The utility of radiological imaging in nonalcoholic fatty liver disease

Gastroenterology, Journal Year: 2002, Volume and Issue: 123(3), P. 745 - 750

Published: Aug. 27, 2002

Language: Английский

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AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

Hepatology, Journal Year: 2023, Volume and Issue: 77(5), P. 1797 - 1835

Published: Feb. 2, 2023

PREAMBLE The study of NAFLD has intensified significantly, with more than 1400 publications since 2018, when the last American Association for Study Liver Diseases (AASLD) Guidance document was published.1 This new AASLD reflects many advances in field pertinent to any practitioner caring patients and emphasizes noninvasive risk stratification therapeutics. A separate guideline focused on management context diabetes been written jointly by Clinical Endocrinology AASLD.2 Given significant growth pediatric NAFLD, it will not be covered here allow a robust discussion diagnosis upcoming Pediatric Guidance. "Guidance" differs from "Guideline" that is bound Grading Recommendations, Assessment Development Evaluation system. Thus, actionable statements rather formal recommendations are provided herein. highest available level evidence used develop these statements, and, where high-level available, expert opinion guidance inform clinical practice. Key points highlight important concepts relevant understanding disease its management. most profound practice biomarkers Biomarkers tests (NITs) can clinically either exclude advanced diseases or identify those high probability cirrhosis.3,4 NIT "cut points" vary populations studied, underlying severity, setting. Those proposed this meant aid decision-making clinic interpreted isolation. Identifying "at-risk" NASH (biopsy-proven stage 2 higher fibrosis) recent area interest. Although definitive staging remain linked histology, tools now assess likelihood fibrosis, predict progression decompensation, make decisions, some degree, response treatment. There an ongoing debate over nomenclature fatty liver disease, which had finalized at time published. At culmination rigorous consensus process, intended change advance without negative impact awareness, trial endpoints, drug development/approval process. Furthermore, should emergence newly recognized subtypes address heterogeneity, including role alcohol, therapy. Input central all stages process ensure minimization nomenclature-related stigma. DEFINITIONS overarching term includes grades refers population ≥5% hepatocytes display macrovesicular steatosis absence readily identified alternative cause (eg, medications, starvation, monogenic disorders) individuals who drink little no alcohol (defined as < 20 g/d women <30 men). spectrum NAFL, characterized hepatic may accompanied mild inflammation, NASH, additionally presence inflammation cellular injury (ballooning), finally cirrhosis, bands fibrous septa leading formation cirrhotic nodules, earlier features longer fully appreciated biopsy. UPDATE ON EPIDEMIOLOGY AND NATURAL HISTORY prevalence rising worldwide parallel increases obesity metabolic comorbid (insulin resistance, dyslipidemia, obesity, hypertension).5,6 adults estimated 25%–30% general population7–9 varies setting, race/ethnicity, geographic region studied but often remains undiagnosed.10–14 associated economic burden attributable substantial.15–17 challenging determine certainty; however, 14% asymptomatic undergoing colon cancer screening.14 also highlights publication prior prospective study,18 fibrosis (stage increased >2-fold. supported projected rise 2030, defined bridging (F3) compensated cirrhosis (F4), increase disproportionately, mirroring doubling NASH.5,19 As such, incidence HCC, death related likewise expected 2- 3-fold 2030.5 further, NASH-related already indication transplantation >65 years age par overall.20–22 Natural history Data meta-analyses pooled studies demonstrate steatohepatitis primary predictors progression.23–25 collinearity between induces makes independent contribution adverse outcomes multivariable analyses.26,27 determinant outcomes, liver-related morbidity mortality nonhepatic malignancy observed even initial biopsy.25 Nevertheless, least (F2), referred have demonstrably mortality.24,28 Fibrosis influenced factors such severity genomic profile, environmental factors. meta-analysis placebo-treated 35 trials found minimal progression, suggesting nonpharmacologic (frequent visits/monitoring, dietary lifestyle counseling, changes) reduce progression.29 An cohorts longitudinal paired biopsies30 demonstrated rate one per 7 versus 14 NAFL.30 determined biopsy noninvasively, because changes require biannual screening HCC well varices monitoring signs symptoms decompensation.31,32 Among decompensation ranges 3% 20% year.12,33–35 common causes overall cardiovascular (CVD) malignancy, followed disease. amount histologically strongly development death.24,26,36,37 Bridging exponentially greater fibrosis.23,24,35 In 1773 patients, all-cause 0–2 0.32 100 person-years, compared 0.89 person-years 1.76 cirrhosis. After correcting multiple factors, (HR, 6.8; 95% CI, 2.2–21.3).35 Cirrhosis regression 6-fold reduction events trials.38Key points: Patients F2–4 considered NASH. rates depending baseline genetic, individual environmental, determinants. CVD malignancies fibrosis; predominates fibrosis. MOLECULAR CELLULAR PATHOGENESIS NAFL substantially govern supply disposition acids, diacylglycerols, ceramides, cholesterol, phospholipids, other intrahepatic lipids. Energy oversupply limited adipose tissue expansion contribute insulin resistance disease.39 When energy intake exceeds needs disposal capacity, carbohydrates, form sugars fructose, sucrose, glucose), drive accumulation fat de novo lipogenesis (DNL).40,41 substantial interindividual heterogeneity DNL among NAFLD.42,43 addition, type consumed plays saturated unsaturated consumption (Figure 1).44–46FIGURE 1: Pathogenic drivers therapeutic targets. Overview major mechanisms lead phenotype consequences, leveraged therapeutically. Not shown areas genetic polymorphisms play modifying types fats [saturated vs. polyunsaturated acid (PUFA)], gut microbiome, uric acid, periodic hypoxia (sleep apnea) influence pathways. driver adipocytes their ability store triglyceride inducing cell stress exceeded, activates inflammatory pathways resistance. Understanding facilitates rational therapies Specific sites intervention might prevent resolve include interventions modulate food portion sizes, bariatric surgery, satiety regulators), exercise, thermogenesis), improve adipocyte sensitivity [eg, peroxisome proliferator-activated receptor (PPAR)γ ligands], impair acetyl-coenzyme carboxylase synthase inhibitors), oxidative metabolism (PPARα ligands thyroid hormone beta agonists), attenuate death, fibrogenesis. Therapeutic agents affecting throughout body potential beneficial effects peptide analogs fibroblast factor-19, factor-21, glucagon-like peptide-1, gastric inhibitory peptide, glucagon) nuclear drugs target PPARα, PPARδ, PPARγ, β, farnesoid X receptor. Abbreviations: ER, endoplasmic reticulum; CVD, disease.Insulin nearly universal present liver, tissue, muscle.47 Adipose release free acids (lipolysis) fasting state48 worsens NASH.39,47,49 Important frequency intensity activation brown energy-consuming thermogenic phenotype, counterregulatory diminish reductions calorie intake.39,50 desire engage regular exercise personal, community, corporate, societal, legislative thus roles contributing pathophysiology impeded diagnostic therapeutics.51 driven substrate overload heavily impacting hepatocyte lipid handling.43 Genetic I148M polymorphism PNPLA3 impairs lipolysis droplets,52 proteins transmembrane 6 superfamily member (TM6SF2), cholesterol metabolism,53 MBOAT7, influences phospholipid metabolism.54 Recently, loss-of-function variants HSD17B13, gene encodes enzyme localizes droplets hepatocytes, protection against progressive HCC.55 Rare mutations CIDEB, protein needed DNL,56 protective.57 host additional review beyond scope guidance, activity progression.49,58–63 Additional production, exposure products derived perhaps low magnesium levels, phenotype.64–69 Transcriptomic profiling large further our progression.70,71 lipotoxic recruitment resident macrophages, contributes hepatocellular stellate part complex interplay types.60,72,73 markers consistent finding pathogenesis humans uncertain.74Key Fundamental elements imbalance nutrient delivery utilization coupled dysfunction. Interindividual differences dietary, behavioral, course. Systemic particularly stemming dysfunctional progression. Insulin promotes COMORBID CONDITIONS ASSOCIATED WITH closely precedes abnormalities hypertension).47,61,75–77 Having several confers histological mortality.8,47,78–81 association comorbidities reflect bidirectional interactions endocrine organs pancreas, muscle) through secretion hepatokines regulate metabolism, action, glucose metabolism,82–88 adipokines, myokines.39,89,90 Obesity progression.91–93 Body distribution contributory (Table 1). Android distribution, truncal subcutaneous visceral irrespective mass index (BMI).94–99 contrast, gynoid predominantly hips buttocks, appears protective NAFLD.39,100 Visceral fat, metabolically active mediates majority risk.101–105 becomes stressed, dysfunctional, inflamed, signaling progressively impaired, promoting inappropriate inflammation.47,106,107 TABLE 1 - Initial evaluation patient History Weight history; medical comorbidities; current medications; family T2DM, cirrhosis; OSA; use, amount, pattern duration Physical examination android gynoid, lipodystrophic), dorsal-cervical pad, acanthosis nigricans), firm splenomegaly, prominent abdominal veins, ascites, gynecomastia, spider angiomata, palmar erythema) Laboratory Hepatic panel, CBC platelets, plasma glycated hemoglobin (A1c), creatinine urine microalbumin ratio, hepatitis C if previously screened. Consider appropriate steatosis/steatohepatitis (). elevated chemistries present: autoimmune serologies, transferrin saturation, ceruloplasmin, alpha-1 antitrypsin genotype, CBC, complete blood count; OSA, obstructive sleep apnea; mellitus. Type mellitus (T2DM) T2DM impactful factor HCC.108–111 pathogenic both surprising (ranging 30% 75%)10,112,113 developing fibrosis.93,114–117 T2DM. there length biases, underscore strong relationship NAFLD. epidemiological studies. Early course, sensitivity,47 overt diabetes. 5-fold incident diabetes,75,118–121 therefore, screened progresses, so does failure, making manage.107 glycemic control NAFLD/NASH controversial, small showing poor fibrosis,68,122 whereas corroborated finding.116,117,123 described diabetes, much lower coexistent BMI).124,125 Hypertension commonly hypertension across spectrum, 6.5 early 14.5 cirrhosis.35 clearly additive respect NASH126,127 progression.30 Whether mechanistically inverse, manifestations drivers, established.128,129 Dyslipidemia twice likely exhibit NAFLD,120 serum subfractions atherogenic NAFLD.130,131 resolution improved HDL levels favorably lipoprotein subfractions, although unclear what extent mechanism intervention.132–134 progress they continue coronary artery disease135 despite normalization lipids lipoproteins due synthetic failure.130,136 Management dyslipidemia use moderate-intensity high-intensity statins first-line therapy based atherosclerotic scores. Combination hypolipemic agents, ezetimibe, PCSK-9 inhibitors, inclisiran, bempedoic fibrates, omega 3 icosapent ethyl, monotherapy statin achieve goals. Statins safe demonstrable mortality.137–140 However, practice, underused extensive data demonstrating safety, cirrhosis.141–144 future risk, confirmatory needed.138 safely decompensated statin-induced population,144 caution warranted. transplantation, careful monitoring.136 severely triglycerides >500 mg/dL), combination fibrates prescription grade omega-3 pancreatitis. Fibrates concentrations ≥200 mg/dL HDL-C <40 mg/dL. high-risk individuals, ethyl indicated adjunct risk. Pioglitazone optimization concomitant benefits profile. Caution taken myopathy. Obstructive apnea (OSA) OSA NAFLD,145 suggest histology.146–151 Intermittent hypoxia, critical consequence mitochondrial dysfunction,145 dysregulation metabolism,152,153 worse resistance,154–156 DNL.157 overweight obese polysomnography NAFLD158; independently drives unclear. exists heart arrhythmias, atrial fibrillation.159–167 Perturbed endothelial function, higher-risk nature lesions, impaired ischemic compensatory support link CVD.130,168–170 prospectively observational cohort, cardiac same stages; number relatively low.35 Optimizing goal reducing improving NAFLD.36,171,172 Aggressively treating conditions hypertension, hyperglycemia smoking cessation recommended decrease risk.173 Chronic kidney (CKD) cross-sectional (n=28,000 individuals) 2-fold CKD.174 overall, specifically, microvascular diabetic complications, especially CKD.175,176 Recently published CRN CKD stages.35 determined.Guidance statements: 1. 2. Limited exist safety efficacy could 3. Hypertriglyceridemia managed supplementation fibrates. 4. 5. Prevalence Death thus, adherence age-appropriate survival. INITIAL EVALUATION OF PATIENT incidentally noted imaging chemistries. It note normal values laboratories true alanine aminotransferase (ALT) 29 33 U/L men 19 25 women.177 comorbidities, assessment intake, exclusion physical profile atypical comorbidities) additional/alternate etiologies, less excluded 2). fibrosing isolation explain exaggerated specific contexts 2).178 Several exacerbate during 3). gene-based currently familial aggregation supports gene-environment fibrosis.209,210 consider testing Condition scenario Diagnostic test Treatment Hypobetalipoproteinemia Low LDL, triglycerides, malabsorption ApoB level, (MTTP, PCSK-9) Low-fat diet, fat-soluble vitamin LAL deficiency Markedly LDL-C HDL-C, xanthelasma, hypersplenism, young age, predominately microvesicular Enzyme assay, replacement Nutrient carnitine, choline) Anorexia, short bowel, bypass surgeries Supplementation Wilson Younger neuropsychiatric symptoms, alkaline phosphatase, ceruloplasmin 24-h copper; quantitative copper Chelation Celiac Iron deficiency, pain, bloating, D bone loss, diarrhea, dermatitis herpetiformis Tissue transglutaminase IgA, duodenal Gluten-free diet ApoB, apolipoprotein B; high-density cholesterol; immunoglobulin A; LAL, lysosomal lipase; LDL-C, LDL cholesterol. Drugs mechanistic links Drug Mechanism Histological References Amiodarone Promotion DNL, impairment β-oxidation steatohepatitis, phospholipidosis, 179–184 5-FU Accumulation catabolites capacity metabolize 185–188 Irinotecan Induces dysfunction, autophagy Steatohepatitis 189–194 Tamoxifen Estrogen modulator, promotion β-oxidation. *May Steatosis 195–203 Methotrexate Mitochondrial (inhibits electron transport chain), canals Hering Steatosis, 204–206 Corticosteroids Exacerbation

Language: Английский

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Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis

Gastroenterology, Journal Year: 2003, Volume and Issue: 125(2), P. 437 - 443

Published: Aug. 1, 2003

Language: Английский

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Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease

Free Radical Biology and Medicine, Journal Year: 2020, Volume and Issue: 152, P. 116 - 141

Published: March 8, 2020

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic worldwide and is strongly associated with presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, NADPH oxidase. Mitochondrial function adapts NAFLD mainly through downregulation electron transport chain (ETC) preserved or enhanced capacity mitochondrial acid oxidation, stimulates ROS overproduction within ETC components upstream cytochrome c However, non-ETC sources ROS, particular, β-oxidation, appear produce more metabolic diseases. Endoplasmic reticulum stress oxidase alterations are also NAFLD, but degree their contribution remains unclear. Increased generation induces changes insulin sensitivity expression activity key enzymes involved metabolism. Moreover, interaction between redox signaling innate immune forms a complex network that regulates inflammatory responses. Based on mechanistic view described above, this review summarizes mechanisms may account for excessive production potential roles drive progression, therapeutic interventions related

Language: Английский

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Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: a Review of Shared Cardiometabolic Risk Factors

Hypertension, Journal Year: 2022, Volume and Issue: 79(7), P. 1319 - 1326

Published: June 8, 2022

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rising. NAFLD/nonalcoholic steatohepatitis (NASH) associated not only with hepatic morbidity and mortality but also an increased cardiovascular risk. NAFLD (CVD) share several risk factors, such as obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, chronic kidney disease. This review summarizes the evidence linking cardiometabolic factors in context for CVD. cause NAFLD/NASH complex, involving a range from genetics to lifestyle energy balance. Genetically driven high fat content does appear be causally CVD In contrast, dysfunction predisposes pathology leads significantly higher Given that pathophysiology influenced by multiple each patient unique their developing pathology. At same time, rising burden closely linked global increase disorders, including obesity diabetes. Therefore, both personalized therapeutic approaches recognize individual pathophysiology, well public health policies address root causes may needed effectively epidemic.

Language: Английский

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Prediction of MAFLD and NAFLD using different screening indexes: A cross-sectional study in U.S. adults

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 19, 2023

Introduction Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as non-alcoholic (NAFLD), has become the most common chronic worldwide. We aimed to explore gender-related association between nine indexes (BMI/WC/VAI/LAP/WHtR/TyG/TyG-BMI/TyG-WC/TyG-WHtR) and MAFLD/NAFLD examine their diagnostic utility for these conditions. Methods Eligible participants were screened from 2017-2018 cycle data of National Health Nutrition Examination Survey (NHANES). Logistic regression receiver operating characteristic (ROC) curve used assess predictive performance 9 MAFLD/NAFLD. Results Among 809 eligible individuals, 478 had MAFLD 499 NAFLD. After adjusting gender, age, ethnicity, FIPR education level, positive associations with risk found all indexes. For female, TyG-WHtR presented best in identifying MAFLD/NAFLD, AUC 0.845 (95% CI = 0.806-0.879) 0.831 0.791-0.867) respectively. male, TyG-WC 0.900 0.867-0.927) 0.855 0.817-0.888) Conclusion BMI/WC/VAI/LAP/WHtR/TyG/TyG-BMI/TyG-WC/TyG-WHtR are important identify

Language: Английский

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TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation

Cell Metabolism, Journal Year: 2020, Volume and Issue: 31(4), P. 726 - 740.e8

Published: April 1, 2020

Language: Английский

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Nonalcoholic Fatty Liver Disease: An Emerging Driver of Cardiac Arrhythmia

Circulation Research, Journal Year: 2021, Volume and Issue: 128(11), P. 1747 - 1765

Published: May 27, 2021

Cardiac arrhythmias and the resulting sudden cardiac death are significant cardiovascular complications that continue to impose a heavy burden on patients society. An emerging body of evidence indicates nonalcoholic fatty liver disease (NAFLD) is closely associated with risk arrhythmias, independent other conventional cardiometabolic comorbidities. Although most studies focus relationship between NAFLD atrial fibrillation, associations ventricular conduction defects have also been reported. Mechanistic investigations suggest number NAFLD-related pathophysiological alterations may potentially elicit structural, electrical, autonomic remodeling in heart, contributing arrhythmogenic substrates heart. now common metabolic world. However, upsurge prevalence as an factor for has received little attention. In this review, we summarize clinical putative mechanisms roles purpose highlighting notion serve potential driving force development progression arrhythmias.

Language: Английский

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Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3

Circulation, Journal Year: 2022, Volume and Issue: 145(5), P. 375 - 391

Published: Jan. 31, 2022

High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high associated with nonalcoholic fatty liver disease, which an independent diseases, it remains elusive whether salt-induced hepatic damage leads to development of diseases.Mice were fed normal or high-salt diet 8 weeks determine effect loading on histological changes and blood pressure, withdrawal metformin treatment also conducted some diet-fed mice. Adeno-associated virus 8, global knockout, tissue-specific knockout mice used manipulate expression target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related 2), AMPK (AMP-activated protein kinase).Mice a displayed obvious steatosis inflammation, accompanied hypertension cardiac dysfunction. All these pathological persisted after withdrawal, displaying memory phenomenon. Gene analysis phenotypes revealed reduced was chief culprit responsible persistent inflammation liver, recovering effectively inhibits sustained damage. Mechanistical studies reveal increases acetylated histone 3 lysine 27 (H3K27ac) promoter hepatocytes, thus inhibiting binding NRF2, results inhibition expression. Treatment activated AMPK, inhibited inflammatory by lowering H3K27ac level promoter, increased ability activate expression.This study demonstrates caused modification key contributes under loading. Avoidance excessive active intervention epigenetic may help stave off status underlies high-salt-induced practice.

Language: Английский

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Nonalcoholic fatty liver disease or metabolic dysfunction‐associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches

European Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 51(7)

Published: Feb. 14, 2021

A consensus of experts has proposed to replace the term nonalcoholic fatty liver disease (NAFLD), whose global prevalence is 25%, with metabolic dysfunction-associated (MAFLD), describe more appropriately related derangements. MAFLD closely intertwined type 2 diabetes, obesity, dyslipidaemia, all linked a rise in risk cardiovascular (CVDs). Since controversy still stands on whether or not NAFLD/MAFLD raises odds CVD, present review aims evaluate impact aetiologies CV health and potential correction by dietary drug approaches.Epidemiological studies indicate that NAFLD fatal non-fatal CVD events. patients have higher arterial plaques stiffness, coronary calcification, endothelial dysfunction. Although genetic environmental factors strongly contribute pathogenesis, Mendelian randomization analysis indicated PNPLA3 variant leading may be causally associated risk. Among other variants NAFLD, TM6SF2 appears protective, whereas MBOAT7 favour venous thromboembolism.NAFLD correlated which ameliorated interventions. This surprising, since new criteria defining include abnormalities fuelling development serious adverse extrahepatic outcomes, for example CVD. The lack targeted pharmacological approach makes identification at (eg hypertension, obesity high levels C-reactive protein) major clinical interest.

Language: Английский

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