TISSUE DAMAGE, (2) THE RELATIVE CONCENTRATION OF PROFIBROGENIC FACTORS AND (3) THE PREVALENT PROFIBROGENIC MECHANISM(S). THE MECHANISMS RESPONSIBLE FOR THE FIBROGENIC EVOLUTION OF CHRONIC LIVER DISEASES CAN BE SUMMARIZED IN THREE MAIN GROUPS: CHRONIC ACTIVATION OF THE WOUND-HEALING REACTION, OXIDATIVE STRESS-RELATED MOLECULAR MECHANISMS, AND THE DERANGEMENT OF THE SO-CALLED 'EPITHELIAL-MESENCHYMAL' INTERACTION LEADING TO THE GENERATION OF REACTIVE CHOLANGIOCYTES AND PERIBILIARY FIBROSIS. MOST OF THE KNOWLEDGE ON THE CELL AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS DERIVES FROM IN VITRO STUDIES EMPLOYING CULTURE OF ACTIVATED HEPATIC STELLATE CELLS ISOLATED FROM RAT, MOUSE OR HUMAN LIVER. IT IS NOW EVIDENT THAT OTHER ECM-PRODUCING CELLS, I.E. FIBROBLASTS AND MYOFIBROBLASTS OF THE PORTAL TRACT AND CIRCULATING 'FIBROCYTES', ARE LIKELY TO CONTRIBUTE TO LIVER FIBROSIS. MORE RECENTLY, THE ATTENTION IS PROGRESSIVELY SHIFTING TO THE PROFIBROTIC MICROENVIRONMENT OF THE LIVER WITH INCREASING INTEREST FOR THE ROLE OF IMMUNE CELLS AND SPECIFIC SUBSETS OF MACROPHAGES REGULATING THE PROGRESSION OR THE REGRESSION OF FIBROSIS, THE ROLE OF INTESTINAL MICROBIOTA AND THE INFLUENCE OF TISSUE STIFFNESS. OTHER MAJOR AREAS OF DEVELOPMENT INCLUDE THE ROLE OF TISSUE HYPOXIA AND THE ESTABLISHMENT OF AN ANAEROBIC PROINFLAMMATORY ENVIRONMENT AND THE INFLUENCE OF EPIGENETIC MODIFICATION IN CONDITIONING THE PROGRESSION OF FIBROSIS. 2015 20 2180 20 EPIGENETIC MECHANISMS OF PANCREATOBILIARY FIBROSIS. PURPOSE OF REVIEW: THE GOAL OF THIS MANUSCRIPT IS TO REVIEW THE CURRENT LITERATURE RELATED TO FIBROGENESIS IN THE PANCREATOBILIARY SYSTEM AND HOW THIS PROCESS CONTRIBUTES TO PANCREATIC AND BILIARY DISEASES. IN PARTICULAR, WE SEEK TO DEFINE THE CURRENT STATE OF KNOWLEDGE REGARDING THE EPIGENETIC MECHANISMS THAT GOVERN AND REGULATE TISSUE FIBROSIS IN THESE ORGANS. A BETTER UNDERSTANDING OF THESE UNDERLYING MOLECULAR EVENTS WILL SET THE STAGE FOR FUTURE EPIGENETIC THERAPEUTICS. RECENT FINDINGS: WE HIGHLIGHT THE SIGNIFICANT ADVANCES THAT HAVE BEEN MADE IN DEFINING THE PATHOGENESIS OF PANCREATOBILIARY FIBROSIS AS IT RELATES TO CHRONIC PANCREATITIS, PANCREATIC CANCER, AND THE FIBRO-OBLITERATIVE CHOLANGIOPATHIES. WE ALSO REVIEW THE CELL TYPES INVOLVED AS WELL AS CONCEPTS RELATED TO EPITHELIAL-MESENCHYMAL CROSSTALK. FURTHERMORE, WE OUTLINE IMPORTANT SIGNALING PATHWAYS (E.G., TGFBETA) AND DIVERSE EPIGENETIC PROCESSES (I.E., DNA METHYLATION, NON-CODING RNAS, HISTONE MODIFICATIONS, AND 3D CHROMATIN REMODELING) THAT REGULATE FIBROGENIC GENE NETWORKS IN THESE CONDITIONS. WE REVIEW A GROWING BODY OF SCIENTIFIC EVIDENCE LINKING EPIGENETIC REGULATORY EVENTS TO FIBROTIC DISEASE STATES IN THE PANCREAS AND BILIARY SYSTEM. ADVANCES IN THIS UNDERSTUDIED AREA WILL BE CRITICAL TOWARD DEVELOPING EPIGENETIC PHARMACOLOGICAL APPROACHES THAT MAY LEAD TO MORE EFFECTIVE TREATMENTS FOR THESE DEVASTATING AND DIFFICULT TO TREAT DISORDERS. 2019