1 3270 86 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 2 4712 34 NON-ALCOHOLIC FATTY LIVER DISEASE: METABOLIC, GENETIC, EPIGENETIC AND ENVIRONMENTAL RISK FACTORS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST FREQUENT CAUSES OF CHRONIC LIVER DISEASE IN THE WESTERN WORLD, PROBABLY DUE TO THE GROWING PREVALENCE OF OBESITY, METABOLIC DISEASES, AND EXPOSURE TO SOME ENVIRONMENTAL AGENTS. IN CERTAIN PATIENTS, SIMPLE HEPATIC STEATOSIS CAN PROGRESS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH), WHICH CAN SOMETIMES LEAD TO LIVER CIRRHOSIS AND ITS COMPLICATIONS INCLUDING HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE MECHANISMS THAT CAUSE THE PROGRESSION OF NAFLD TO NASH IS CRUCIAL TO BE ABLE TO CONTROL THE ADVANCEMENT OF THE DISEASE. THE MAIN HYPOTHESIS CONSIDERS THAT IT IS DUE TO MULTIPLE FACTORS THAT ACT TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO SUFFER FROM NAFLD INCLUDING INSULIN RESISTANCE, NUTRITIONAL FACTORS, GUT MICROBIOTA, AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE WILL DISCUSS THE EPIDEMIOLOGY OF NAFLD, AND WE OVERVIEW SEVERAL TOPICS THAT INFLUENCE THE DEVELOPMENT OF THE DISEASE FROM SIMPLE STEATOSIS TO LIVER CIRRHOSIS AND ITS POSSIBLE COMPLICATIONS. 2021 3 4464 36 MOLECULAR MECHANISMS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE AND HAS GARNERED INCREASING ATTENTION IN RECENT DECADES. NAFLD IS CHARACTERIZED BY A WIDE RANGE OF LIVER CHANGES, FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE PATHOGENESIS OF NAFLD/NASH IS VERY COMPLICATED AND INVOLVES LIPID ACCUMULATION, INSULIN RESISTANCE, INFLAMMATION, AND FIBROGENESIS. IN ADDITION, NAFLD IS CLOSELY ASSOCIATED WITH COMPLICATIONS SUCH AS OBESITY, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN PARTICULAR, THE CLINICAL SPECTRUM, PATHOPHYSIOLOGY, AND THERAPEUTIC OPTIONS OF NAFLD SHARE MANY THINGS IN COMMON WITH DIABETES. INSULIN RESISTANCE IS AN UNDERLYING BASIS FOR THE PATHOGENESIS OF DIABETES AND NAFLD. THIS CHAPTER FOCUSES ON THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF INSULIN RESISTANCE, DIABETES, AND NASH/NAFLD INCLUDING THOSE THAT DRIVE DISEASE PROGRESSION SUCH AS OXIDATIVE STRESS, GENETIC AND EPIGENETIC MECHANISMS, ADIPONECTIN, CYTOKINES, AND IMMUNE CELLS. 2021 4 4326 37 MICRORNAS IN THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), OR, MORE ACCURATELY, METABOLIC ASSOCIATED FATTY LIVER DISEASE, ACCOUNTS FOR A LARGE PROPORTION OF CHRONIC LIVER DISORDERS WORLDWIDE AND IS CLOSELY ASSOCIATED WITH OTHER CONDITIONS SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND TYPE 2 DIABETES MELLITUS. NAFLD RANGES FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH) AND CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, ALSO HEPATOCELLULAR CARCINOMA. THE MORBIDITY AND MORTALITY ASSOCIATED WITH NAFLD ARE INCREASING RAPIDLY YEAR ON YEAR. CONSEQUENTLY, THERE IS AN URGENT NEED TO UNDERSTAND THE ETIOLOGY AND PATHOGENESIS OF NAFLD AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. MICRORNAS (MIRNAS), IMPORTANT EPIGENETIC FACTORS, HAVE RECENTLY BEEN PROPOSED TO PARTICIPATE IN NAFLD PATHOGENESIS. HERE, WE REVIEW THE ROLES OF MIRNAS IN LIPID METABOLISM, INFLAMMATION, APOPTOSIS, FIBROSIS, HEPATIC STELLATE CELL ACTIVATION, INSULIN RESISTANCE, AND OXIDATIVE STRESS, KEY FACTORS THAT CONTRIBUTE TO THE OCCURRENCE AND PROGRESSION OF NAFLD. ADDITIONALLY, WE SUMMARIZE THE ROLE OF MIRNA-ENRICHED EXTRACELLULAR VESICLES IN NAFLD. THESE MIRNAS MAY COMPRISE SUITABLE THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS CONDITION. 2021 5 4720 34 NONCODING RNAS AS ADDITIONAL MEDIATORS OF EPIGENETIC REGULATION IN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS EMERGED AS THE MOST COMMON CAUSE OF CHRONIC LIVER DISORDER WORLDWIDE. IT REPRESENTS A SPECTRUM THAT INCLUDES A CONTINUUM OF DIFFERENT CLINICAL ENTITIES RANGING FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, WHICH CAN EVOLVE TO CIRRHOSIS AND IN SOME CASES TO HEPATOCELLULAR CARCINOMA, ULTIMATELY LEADING TO LIVER FAILURE. THE PATHOGENESIS OF NAFLD AND THE MECHANISMS UNDERLYING ITS PROGRESSION TO MORE PATHOLOGICAL STAGES ARE NOT COMPLETELY UNDERSTOOD. BESIDES GENETIC FACTORS, EVIDENCE INDICATES THAT EPIGENETIC MECHANISMS OCCURRING IN RESPONSE TO ENVIRONMENTAL STIMULI ALSO CONTRIBUTE TO THE DISEASE RISK. NONCODING RNAS (NCRNAS), INCLUDING MICRORNAS, LONG NONCODING RNAS, AND CIRCULAR RNAS, ARE ONE OF THE EPIGENETIC FACTORS THAT PLAY KEY REGULATORY ROLES IN THE DEVELOPMENT OF NAFLD. AS THE FIELD OF NCRNAS IS RAPIDLY EVOLVING, THE PRESENT REVIEW AIMS TO EXPLORE THE CURRENT STATE OF KNOWLEDGE ON THE ROLES OF THESE RNA SPECIES IN THE PATHOGENESIS OF NAFLD, HIGHLIGHT RELEVANT MECHANISMS BY WHICH SOME NCRNAS CAN MODULATE REGULATORY NETWORKS IMPLICATED IN NAFLD, AND DISCUSS KEY CHALLENGES AND FUTURE DIRECTIONS FACING CURRENT RESEARCH IN THE HOPES OF DEVELOPING NCRNAS AS NEXT-GENERATION NON-INVASIVE DIAGNOSTICS AND THERAPIES IN NAFLD AND SUBSEQUENT PROGRESSION TO HEPATOCELLULAR CARCINOMA. 2022 6 1942 38 EPIDEMIOLOGY OF LIVER CANCER IN AFRICA: CURRENT AND FUTURE TRENDS. HEPATOCELLULAR CARCINOMA (HCC) IS A DISEASE OF GLOBAL PUBLIC HEALTH SIGNIFICANCE WITH MORTALITY ON THE RISE, DESPITE THE PREVENTABLE NATURE OF ITS RISK FACTORS ESPECIALLY IN AFRICA. IT IS NOW THE SIXTH MOST COMMON CANCER WORLDWIDE, FIFTH IN MALES, AND NINTH IN FEMALES. HCC INCIDENCE AND MORTALITY ARE PREDICTED TO INCREASE IN AFRICAN COUNTRIES CONSTRAINED BY LIMITED RESOURCES TO COMBAT ENDEMIC LEVELS OF VIRAL INFECTION AND SYNERGISTIC ENVIRONMENTAL RISK FACTORS. THE CHANGING NATURE OF HCC ETIOLOGY IS PARTICULARLY ILLUSTRATED HERE WITH THE TRADITIONAL RISK FACTORS LIKE VIRAL HEPATITIS COEXISTING ALONGSIDE HIGH HUMAN IMMUNODEFICIENCY VIRUS (HIV) PREVALENCE AND RAPIDLY INCREASING URBANIZATION THAT HAVE PROMOTED A SHARP INCREASE IN ADDITIONAL RISK FACTORS LIKE COINFECTION, TYPE 2 DIABETES MELLITUS, AND OBESITY. ALTHOUGH THERE ARE SOME DIFFERENCES IN ETIOLOGY BETWEEN NORTH AFRICA AND SUB-SAHARAN AFRICA, RISK FACTORS LIKE CHRONIC VIRAL HEPATITIS B AND C, AFLATOXIN EXPOSURE, AND IRON OVERLOAD PREDOMINATE. AGGRESSIVE HEPATITIS B GENOTYPES, COMBINED WITH HEPATITIS B VIRUS/HEPATITIS C VIRUS/HIV COINFECTIONS AND AFLATOXIN EXPOSURE, PROMOTE A MORE AGGRESSIVE MOLECULAR PHENOTYPE. IN PARALLEL TO A BETTER UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF HCC, POLICY AND PLANNING INITIATIVES TO ADDRESS THE BURDEN OF HCC MUST BE ANCHORED WITHIN THE REALITY OF THE LIMITED RESOURCES AVAILABLE. ESTABLISHMENT AND COORDINATION OF CANCER REGISTRIES ACROSS AFRICA IS NEEDED TO IMPROVE THE QUALITY OF DATA NECESSARY TO GALVANIZE ACTION. PREVENTIVE MEASURES INCLUDING HEPATITIS B VACCINATION PROGRAMS, MEASURES TO PREVENT MATERNAL-TO-CHILD AND CHILD-TO-CHILD TRANSMISSION, DELIVERY OF UNIVERSALLY ACCESSIBLE ANTIRETROVIRAL AND ANTIVIRAL TREATMENTS, AND REDUCTION OF DIETARY AFLATOXIN EXPOSURE CAN CONTRIBUTE MARKEDLY TO REDUCE HCC INCIDENCE. FINALLY, THE DEVELOPMENT OF BIOMARKERS AND NEW THERAPEUTIC INTERVENTIONS WILL NEED A BETTER UNDERSTANDING OF THE UNIQUE GENETIC AND EPIGENETIC CHARACTERISTICS OF HCC ON THE CONTINENT. WE PRESENT A NARRATIVE REVIEW OF HCC IN AFRICA, DISCUSSING PRESENT AND FUTURE TRENDS. 2020 7 3022 28 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 8 4478 34 MOLECULAR PATHOGENESIS OF NONALCOHOLIC STEATOHEPATITIS- (NASH-) RELATED HEPATOCELLULAR CARCINOMA. THE PROPORTION OF OBESE OR DIABETIC POPULATION HAS BEEN ANTICIPATED TO INCREASE IN THE UPCOMING DECADES, WHICH RISES THE PREVALENCE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND ITS PROGRESSION TO NONALCOHOLIC STEATOHEPATITIS (NASH). RECENT EVIDENCE INDICATES THAT NASH IS THE MAIN CAUSE OF CHRONIC LIVER DISEASES AND IT IS AN IMPORTANT RISK FACTOR FOR DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). ALTHOUGH THE LITERATURE ADDRESSING NASH-HCC IS GROWING RAPIDLY, LIMITED DATA IS AVAILABLE ABOUT THE ETIOLOGY OF NASH-RELATED HCC. EXPERIMENTAL STUDIES ON THE MOLECULAR MECHANISM OF HCC DEVELOPMENT IN NASH REVEAL THAT THE CARCINOGENESIS IS RELEVANT TO COMPLEX CHANGES IN SIGNALING PATHWAYS THAT MEDIATE CELL PROLIFERATION AND ENERGY METABOLISM. GENETIC OR EPIGENETIC MODIFICATIONS AND ALTERATIONS IN METABOLIC, IMMUNOLOGIC, AND ENDOCRINE PATHWAYS HAVE BEEN SHOWN TO BE CLOSELY RELATED TO INFLAMMATION, LIVER INJURY, AND FIBROSIS IN NASH ALONG WITH ITS SUBSEQUENT PROGRESSION TO HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW ON THE CURRENT KNOWLEDGE OF NASH-RELATED HCC DEVELOPMENT AND EMPHASIZE MOLECULAR SIGNALING PATHWAYS REGARDING THEIR MECHANISM OF ACTION IN NASH-DERIVED HCC. 2018 9 3928 28 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 10 3621 32 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 11 4722 32 NONCODING RNAS IN NONALCOHOLIC FATTY LIVER DISEASE: POTENTIAL DIAGNOSIS AND PROGNOSIS BIOMARKERS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS CURRENTLY THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE IN PART DUE TO THE CONCOMITANT OBESITY PANDEMIC AND INSULIN RESISTANCE (IR). IT IS INCREASINGLY BECOMING EVIDENT THAT NAFLD IS A DISEASE AFFECTING NUMEROUS EXTRAHEPATIC VITAL ORGANS AND REGULATORY PATHWAYS. THE MOLECULAR MECHANISMS UNDERLYING THE NONALCOHOLIC STEATOSIS FORMATION ARE POORLY UNDERSTOOD, AND LITTLE INFORMATION IS AVAILABLE ON THE PATHWAYS THAT ARE RESPONSIBLE FOR THE PROGRESSIVE HEPATOCELLULAR DAMAGE THAT FOLLOWS LIPID ACCUMULATION. RECENTLY, MUCH RESEARCH HAS FOCUSED ON THE IDENTIFICATION OF THE EPIGENETIC MODIFICATIONS THAT CONTRIBUTE TO NAFLD PATHOGENESIS. NONCODING RNAS (NCRNAS) ARE ONE OF SUCH EPIGENETIC FACTORS THAT COULD BE IMPLICATED IN THE NAFLD DEVELOPMENT AND PROGRESSION. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC FACTORS POTENTIALLY UNDERLYING THE DISEASE. PARTICULAR EMPHASIS WILL BE PUT ON THE CONTRIBUTION OF MICRORNAS (MIRNAS), LONG NONCODING RNAS (LNCRNAS), AND CIRCULAR RNAS (CIRCRNAS) TO THE PATHOPHYSIOLOGY OF NAFLD AS WELL AS THEIR POTENTIAL USE AS THERAPEUTIC TARGETS OR AS MARKERS FOR THE PREDICTION AND THE PROGRESSION OF THE DISEASE. 2020 12 2287 36 EPIGENETIC REGULATION IN LEAN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), THE MOST PROMINENT CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE, IS A RAPIDLY GROWING EPIDEMIC. IT CONSISTS OF A WIDE RANGE OF LIVER DISEASES, FROM STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, AND PREDISPOSES PATIENTS TO LIVER FIBROSIS, CIRRHOSIS, AND EVEN HEPATOCELLULAR CARCINOMA. NAFLD IS STRONGLY CORRELATED WITH OBESITY; HOWEVER, IT HAS BEEN EXTENSIVELY REPORTED AMONG LEAN/NONOBESE INDIVIDUALS IN RECENT YEARS. ALTHOUGH LEAN PATIENTS DEMONSTRATE A LOWER PREVALENCE OF DIABETES MELLITUS, CENTRAL OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND METABOLIC SYNDROME, A PERCENTAGE OF THESE PATIENTS MAY DEVELOP STEATOHEPATITIS, ADVANCED LIVER FIBROSIS, AND CARDIOVASCULAR DISEASE, AND HAVE INCREASED ALL-CAUSE MORTALITY. THE PATHOPHYSIOLOGICAL MECHANISMS OF LEAN NAFLD REMAIN VAGUE. STUDIES HAVE REPORTED THAT LEAN NAFLD DEMONSTRATES A CLOSE ASSOCIATION WITH ENVIRONMENTAL FACTORS, GENETIC PREDISPOSITION, AND EPIGENETIC MODIFICATIONS. IN THIS REVIEW, WE AIM TO DISCUSS AND SUMMARIZE THE EPIGENETIC MECHANISMS INVOLVED IN LEAN NAFLD AND TO INTRODUCE THE INTERACTION BETWEEN EPIGENETIC PATTERNS AND GENETIC OR NON GENETIC FACTORS. SEVERAL EPIGENETIC MECHANISMS HAVE BEEN IMPLICATED IN THE REGULATION OF LEAN NAFLD. THESE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING-RNA-MEDIATED GENE REGULATION. EPIGENETICS IS AN AREA OF SPECIAL INTEREST IN THE SETTING OF LEAN NAFLD AS IT COULD PROVIDE NEW INSIGHTS INTO THE THERAPEUTIC OPTIONS AND NONINVASIVE BIOMARKERS THAT TARGET THIS UNDER-RECOGNIZED AND CHALLENGING DISORDER. 2023 13 5807 29 STRATEGIES, MODELS AND BIOMARKERS IN EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE RESEARCH. NON-ALCOHOLIC FATTY LIVER DISEASE ENCOMPASSES A SPECTRUM OF LIVER DISEASES, INCLUDING SIMPLE STEATOSIS, STEATOHEPATITIS, LIVER FIBROSIS AND CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NON-ALCOHOLIC FATTY LIVER DISEASE IS CURRENTLY THE MOST DOMINANT CHRONIC LIVER DISEASE IN WESTERN COUNTRIES DUE TO THE FACT THAT HEPATIC STEATOSIS IS ASSOCIATED WITH INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, OBESITY, METABOLIC SYNDROME AND DRUG-INDUCED INJURY. A VARIETY OF CHEMICALS, MAINLY DRUGS, AND DIETS IS KNOWN TO CAUSE HEPATIC STEATOSIS IN HUMANS AND RODENTS. EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE MODELS RELY ON THE APPLICATION OF A DIET OR THE ADMINISTRATION OF DRUGS TO LABORATORY ANIMALS OR THE EXPOSURE OF HEPATIC CELL LINES TO THESE DRUGS. MORE RECENTLY, GENETICALLY MODIFIED RODENTS OR ZEBRAFISH HAVE BEEN INTRODUCED AS NON-ALCOHOLIC FATTY LIVER DISEASE MODELS. CONSIDERABLE INTEREST NOW LIES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL NON-INVASIVE BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, WITH SPECIFIC FOCUS ON HEPATIC STEATOSIS. EXPERIMENTAL DIAGNOSTIC BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, SUCH AS (EPI)GENETIC PARAMETERS AND '-OMICS'-BASED READ-OUTS ARE STILL IN THEIR INFANCY, BUT SHOW GREAT PROMISE. IN THIS PAPER, THE ARRAY OF TOOLS AND MODELS FOR THE STUDY OF LIVER STEATOSIS IS DISCUSSED. FURTHERMORE, THE CURRENT STATE-OF-ART REGARDING EXPERIMENTAL BIOMARKERS SUCH AS EPIGENETIC, GENETIC, TRANSCRIPTOMIC, PROTEOMIC AND METABONOMIC BIOMARKERS WILL BE REVIEWED. 2015 14 74 42 A MULTIDISCIPLINARY APPROACH AND CURRENT PERSPECTIVE OF NONALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW. IN RECENT TIMES, NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BEEN CONSIDERED ONE OF THE MAJOR CAUSES OF LIVER DISEASE ACROSS THE WORLD. NAFLD IS DEFINED AS THE DEPOSITION OF TRIGLYCERIDES IN THE LIVER AND IS ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME. HYPERINSULINEMIA, INSULIN RESISTANCE (IR), FATTY LIVER, HEPATOCYTE INJURY, UNBALANCED PROINFLAMMATORY CYTOKINES, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIVER INFLAMMATION, AND FIBROSIS ARE THE MAIN PATHOGENESIS IN NAFLD. RECENT STUDIES SUGGEST THAT THE ACTION OF INTESTINAL MICROBIOTA THROUGH CHRONIC INFLAMMATION, INCREASED INTESTINAL PERMEABILITY, AND ENERGY UPTAKE PLAYS A VITAL ROLE IN NAFLD. MOREOVER, POLYCYSTIC OVARIAN SYNDROME ALSO CAUSES NAFLD DEVELOPMENT THROUGH IR. AGE, GENDER, RACE, ETHNICITY, SLEEP, DIET, SEDENTARY LIFESTYLE, AND GENETIC AND EPIGENETIC PATHWAYS ARE SOME CONTRIBUTING FACTORS OF NAFLD THAT CAN EXACERBATE THE RISK OF LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC) AND EVENTUALLY LEAD TO DEATH. NAFLD HAS VARIOUS PRESENTATIONS, INCLUDING FATIGUE, UNEXPLAINED WEIGHT LOSS, BLOATING, UPPER ABDOMINAL PAIN, DECREASED APPETITE, HEADACHE, ANXIETY, POOR SLEEP, INCREASED THIRST, PALPITATION, AND A FEELING OF WARMTH. SOME STUDIES HAVE SHOWN THAT NAFLD WITH SEVERE CORONAVIRUS DISEASE 2019 (COVID-19) HAS POOR OUTCOMES. THE GOLD STANDARD FOR NAFLD DIAGNOSIS IS LIVER BIOPSY. OTHER DIAGNOSTIC TOOLS ARE IMAGING TESTS, SERUM BIOMARKERS, MICROBIOTA MARKERS, AND TESTS FOR EXTRAHEPATIC COMPLICATIONS. THERE ARE NO SPECIFIC TREATMENTS FOR NAFLD. THEREFORE, THE MAIN CONCERN FOR NAFLD IS TREATING THE COMORBID CONDITIONS SUCH AS ANTI-DIABETIC AGENTS FOR TYPE 2 DIABETES MELLITUS, STATINS TO REDUCE HCC PROGRESSION, ANTIOXIDANTS TO PREVENT HEPATOCELLULAR DAMAGE, AND BARIATRIC SURGERY FOR PATIENTS WITH A BMI OF >40 KG/M(2) AND >35 KG/M(2) WITH COMORBIDITIES. LIFESTYLE AND DIETARY CHANGES ARE CONSIDERED PREVENTIVE STRATEGIES AGAINST NAFLD ADVANCEMENT. INADEQUATE TREATMENT OF NAFLD FURTHER LEADS TO CARDIAC CONSEQUENCES, SLEEP APNEA, CHRONIC KIDNEY DISEASE, AND INFLAMMATORY BOWEL DISEASE. IN THIS SYSTEMATIC REVIEW, WE HAVE BRIEFLY DISCUSSED THE RISK FACTORS, PATHOGENESIS, CLINICAL FEATURES, AND NUMEROUS CONSEQUENCES OF NAFLD. WE HAVE ALSO REVIEWED VARIOUS GUIDELINES FOR NAFLD DIAGNOSIS ALONG WITH EXISTING THERAPEUTIC STRATEGIES FOR THE MANAGEMENT AND PREVENTION OF THE DISEASE. 2022 15 6264 28 THE MULTIPLE-HIT PATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS INCREASINGLY PREVALENT AND REPRESENTS A GROWING CHALLENGE IN TERMS OF PREVENTION AND TREATMENT. DESPITE ITS HIGH PREVALENCE, ONLY A SMALL MINORITY OF AFFECTED PATIENTS DEVELOPS INFLAMMATION AND SUBSEQUENTLY FIBROSIS AND CHRONIC LIVER DISEASE, WHILE MOST OF THEM ONLY EXHIBIT SIMPLE STEATOSIS. IN THIS CONTEXT, THE FULL UNDERSTANDING OF THE MECHANISMS UNDERLYING THE DEVELOPMENT OF NAFLD AND NON-ALCOHOLIC STEATOHEPATITIS (NASH) IS OF EXTREME IMPORTANCE; DESPITE ADVANCES IN THIS FIELD, KNOWLEDGE ON THE PATHOGENESIS OF NAFLD IS STILL INCOMPLETE. THE 'TWO-HIT' HYPOTHESIS IS NOW OBSOLETE, AS IT IS INADEQUATE TO EXPLAIN THE SEVERAL MOLECULAR AND METABOLIC CHANGES THAT TAKE PLACE IN NAFLD. THE "MULTIPLE HIT" HYPOTHESIS CONSIDERS MULTIPLE INSULTS ACTING TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO INDUCE NAFLD AND PROVIDES A MORE ACCURATE EXPLANATION OF NAFLD PATHOGENESIS. SUCH HITS INCLUDE INSULIN RESISTANCE, HORMONES SECRETED FROM THE ADIPOSE TISSUE, NUTRITIONAL FACTORS, GUT MICROBIOTA AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE REVIEW THE FACTORS THAT FORM THIS HYPOTHESIS. 2016 16 4709 35 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 17 5772 41 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 18 3269 34 HEPATOCELLULAR CARCINOMA IN ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER DISEASE-ONE OF A KIND OR TWO DIFFERENT ENEMIES? HEPATOCELLULAR CANCER (HCC) IS A CANCER WITH AN OVERALL POOR PROGNOSIS AND AN ALARMING GLOBALLY RISING INCIDENCE. WHILE VIRAL ETIOLOGY OF CHRONIC LIVER DISEASE AND HCC IS DOWN-TRENDING, ALCOHOL AND EXCESS CALORIE INTAKE HAVE EMERGED AS MAJOR CULPRITS. ALCOHOL RELATED LIVER DISEASE (ALD) AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) SHARE SIMILAR PATHOGENETIC MECHANISM OF HEPATIC INJURY AND IN PROMOTING DEVELOPMENT OF HCC; YET SOME GENETIC AND EPIGENETIC FEATURES ARE DISTINCT AND MAY PROMISE CLINICAL UTILITY. POPULATION BASED INTERVENTION ARE URGENTLY NEEDED TO REDUCE ALCOHOL USE AND IMPROVE METABOLIC FACTORS SUCH AS OBESITY AND DIABETES. THE GOAL IS TO IDENTIFY AT-RISK PATIENTS, TO LINK THESE PATIENTS TO CARE AND TO PROVIDE EFFECTIVE MANAGEMENT OF CHRONIC LIVER DISEASE AND HCC. THIS REVIEW FOCUSES ON THE EPIDEMIOLOGY, PATHOPHYSIOLOGY INCLUDING GENETIC AND EPIGENETIC ALTERCATION AS WELL AS CLINICAL ASPECTS OF ALD AND NAFLD ASSOCIATED HCC. 2019 19 4108 25 MECHANISMS AND DISEASE CONSEQUENCES OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CHRONIC LIVER DISEASE WORLDWIDE. ITS MORE ADVANCED SUBTYPE, NONALCOHOLIC STEATOHEPATITIS (NASH), CONNOTES PROGRESSIVE LIVER INJURY THAT CAN LEAD TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HERE WE PROVIDE AN IN-DEPTH DISCUSSION OF THE UNDERLYING PATHOGENETIC MECHANISMS THAT LEAD TO PROGRESSIVE LIVER INJURY, INCLUDING THE METABOLIC ORIGINS OF NAFLD, THE EFFECT OF NAFLD ON HEPATIC GLUCOSE AND LIPID METABOLISM, BILE ACID TOXICITY, MACROPHAGE DYSFUNCTION, AND HEPATIC STELLATE CELL ACTIVATION, AND CONSIDER THE ROLE OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT PROMOTE FIBROSIS PROGRESSION AND RISK OF HEPATOCELLULAR CARCINOMA IN NASH. 2021 20 3265 30 HEPATOCARCINOMA: GENETIC AND EPIGENETIC FEATURES. HCC IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE, ACCOUNTING FOR ABOUT 1 MILLION DEATHS ANNUALLY. THE INCIDENCE OF HCC IS HIGHEST IN ASIA AND AFRICA, WHERE THE ENDEMIC HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C STRONGLY PREDISPOSES TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE AND SUBSEQUENT DEVELOPMENT OF HCC. PATIENTS WITH HCC GENERALLY PRESENT AT AN ADVANCED STAGE DUE TO COMPENSATED CIRRHOSIS DEFINED BY THE ABSENCE OF PATHOGNOMONIC SYMPTOMS, RESULTING IN DEATH WITHIN 6 TO 20 MONTHS, SUGGESTING AN URGENT NEED IN TREATMENT MODALITIES THAT WILL DRAMATICALLY DECREASE THE MORTALITY RATE OF HCC. THE MOLECULAR HEPATOCARCINOGENESIS IS, HOWEVER, A GRADUAL PROCESS DURING WHICH GENETIC ALTERATIONS PROGRESSIVELY ACCUMULATE AND LEAD TO HCC THROUGH INTERMEDIATE PRENEOPLASTIC STAGES. WITH THE ADVENT OF WHOLE GENOME SEQUENCING TOOLS, VARIOUS MUTATIONS ASSOCIATED WITH HCC HAVE BEEN IDENTI FI ED, WHICH HAVE ADVANCED OUR MOLECULAR UNDERSTANDING OF HCC. HOWEVER, THE FREQUENCY OF THESE MUTATIONS IS RARE, AND THESE GENETIC MUTATIONS ONLY PARTLY EXPLAIN THE ETIOLOGY OF THE DISEASE. BETTER UNDERSTANDING AND CHARACTERIZATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS, WHICH ARE IMPORTANT TO HEPATOCARCINOGENESIS, MAY HELP UNDERSTAND THE MOLECULAR PATHOGENESIS OF HCC, AS WELL AS PROVIDING NOVEL THERAPEUTIC TARGETS FOR HCC TREATMENT. FURTHER CONSIDERATION SHOULD BE GIVEN TO DEVELOPING MORE EFFECTIVE MOLECULAR DIAGNOSTIC MARKERS AND TARGETED DRUG THERAPY. 2018