1 5772 132 SPECTRUM, SCREENING, AND DIAGNOSIS OF ALCOHOL-RELATED LIVER DISEASE. ALCOHOL-RELATED LIVER DISEASE (ALD) REPRESENTS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASE AND IS A MAJOR CAUSE OF LIVER-RELATED DEATHS WORLDWIDE. ALD ENCOMPASSES A RANGE OF DISORDERS INCLUDING SIMPLE STEATOSIS, ALCOHOLIC STEATOHEPATITIS, FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. PATIENTS WITH UNDERLYING ALD AND CONTINUED HEAVY ALCOHOL CONSUMPTION CAN ALSO DEVELOP AN EPISODE OF ACUTE-ON-CHRONIC LIVER INJURY CALLED ALCOHOL-ASSOCIATED HEPATITIS, THE MOST SEVERE FORM OF THE DISEASE, WHICH PORTENDS A POOR PROGNOSIS. THE MOST IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF ALD IS THE AMOUNT OF ALCOHOL CONSUMED. INDIVIDUAL SUSCEPTIBILITY TO PROGRESSION TO ADVANCED FIBROSIS AMONG HEAVY DRINKERS IS LIKELY DETERMINED BY A COMBINATION OF BEHAVIORAL, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS, BUT THE MECHANISMS ARE LARGELY UNKNOWN. THE ONLY EFFECTIVE THERAPY FOR ALD IS PROLONGED ALCOHOL ABSTINENCE. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. IN CLINICAL PRACTICE, THE HISTOLOGICAL ASSESSMENT FOR ALD DIAGNOSIS IS UNCOMMON, AND IT IS USUALLY BASED ON THE MEDICAL HISTORY, CLINICAL MANIFESTATIONS, AND LABORATORY AND IMAGING TESTS. SEVERAL PROMISING BIOMARKERS THAT CAN HAVE BOTH DIAGNOSTIC AND PROGNOSTIC VALUE IN PATIENTS WITH ALD HAVE BEEN IDENTIFIED IN RECENT YEARS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CLINICAL SPECTRUM OF ALD, THE DIAGNOSTIC APPROACH OF THE DISEASE FROM DIFFERENT PERSPECTIVES AS WELL AS CURRENT DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. 2023 2 321 53 ALCOHOLIC-RELATED LIVER DISEASE: PATHOGENESIS, MANAGEMENT AND FUTURE THERAPEUTIC DEVELOPMENTS. ALCOHOL-RELATED LIVER DISEASE (ALD) IS THE MOST FREQUENT CAUSE OF ADVANCED CHRONIC LIVER DISEASE WORLDWIDE. EXCESSIVE AND PROLONGED ALCOHOL USE LEADS TO ALD, WHICH RANGES FROM EARLY FORMS SUCH AS ALCOHOLIC FATTY LIVER (AFL) AND ALCOHOLIC STEATOHEPATITIS (ASH), THROUGH PROGRESSIVE FIBROSIS TO CIRRHOSIS AND THE DEVELOPMENT OF HEPATOCELLULAR CANCER (HCC). IN ADDITION, PATIENTS WITH UNDERLYING ALD AND CONTINUOUS ALCOHOL USE CAN DEVELOP ALCOHOLIC HEPATITIS (AH), WHICH PRESENTS A RAPID PROGRESSION OF LIVER FAILURE AND HAS A HIGH SHORT-TERM MORTALITY. GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS INFLUENCE THE PROGRESSION OF ALD TO MORE SEVERE FORMS. THE PATHOGENESIS OF ALD IS COMPLEX AND INVOLVES MULTIPLE PATHWAYS. RECENT TRANSLATIONAL STUDIES HAVE DEMONSTRATED A KEY ROLE OF THE GUT-LIVER AXIS AND INNATE IMMUNITY IN HEPATOCELLULAR DAMAGE AND FIBROSIS. IN SEVERE FORMS, HEPATOCELLULAR DE-DIFFERENTIATION AND SYSTEMIC INFLAMMATION CONTRIBUTE TO LIVER FAILURE AND MULTIORGAN FAILURE. ALCOHOL ABSTINENCE IS THE CORNERSTONE OF THERAPY FOR ALD AND THE PREVENTION OF ITS COMPLICATIONS, BUT THE EFFICACY AND ACCESSIBILITY OF PSYCHO-FAMILIAL-SOCIAL INTERVENTIONS IS STILL POOR AND EFFECTIVE PUBLIC HEALTH POLICIES TO LIMIT PROBLEMATIC ALCOHOL USE NEED TO BE IMPLEMENTED. PREDNISOLONE IS THE ONLY CURRENT OPTION FOR AH, WITH A TRANSIENT BENEFICIAL EFFECT OVER PLACEBO. FOR PATIENTS WITH DECOMPENSATED ALD-CIRRHOSIS AND/OR DEVELOPMENT OF HCC, LIVER TRANSPLANTATION (LT) MAY BE REQUIRED. IN RECENT YEARS, EARLY LT IS BEING INCREASINGLY OFFERED TO CAREFULLY SELECTED AH PATIENTS, WITH EXCELLENT LONG-TERM SURVIVAL. NEW TRIALS OF AH TREATMENTS ARE CURRENTLY ONGOING, AND TRANSLATIONAL STUDIES IN HUMAN SAMPLES ARE PAVING THE WAY TO NEW PROMISING TARGETED THERAPIES. 2020 3 320 50 ALCOHOLIC LIVER DISEASE: PATHOGENESIS AND NEW THERAPEUTIC TARGETS. ALCOHOLIC LIVER DISEASE (ALD) IS A MAJOR CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND CAN LEAD TO FIBROSIS AND CIRRHOSIS. THE LATEST SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM SHOWED THAT LIVER CIRRHOSIS WAS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES, WITH A TOTAL OF 29,925 DEATHS IN 2007, 48% OF WHICH WERE ALCOHOL RELATED. THE SPECTRUM OF ALD INCLUDES SIMPLE STEATOSIS, ALCOHOLIC HEPATITIS, FIBROSIS, CIRRHOSIS, AND SUPERIMPOSED HEPATOCELLULAR CARCINOMA. EARLY WORK ON THE PATHOGENESIS OF THE DISEASE FOCUSED ON ETHANOL METABOLISM-ASSOCIATED OXIDATIVE STRESS AND GLUTATHIONE DEPLETION, ABNORMAL METHIONINE METABOLISM, MALNUTRITION, AND PRODUCTION OF ENDOTOXINS THAT ACTIVATE KUPFFER CELLS. WE REVIEW FINDINGS FROM RECENT STUDIES THAT HAVE CHARACTERIZED SPECIFIC INTRACELLULAR SIGNALING PATHWAYS, TRANSCRIPTIONAL FACTORS, ASPECTS OF INNATE IMMUNITY, CHEMOKINES, EPIGENETIC FEATURES, MICRORNAS, AND STEM CELLS THAT ARE ASSOCIATED WITH ALD, IMPROVING OUR UNDERSTANDING OF ITS PATHOGENESIS. DESPITE THIS PROGRESS, NO TARGETED THERAPIES ARE AVAILABLE. THE CORNERSTONE OF TREATMENT FOR ALCOHOLIC HEPATITIS REMAINS AS IT WAS 40 YEARS AGO: ABSTINENCE, NUTRITIONAL SUPPORT, AND CORTICOSTEROIDS. THERE IS AN URGENT NEED TO DEVELOP NEW PATHOPHYSIOLOGY-ORIENTED THERAPIES. RECENT TRANSLATIONAL STUDIES OF HUMAN SAMPLES AND ANIMAL MODELS HAVE IDENTIFIED PROMISING THERAPEUTIC TARGETS. 2011 4 319 52 ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS THE MOST PREVALENT TYPE OF CHRONIC LIVER DISEASE WORLDWIDE. ALD CAN PROGRESS FROM ALCOHOLIC FATTY LIVER (AFL) TO ALCOHOLIC STEATOHEPATITIS (ASH), WHICH IS CHARACTERIZED BY HEPATIC INFLAMMATION. CHRONIC ASH CAN EVENTUALLY LEAD TO FIBROSIS AND CIRRHOSIS AND IN SOME CASES HEPATOCELLULAR CANCER (HCC). IN ADDITION, SEVERE ASH (WITH OR WITHOUT CIRRHOSIS) CAN LEAD TO ALCOHOLIC HEPATITIS, WHICH IS AN ACUTE CLINICAL PRESENTATION OF ALD THAT IS ASSOCIATED WITH LIVER FAILURE AND HIGH MORTALITY. MOST INDIVIDUALS CONSUMING >40 G OF ALCOHOL PER DAY DEVELOP AFL; HOWEVER, ONLY A SUBSET OF INDIVIDUALS WILL DEVELOP MORE ADVANCED DISEASE. GENETIC, EPIGENETIC AND NON-GENETIC FACTORS MIGHT EXPLAIN THE CONSIDERABLE INTERINDIVIDUAL VARIATION IN ALD PHENOTYPE. THE PATHOGENESIS OF ALD INCLUDES HEPATIC STEATOSIS, OXIDATIVE STRESS, ACETALDEHYDE-MEDIATED TOXICITY AND CYTOKINE AND CHEMOKINE-INDUCED INFLAMMATION. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. THE DEGREE OF AFL AND LIVER FIBROSIS CAN BE DETERMINED BY ULTRASONOGRAPHY, TRANSIENT ELASTOGRAPHY, MRI, MEASUREMENT OF SERUM BIOMARKERS AND LIVER BIOPSY HISTOLOGY. ALCOHOL ABSTINENCE ACHIEVED BY PSYCHOSOMATIC INTERVENTION IS THE BEST TREATMENT FOR ALL STAGES OF ALD. IN THE CASE OF ADVANCED DISEASE SUCH AS CIRRHOSIS OR HCC, LIVER TRANSPLANTATION MAY BE REQUIRED. THUS, NEW THERAPIES ARE URGENTLY NEEDED. 2018 5 4709 56 NON-ALCOHOLIC FATTY LIVER DISEASE AND ALCOHOL-RELATED LIVER DISEASE: TWO INTERTWINED ENTITIES. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE, WITH A PREVALENCE OF 25-30%. SINCE ITS FIRST DESCRIPTION IN 1980, NAFLD HAS BEEN CONCEIVED AS A DIFFERENT ENTITY FROM ALCOHOL-RELATED FATTY LIVER DISEASE (ALD), DESPITE THAT, BOTH DISEASES HAVE AN OVERLAP IN THE PATHOPHYSIOLOGY, SHARE GENETIC-EPIGENETIC FACTORS, AND FREQUENTLY COEXIST. BOTH ENTITIES ARE CHARACTERIZED BY A BROAD SPECTRUM OF HISTOLOGICAL FEATURES RANGING FROM ISOLATED STEATOSIS TO STEATOHEPATITIS AND CIRRHOSIS. DISTINCTION BETWEEN NAFLD AND ALD IS BASED ON THE AMOUNT OF CONSUMED ALCOHOL, WHICH HAS BEEN ARBITRARILY ESTABLISHED. IN THIS CONTEXT, A PROPOSAL OF POSITIVE CRITERIA FOR NAFLD DIAGNOSIS NOT CONSIDERING EXCLUSION OF ALCOHOL CONSUMPTION AS A PREREQUISITE CRITERION FOR DIAGNOSIS HAD EMERGED, RECOGNIZING THE POSSIBILITY OF A DUAL ETIOLOGY OF FATTY LIVER IN SOME INDIVIDUALS. THE IMPACT OF MODERATE ALCOHOL USE ON THE SEVERITY OF NAFLD IS ILL-DEFINED. SOME STUDIES SUGGEST PROTECTIVE EFFECTS IN MODERATE DOSES, BUT CURRENT EVIDENCE SHOWS THAT THERE IS NO SAFE THRESHOLD FOR ALCOHOL CONSUMPTION FOR NAFLD. IN FACT, GIVEN THE SYNERGISTIC EFFECT BETWEEN ALCOHOL CONSUMPTION, OBESITY, AND METABOLIC DYSFUNCTION, IT IS LIKELY THAT ALCOHOL USE SERVES AS A SIGNIFICANT RISK FACTOR FOR THE PROGRESSION OF LIVER DISEASE IN NAFLD AND METABOLIC SYNDROME. THIS ALSO AFFECTS THE INCIDENCE OF HEPATOCELLULAR CARCINOMA. IN THIS REVIEW, WE SUMMARIZE THE OVERLAPPING PATHOPHYSIOLOGY OF NAFLD AND ALD, THE CURRENT DATA ON ALCOHOL CONSUMPTION IN PATIENTS WITH NAFLD, AND THE EFFECTS OF METABOLIC DYSFUNCTION AND OVERWEIGHT IN ALD. 2020 6 3022 45 GENETICS AND EPIGENETICS PURPOSE IN NONALCOHOLIC FATTY LIVER DISEASE. INTRODUCTION: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) COMPRISES A BROAD SPECTRUM OF DISEASES, WHICH CAN PROGRESS FROM BENIGN STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE IN DEVELOPED COUNTRIES, AFFECTING APPROXIMATELY 25% OF THE GENERAL POPULATION. INSULIN RESISTANCE, ADIPOSE TISSUE DYSFUNCTION, MITOCHONDRIAL AND ENDOPLASMIC RETICULUM STRESS, CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS ARE NAFLD TRIGGERS THAT CONTROL THE DISEASE SUSCEPTIBILITY AND PROGRESSION. AREAS COVERED: IN RECENT YEARS A LARGE NUMBER OF INVESTIGATIONS HAVE BEEN CARRIED OUT TO ELUCIDATE GENETIC AND EPIGENETIC FACTORS IN THE DISEASE PATHOGENESIS, AS WELL AS THE SEARCH FOR DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS. THIS PAPER OBJECTIVE IS TO REPORT THE MOST STUDIED GENETIC AND EPIGENETIC VARIANTS AROUND NAFLD. EXPERT OPINION: NAFLD LEAD TO VARIOUS COMORBIDITIES, WHICH HAVE A CONSIDERABLE IMPACT ON THE PATIENT WELLNESS AND LIFE QUALITY, AS WELL AS ON THE COSTS THEY GENERATE FOR THE COUNTRY'S HEALTH SERVICES. IT IS ESSENTIAL TO CONTINUE WITH MOLECULAR RESEARCH, SINCE IT COULD BE USED AS A CLINICAL TOOL FOR PROGNOSIS AND DISEASE SEVERITY. SPECIFICALLY, IN THE FIELD OF HEPATOLOGY, PLASMA MIRNAS COULD PROVIDE A NOVEL TOOL IN LIVER DISEASES DIAGNOSIS AND MONITORING, REPRESENTING AN ALTERNATIVE TO INVASIVE DIAGNOSTIC PROCEDURES. 2020 7 4659 52 NEW APPROACHES FOR STUDYING ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS MAJOR CAUSE OF CHRONIC LIVER INJURY WHICH RESULTS IN LIVER FIBROSIS AND CIRRHOSIS. ACCORDING TO THE SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, LIVER CIRRHOSIS IS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES WITH 48 % OF THESE DEATHS BEING ATTRIBUTED TO EXCESSIVE ALCOHOL CONSUMPTION. ALD INCLUDES A SPECTRUM OF DISORDERS FROM SIMPLE STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HEPATOCELLULAR CARCINOMA. SEVERAL MECHANISMS PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF ALD. THESE INCLUDE ETHANOL-INDUCED OXIDATIVE STRESS AND DEPLETION OF GLUTATHIONE, PATHOLOGICAL METHIONINE METABOLISM, INCREASED GUT PERMEABILITY AND RELEASE OF ENDOTOXINS INTO THE PORTAL BLOOD, RECRUITMENT AND ACTIVATION OF INFLAMMATORY CELLS INCLUDING BONE MARROW-DERIVED AND LIVER RESIDENT MACROPHAGES (KUPFFER CELLS). CHRONIC ALCOHOL CONSUMPTION RESULTS IN LIVER DAMAGE AND ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND MYOFIBROBLASTS, LEADING TO LIVER FIBROSIS. HERE WE DISCUSS THE CURRENT VIEW ON FACTORS THAT ARE SPECIFIC FOR DIFFERENT STAGES OF ALD AND THOSE THAT REGULATE ITS PROGRESSION, INCLUDING CYTOKINES AND CHEMOKINES, ALCOHOL-RESPONSIVE INTRACELLULAR SIGNALING PATHWAYS, AND TRANSCRIPTIONAL FACTORS. WE ALSO REVIEW RECENT STUDIES DEMONSTRATING THAT ALCOHOL-MEDIATED CHANGES CAN BE REGULATED ON AN EPIGENETIC LEVEL, INCLUDING MICRORNAS. FINALLY, WE DISCUSS THE REVERSIBILITY OF LIVER FIBROSIS AND INACTIVATION OF HSCS AS A POTENTIAL STRATEGY FOR TREATING ALCOHOL-INDUCED LIVER DAMAGE. 2014 8 2691 28 EVOLUTION OF HEPATIC FIBROSIS RESEARCH. MOLECULAR ANALYSIS OF HEPATIC FIBROGENESIS HAS PROGRESSED WITH RESPECT TO BOTH FIBROSIS PROGRESSION AND REGRESSION BY USING CELL BIOLOGICAL, MOLECULAR BIOLOGICAL AND (EPI)GENETIC APPROACHES. RECENT RESEARCHES HAVE REVEALED SOURCES OF COLLAGEN-PRODUCING CELLS OTHER THAN HEPATIC STELLATE CELLS IN THE LIVER, AND THE INVOLVEMENT OF THE INNATE IMMUNE SYSTEM AND OXIDATIVE STRESS IN THE FIBROTIC PROCESS HAS ATTRACTED NEW ATTENTION. TOGETHER WITH THESE ADVANCEMENTS IN BASIC KNOWLEDGE ON THE CELLULAR AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS, CLINICAL RESEARCHES HAVE LINKED THE CLARIFICATION OF THE RELATIONSHIP BETWEEN PROGRESSION OF THE FIBROSIS STAGE AND THERAPEUTIC EFFICACY FOR CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS AND VALIDATION OF THE REGRESSION OF ADVANCED FIBROSIS, EVEN CIRRHOSIS, OF APPROPRIATE THERAPIES USING MODERN MEDICINES. FURTHERMORE, NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS USING AN ULTRASOUND-BASED MODALITY HAS BECOME A FOCUS IN THE CLINICAL DIAGNOSIS OF LIVER FIBROSIS INSTEAD OF LIVER BIOPSY. TAKEN TOGETHER, LIVER FIBROSIS RESEARCH HAS BEEN EVOLVING BOTH BASICALLY AND CLINICALLY IN THE PAST THREE DECADES. 2011 9 3621 38 IN VIVO AND IN VITRO MODELS OF HEPATOCELLULAR CARCINOMA: CURRENT STRATEGIES FOR TRANSLATIONAL MODELING. HEPATOCELLULAR CARCINOMA (HCC) IS THE SIXTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH GLOBALLY. HCC IS A COMPLEX MULTISTEP DISEASE AND USUALLY EMERGES IN THE SETTING OF CHRONIC LIVER DISEASES. THE MOLECULAR PATHOGENESIS OF HCC VARIES ACCORDING TO THE ETIOLOGY, MAINLY CAUSED BY CHRONIC HEPATITIS B AND C VIRUS INFECTIONS, CHRONIC ALCOHOL CONSUMPTION, AFLATOXIN-CONTAMINATED FOOD, AND NON-ALCOHOLIC FATTY LIVER DISEASE ASSOCIATED WITH METABOLIC SYNDROME OR DIABETES MELLITUS. THE ESTABLISHMENT OF HCC MODELS HAS BECOME ESSENTIAL FOR BOTH BASIC AND TRANSLATIONAL RESEARCH TO IMPROVE OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY AND UNRAVEL NEW MOLECULAR DRIVERS OF THIS DISEASE. THE IDEAL MODEL SHOULD RECAPITULATE KEY EVENTS OBSERVED DURING HEPATOCARCINOGENESIS AND HCC PROGRESSION IN VIEW OF ESTABLISHING EFFECTIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO BE TRANSLATED INTO CLINICAL PRACTICE. DESPITE CONSIDERABLE EFFORTS CURRENTLY DEVOTED TO LIVER CANCER RESEARCH, ONLY A FEW ANTI-HCC DRUGS ARE AVAILABLE, AND PATIENT PROGNOSIS AND SURVIVAL ARE STILL POOR. THE PRESENT PAPER PROVIDES A STATE-OF-THE-ART OVERVIEW OF IN VIVO AND IN VITRO MODELS USED FOR TRANSLATIONAL MODELING OF HCC WITH A SPECIFIC FOCUS ON THEIR KEY MOLECULAR HALLMARKS. 2021 10 2954 45 GENETIC AND EPIGENETIC FACTORS DETERMINING NAFLD RISK. BACKGROUND: HEPATIC STEATOSIS IS A COMMON CHRONIC LIVER DISEASE THAT CAN PROGRESS INTO MORE SEVERE STAGES OF NAFLD OR PROMOTE THE DEVELOPMENT OF LIFE-THREATENING SECONDARY DISEASES FOR SOME OF THOSE AFFECTED. THESE INCLUDE THE LIVER ITSELF (NONALCOHOLIC STEATOHEPATITIS OR NASH; FIBROSIS AND CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA) OR OTHER ORGANS SUCH AS THE VESSELS AND THE HEART (CARDIOVASCULAR DISEASE) OR THE ISLETS OF LANGERHANS (TYPE 2 DIABETES). IN ADDITION TO ELEVATED CALORIC INTAKE AND A SEDENTARY LIFESTYLE, GENETIC AND EPIGENETIC PREDISPOSITION CONTRIBUTE TO THE DEVELOPMENT OF NAFLD AND THE SECONDARY DISEASES. SCOPE OF REVIEW: WE PRESENT DATA FROM GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND FUNCTIONAL STUDIES IN RODENTS WHICH DESCRIBE POLYMORPHISMS IDENTIFIED IN GENES RELEVANT FOR THE DISEASE AS WELL AS CHANGES CAUSED BY ALTERED DNA METHYLATION AND GENE REGULATION VIA SPECIFIC MIRNAS. THE REVIEW ALSO PROVIDES INFORMATION ON THE CURRENT STATUS OF THE USE OF GENETIC AND EPIGENETIC FACTORS AS RISK MARKERS. MAJOR CONCLUSION: WITH OUR OVERVIEW WE PROVIDE AN INSIGHT INTO THE GENETIC AND EPIGENETIC LANDSCAPE OF NAFLD AND ARGUE ABOUT THE APPLICABILITY OF CURRENTLY DEFINED RISK SCORES FOR RISK STRATIFICATION AND CONCLUDE THAT FURTHER EFFORTS ARE NEEDED TO MAKE THE SCORES MORE USABLE AND MEANINGFUL. 2021 11 1285 46 DECIPHERING THE ROLE OF ABERRANT DNA METHYLATION IN NAFLD AND NASH. THE GLOBAL INCIDENCE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS MOUNTING INCESSANTLY, AND IT IS EMERGING AS THE MOST FREQUENT CAUSE OF CHRONIC AND END STAGE LIVER DISORDERS. IT IS THE STARTING POINT FOR A RANGE OF CONDITIONS FROM SIMPLE STEATOSIS TO MORE PROGRESSIVE NONALCOHOLIC STEATOHEPATITIS (NASH) AND ASSOCIATED HEPATOCELLULAR CARCINOMA (HCC). DYSREGULATION OF INSULIN SECRETION AND DYSLIPIDEMIA DUE TO OBESITY AND OTHER LIFESTYLE VARIABLES ARE THE PRIMARY CONTRIBUTORS TO ESTABLISHMENT OF NAFLD. ONSET AND PROGRESSION OF NAFLD IS ORCHESTRATED BY AN INTERPLAY OF METABOLIC ENVIRONMENT WITH GENETIC AND EPIGENETIC FACTORS. AN INCOMPLETELY UNDERSTOOD MECHANISM OF NAFLD PROGRESSION HAS GREATLY HAMPERED THE PROGRESS IN IDENTIFICATION OF NOVEL PROGNOSTIC AND THERAPEUTIC STRATEGIES. EMERGING EVIDENCE SUGGESTS ALTERED DNA METHYLATION PATTERN AS A KEY DETERMINANT OF NAFLD PATHOGENESIS. ENVIRONMENTAL AND LIFESTYLE FACTORS CAN MANIPULATE DNA METHYLATION PATTERNS IN A REVERSIBLE MANNER, WHICH MANIFESTS AS CHANGES IN GENE EXPRESSION. IN THIS REVIEW WE ATTEMPT TO HIGHLIGHT THE IMPORTANCE OF DNA METHYLATION IN ESTABLISHMENT AND PROGRESSION OF NAFLD. DEVELOPMENT OF NOVEL DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC STRATEGIES CENTERED AROUND DNA METHYLATION SIGNATURES AND MODIFIERS HAS ALSO BEEN EXPLORED. 2022 12 2544 27 EPIGENETICS IN LIVER DISEASE: FROM BIOLOGY TO THERAPEUTICS. KNOWLEDGE OF THE FUNDAMENTAL EPIGENETIC MECHANISMS GOVERNING GENE EXPRESSION AND CELLULAR PHENOTYPE ARE SUFFICIENTLY ADVANCED THAT NOVEL INSIGHTS INTO THE EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE ARE NOW EMERGING. HEPATOLOGISTS ARE IN THE PROCESS OF SHEDDING LIGHT ON THE ROLES PLAYED BY DNA METHYLATION, HISTONE/CHROMATIN MODIFICATIONS AND NON-CODING RNAS IN SPECIFIC LIVER PATHOLOGIES. ALONGSIDE THESE DISCOVERIES ARE ADVANCES IN THE TECHNOLOGIES FOR THE DETECTION AND QUANTIFICATION OF EPIGENETIC BIOMARKERS, EITHER DIRECTLY FROM PATIENT TISSUE OR FROM BODY FLUIDS. THE PREMISE FOR THIS REVIEW IS TO SURVEY THE RECENT ADVANCES IN THE FIELD OF LIVER EPIGENETICS AND TO EXPLORE THEIR POTENTIAL FOR TRANSLATION BY INDUSTRY AND CLINICAL HEPATOLOGISTS FOR THE DESIGN OF NOVEL THERAPEUTICS AND DIAGNOSTIC/PROGNOSTIC BIOMARKERS. IN PARTICULAR, WE PRESENT FINDINGS IN THE CONTEXT OF HEPATOCELLULAR CARCINOMA, FIBROSIS AND NON-ALCOHOLIC FATTY LIVER DISEASE, WHERE THERE IS URGENT UNMET NEED FOR NEW CLINICAL INTERVENTIONS AND BIOMARKERS. 2016 13 3928 30 LIVER CELL CIRCUITS AND THERAPEUTIC DISCOVERY FOR ADVANCED LIVER DISEASE AND CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR GLOBAL HEALTH CHALLENGE WITH RISING INCIDENCE. DESPITE THE PREVIOUS APPROVAL OF SEVERAL NOVEL THERAPEUTIC APPROACHES, HCC REMAINS THE SECOND COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE VAST MAJORITY OF HCCS ARISES IN THE CONTEXT OF CHRONIC FIBROTIC LIVER DISEASES CAUSED BY VIRAL OR METABOLIC ETIOLOGIES. IN PATIENTS WITH ADVANCED LIVER DISEASE THE RISK OF HCC PERSISTS EVEN AFTER VIRAL CURE OR CONTROL OF INFECTION. MOREOVER, GIVEN THE CHANGE IN THE LIFESTYLE AND INCREASE OF OBESITY AND METABOLIC DISORDERS, HCC INCIDENCE IS PREDICTED TO DRASTICALLY AUGMENT IN THE NEXT DECADE. EARLY DETECTION, IMPROVEMENT OF THE SCREENING METHOD IN PATIENT AT-RISK AND DEVELOPMENT OF CHEMOPREVENTIVE STRATEGIES ARE THEREFORE URGENTLY NEEDED TO REDUCE HCC RISK. THIS REVIEW SUMMARIZES THE MAJOR CHALLENGES IN THE IDENTIFICATION OF PATIENT AT RISK FOR HCC AND THE EMERGENT STRATEGIES FOR HCC PREVENTION TO IMPROVE PATIENTS' OUTCOME. 2021 14 3793 46 INTERLEUKIN-22 IN ALCOHOLIC HEPATITIS AND BEYOND. ALCOHOLIC HEPATITIS (AH) IS A CLINICAL SYNDROME CHARACTERIZED BY JAUNDICE AND PROGRESSIVE INFLAMMATORY LIVER INJURY IN PATIENTS WITH A HISTORY OF PROLONGED PERIODS OF EXCESS ALCOHOL CONSUMPTION AND RECENT HEAVY ALCOHOL ABUSE. SEVERE AH IS A LIFE-THREATENING FORM OF ALCOHOL-ASSOCIATED LIVER DISEASE WITH A HIGH SHORT-TERM MORTALITY RATE AROUND 30-50% AT ONE MONTH FROM THE INITIAL PRESENTATION. A LARGE NUMBER OF PRO-INFLAMMATORY MEDIATORS, METABOLIC PATHWAYS, TRANSCRIPTIONAL FACTORS AND EPIGENETIC FACTORS HAVE BEEN SUGGESTED TO BE ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF AH. SEVERAL FACTORS MAY CONTRIBUTE TO LIVER FAILURE AND MORTALITY IN PATIENTS WITH SEVERE AH INCLUDING HEPATOCYTE DEATH, INFLAMMATION, AND IMPAIRED LIVER REGENERATION. ALTHOUGH THE PATHOGENESES OF AH HAVE BEEN EXTENSIVELY INVESTIGATED AND MANY THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED OVER THE LAST FIVE DECADES, NO NEW DRUGS FOR AH HAVE BEEN SUCCESSFULLY DEVELOPED. IN THIS REVIEW, WE DISCUSS INTERLEUKIN-22 (IL-22) BIOLOGY AND ITS ROLES OF ANTI-APOPTOSIS, ANTI-FIBROSIS, ANTI-OXIDATION, ANTI-BACTERIAL INFECTION AND REGENERATIVE STIMULATION IN PROTECTING AGAINST LIVER INJURY IN MANY PRECLINICAL MODELS INCLUDING SEVERAL RECENTLY DEVELOPED MODELS SUCH AS CHRONIC-PLUS-BINGE ETHANOL FEEDING, ACUTE-ON-CHRONIC LIVER FAILURE, C-X-C MOTIF CHEMOKINE LIGAND 1 PLUS HIGH-FAT DIET-INDUCED NONALCOHOLIC STEATOHEPATITIS. FINALLY, CLINICAL TRIALS OF IL-22 FOR THE TREATMENT OF AH ARE ALSO DISCUSSED, WHICH SHOWED SOME PROMISING BENEFITS FOR AH PATIENTS. 2020 15 6900 46 [THE DIAGNOSTIC IMPORTANCE OF CIRCULATING MICRORNA FOR NON-ALCOHOLIC FATTY LIVER DISEASE (REVIEW OF LITERATURE).]. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASES IN THE WORLD. THE BIOPSY IS REQUIRED TO CONFIRM THE DIAGNOSIS BUT DUE TO ITS INVASIVENESS, THIS PROCEDURE IS NOT SUITABLE FOR THE MASSIVE SCREENING. THERE ARE LABORATORY CRITERIA OF PRIMARY MEDICAL EXAMINATION OF THE PATIENTS WHO ARE SUSPECTED TO HAVE NAFLD THAT ALLOW DIAGNOSING THE PATHOLOGICAL PROCESS, BUT THESE CRITERIA DO NOT COMPLY WITH CLINICIANS' REQUIREMENTS. AT THE SAME TIME, IT IS CRUCIAL TO IDENTIFY THE PATIENTS IN THE INITIAL STAGES OF NAFLD. RECENTLY, THE ATTENTION OF THE SCIENTISTS WAS CONCENTRATED ON THE RESEARCH OF THE MECHANISM OF NAFLD DEVELOPMENT AND NEW DIAGNOSTIC APPROACHES. ACCUMULATING RESULTS OF THIS RESEARCH SHOW THAT NAFLD DEVELOPMENT IS REGULATED WITH EPIGENETIC FACTORS, INCLUDING MICRORNAS FAMILY (MICRORNA, MIR), THAT MAY HAVE HIGH DIAGNOSTIC AND PROGNOSTIC VALUE. IN THIS REVIEW, DATA EXTRACTED FROM PUBMED ARE USED TO DISCUSS THE POTENTIAL ROLE OF MICRORNA IN THE LIVER LIPID METABOLISM AND FATTY LIVER DISEASE. THE POSSIBILITIES OF MICRO RNA (MIR-16, MIR-21, MIR-34A, MIR-103, MIR-122, MIR-145, MIR-192, AND OTHERS) USE AS PROSPECTIVE BIOMARKERS FOR LOW-INVASIVE NAFLD DIAGNOSTIC, EVALUATION OF STEATOSIS ACTIVITY AND FIBROSIS SCORE AND STAGES, AND PROGNOSTIC MARKERS OF THE DISEASE ARE REVIEWED. THIS RESEARCH DISCUSSES THE ANALYTICAL CHARACTERISTICS, BENEFITS AND POSSIBLE LIMITATIONS OF THEIR USE IN THE CLINICAL PRACTICE. THE PRELIMINARY DATA ALLOW CLAIMING THAT SOME MICRORNAS ARE EXTREMELY PERSPECTIVE LOW-INVASIVE DIAGNOSTIC INSTRUMENT AND FURTHER RESEARCH IS REQUIRED TO INVESTIGATE THE IMPACT OF CERTAIN MICRORNAS IN THE PATHOGENETIC MECHANISM OF NAFLD DEVELOPMENT. 2019 16 1858 36 ELUCIDATING POTENTIAL PROFIBROTIC MECHANISMS OF EMERGING BIOMARKERS FOR EARLY PROGNOSIS OF HEPATIC FIBROSIS. HEPATIC FIBROSIS HAS BEEN ASSOCIATED WITH A SERIES OF PATHOPHYSIOLOGICAL PROCESSES CAUSING EXCESSIVE ACCUMULATION OF EXTRACELLULAR MATRIX PROTEINS. SEVERAL CELLULAR PROCESSES AND MOLECULAR MECHANISMS HAVE BEEN IMPLICATED IN THE DISEASED LIVER THAT AUGMENTS FIBROGENESIS, FIBROGENIC CYTOKINES AND ASSOCIATED LIVER COMPLICATIONS. LIVER BIOPSY REMAINS AN ESSENTIAL DIAGNOSTIC TOOL FOR HISTOLOGICAL EVALUATION OF HEPATIC FIBROSIS TO ESTABLISH A PROGNOSIS. IN ADDITION TO BEING INVASIVE, THIS METHODOLOGY PRESENTS WITH SEVERAL LIMITATIONS INCLUDING POOR COST-EFFECTIVENESS, PROLONGED HOSPITALIZATIONS, AND RISKS OF PERITONEAL BLEEDING, WHILE THE CLINICAL USE OF THIS METHOD DOES NOT REVEAL UNDERLYING PATHOGENIC MECHANISMS. SEVERAL ALTERNATE NONINVASIVE DIAGNOSTIC STRATEGIES HAVE BEEN DEVELOPED, TO DETERMINE THE EXTENT OF HEPATIC FIBROSIS, INCLUDING THE USE OF DIRECT AND INDIRECT BIOMARKERS. IMMEDIATE DIAGNOSIS OF HEPATIC FIBROSIS BY NONINVASIVE MEANS WOULD BE MORE PALATABLE THAN A BIOPSY AND COULD ASSIST CLINICIANS IN TAKING EARLY INTERVENTIONS TIMELY, AVOIDING FATAL COMPLICATIONS, AND IMPROVING PROGNOSIS. THEREFORE, WE SOUGHT TO REVIEW SOME COMMON BIOMARKERS OF LIVER FIBROSIS ALONG WITH SOME EMERGING CANDIDATES, INCLUDING THE OXIDATIVE STRESS-MEDIATED BIOMARKERS, EPIGENETIC AND GENETIC MARKERS, EXOSOMES, AND MIRNAS THAT NEEDS FURTHER EVALUATION AND WOULD HAVE BETTER SENSITIVITY AND SPECIFICITY. WE ALSO AIM TO ELUCIDATE THE POTENTIAL ROLE OF CARDIOTONIC STEROIDS (CTS) AND EVALUATE THE PRO-INFLAMMATORY AND PROFIBROTIC EFFECTS OF CTS IN EXACERBATING HEPATIC FIBROSIS. BY UNDERSTANDING THE UNDERLYING PATHOGENIC PROCESSES, THE EFFICACY OF THESE BIOMARKERS COULD ALLOW FOR EARLY DIAGNOSIS AND TREATMENT OF HEPATIC FIBROSIS IN CHRONIC LIVER DISEASES, ONCE VALIDATED. 2020 17 3105 50 GENOMICS AND PROTEOMICS IN LIVER FIBROSIS AND CIRRHOSIS. GENOMICS AND PROTEOMICS HAVE BECOME INCREASINGLY IMPORTANT IN BIOMEDICAL SCIENCE IN THE PAST DECADE, AS THEY PROVIDE AN OPPORTUNITY FOR HYPOTHESIS-FREE EXPERIMENTS THAT CAN YIELD MAJOR INSIGHTS NOT PREVIOUSLY FORESEEN WHEN SCIENTIFIC AND CLINICAL QUESTIONS ARE BASED ONLY ON HYPOTHESIS-DRIVEN APPROACHES. USE OF THESE TOOLS, THEREFORE, OPENS NEW AVENUES FOR UNCOVERING PHYSIOLOGICAL AND PATHOLOGICAL PATHWAYS. LIVER FIBROSIS IS A COMPLEX DISEASE PROVOKED BY A RANGE OF CHRONIC INJURIES TO THE LIVER, AMONG WHICH ARE VIRAL HEPATITIS, (NON-) ALCOHOLIC STEATOHEPATITIS AND AUTOIMMUNE DISORDERS. SOME CHRONIC LIVER PATIENTS WILL NEVER DEVELOP FIBROSIS OR CIRRHOSIS, WHEREAS OTHERS RAPIDLY PROGRESS TOWARDS CIRRHOSIS IN A FEW YEARS. THIS VARIETY CAN BE CAUSED BY DISEASE-RELATED FACTORS (FOR EXAMPLE, VIRAL GENOTYPE) OR HOST-FACTORS (GENETIC/EPIGENETIC). IT IS VITAL TO ESTABLISH ACCURATE TOOLS TO IDENTIFY THOSE PATIENTS AT HIGHEST RISK FOR DISEASE SEVERITY OR PROGRESSION IN ORDER TO DETERMINE WHO ARE IN NEED OF IMMEDIATE THERAPIES. MOREOVER, THERE IS AN URGENT IMPERATIVE TO IDENTIFY NON-INVASIVE MARKERS THAT CAN ACCURATELY DISTINGUISH MILD AND INTERMEDIATE STAGES OF FIBROSIS. IDEALLY, BIOMARKERS CAN BE USED TO PREDICT DISEASE PROGRESSION AND TREATMENT RESPONSE, BUT THESE STUDIES WILL TAKE MANY YEARS DUE TO THE REQUIREMENT FOR LENGTHY FOLLOW-UP PERIODS TO ASSESS OUTCOMES. CURRENT GENOMIC AND PROTEOMIC RESEARCH PROVIDES MANY CANDIDATE BIOMARKERS, BUT INDEPENDENT VALIDATION OF THESE BIOMARKERS IS LACKING, AND REPRODUCIBILITY IS STILL A KEY CONCERN. THUS, GREAT OPPORTUNITIES AND CHALLENGES LIE AHEAD IN THE FIELD OF GENOMICS AND PROTEOMICS, WHICH, IF SUCCESSFUL, COULD TRANSFORM THE DIAGNOSIS AND TREATMENT OF CHRONIC FIBROSING LIVER DISEASES. 2012 18 4884 51 OVERVIEW OF THE PATHOGENESIS, GENETIC, AND NON-INVASIVE CLINICAL, BIOCHEMICAL, AND SCORING METHODS IN THE ASSESSMENT OF NAFLD. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST PREVALENT CHRONIC LIVER DISEASE WORLDWIDE. IT REPRESENTS A RANGE OF DISORDERS, INCLUDING SIMPLE STEATOSIS, NONALCOHOLIC STEATOHEPATITIS (NASH), AND LIVER CIRRHOSIS, AND ITS PREVALENCE CONTINUES TO RISE. IN SOME CASES, HEPATOCELLULAR CARCINOMA (HCC) MAY DEVELOP. THE DEVELOP;MENT OF NON-INVASIVE DIAGNOSTIC AND SCREENING TOOLS IS NEEDED, IN ORDER TO REDUCE THE FREQUENCY OF LIVER BIOPSIES. THE MOST PROMISING METHODS ARE THOSE ABLE TO EXCLUDE ADVANCED FIBROSIS AND QUANTIFY STEATOSIS. IN THIS STUDY, NEW PERSPECTIVE MARKERS FOR INFLAMMATION, OXIDATIVE STRESS, APOPTOSIS, AND FIBROGENESIS; EMERGING SCORING MODELS FOR DETECTING HEPATIC STEATOSIS AND FIBROSIS; AND NEW GENETIC, EPIGENETIC, AND MULTIOMIC STUDIES ARE DISCUSSED. AS ISOLATED BIOCHEMICAL PARAMETERS ARE NOT SPECIFIC OR SENSITIVE ENOUGH TO PREDICT THE PRESENCE OF NASH AND FIBROSIS, THERE IS A TENDENCY TO USE VARIOUS MARKERS AND COMBINE THEM INTO MATHEMATICAL ALGORITHMS. SEVERAL PREDICTIVE MODELS AND SCORING SYSTEMS HAVE BEEN DEVELOPED. CURRENT DATA SUGGESTS THAT PANELS OF MARKERS (NAFLD FIBROSIS SCORE, FIB-4 SCORE, BARD SCORE, AND OTHERS) ARE USEFUL DIAGNOSTIC MODALITIES TO MINIMIZE THE NUMBER OF LIVER BIOPSIES. THE REVIEW UNVEILS PATHOPHYSIOLOGICAL ASPECTS RELATED TO NEW TRENDS IN CURRENT NON-INVASIVE BIOCHEMICAL, GENETIC, AND SCORING METHODS, AND PROVIDES INSIGHT INTO THEIR DIAGNOSTIC ACCURACIES AND SUITABILITY IN CLINICAL PRACTICE. 2019 19 3270 41 HEPATOCELLULAR CARCINOMA IN THE CONTEXT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH): RECENT ADVANCES IN THE PATHOGENIC MECHANISMS. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER. HCC IS PARTICULARLY AGGRESSIVE AND IS ONE OF THE LEADING CAUSES OF CANCER MORTALITY. IN RECENT DECADES, THE EPIDEMIOLOGICAL LANDSCAPE OF HCC HAS UNDERGONE SIGNIFICANT CHANGES. WHILE CHRONIC VIRAL HEPATITIS AND EXCESSIVE ALCOHOL CONSUMPTION HAVE LONG BEEN IDENTIFIED AS THE MAIN RISK FACTORS FOR HCC, NON-ALCOHOLIC STEATOHEPATITIS (NASH), PARALLELING THE WORLDWIDE EPIDEMIC OF OBESITY AND TYPE 2 DIABETES, HAS BECOME A GROWING CAUSE OF HCC IN THE US AND EUROPE. HERE, WE REVIEW THE RECENT ADVANCES IN EPIDEMIOLOGICAL, GENETIC, EPIGENETIC AND PATHOGENIC MECHANISMS AS WELL AS EXPERIMENTAL MOUSE MODELS THAT HAVE IMPROVED THE UNDERSTANDING OF NASH PROGRESSION TOWARD HCC. WE ALSO DISCUSS THE CLINICAL MANAGEMENT OF PATIENTS WITH NASH-RELATED HCC AND POSSIBLE THERAPEUTIC APPROACHES. 2020 20 5622 37 SEARCH FOR USEFUL BIOMARKERS IN HEPATOCELLULAR CARCINOMA, TUMOR FACTORS AND BACKGROUND LIVER FACTORS (REVIEW). HEPATOCARCINOGENESIS IS A COMPLEX AND MULTISTEP PROCESS THAT INVOLVES THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES. TO UNDERSTAND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CURRENT RESEARCH HAS UTILIZED IMPROVED ARRAY TECHNOLOGIES. THE IDENTIFICATION OF CANCER-RELATED MOLECULES COULD LEAD TO THE DEVELOPMENT OF NOVEL MOLECULAR TARGETS FOR TREATMENT AND BIOMARKERS FOR PREDICTING PROGNOSIS. HOWEVER, PROGNOSTIC PREDICTION IS INSUFFICIENT WHEN CONSIDERING ONLY TUMOR FACTORS, SINCE HEPATOCARCINOGENESIS IS ALSO GREATLY INFLUENCED BY THE STATUS OF THE BACKGROUND LIVER. CLINICAL BACKGROUND LIVER FACTORS, SUCH AS THE PRESENCE OF CHRONIC ACTIVE HEPATITIS OR CIRRHOSIS, ARE WELL KNOWN AS RISK FACTORS FOR DEVELOPING HCC. IN CONTRAST, GENETIC OR EPIGENETIC BACKGROUND LIVER FACTORS REMAIN UNKNOWN, ALBEIT THOSE ARE IMPORTANT TO UNDERSTAND THE DEVELOPING PROCESS OF HCC. INVESTIGATING BACKGROUND LIVER FACTORS COULD CONTRIBUTE TO THE DEVELOPMENT OF CARCINOGENIC MARKERS OF HCC AND TO THE PREVENTION OF THE DEVELOPMENT OF HCC. IN THE PRESENT STUDY, WE REVIEW THE CURRENTLY IDENTIFIED TUMOR FACTORS AND BACKGROUND LIVER FACTORS FROM A MOLECULAR BIOLOGICAL VIEWPOINT AND ALSO INTRODUCE OUR COMBINATION ARRAY ANALYSIS. 2017