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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Current epidemiology in hepatocellular carcinoma

Expert Review of Gastroenterology & Hepatology, Journal Year: 2021, Volume and Issue: 15(11), P. 1295 - 1307

Published: Oct. 10, 2021

Hepatocellular carcinoma (HCC) is the sixth most common cancer and third-leading cause of cancer-related mortality in world.This review will discuss risk factors, demographic differences, global trends, economic burden HCC. Viral hepatitis, particularly hepatitis B virus (HBV) infection, underlying liver disease leading to HCC those with cirrhosis. Other important factors include alcoholic disease, nonalcoholic fatty metabolic syndrome, etc. With introduction direct-acting antiviral agents for C routine vaccination against HBV, increasing support robust public screening programs, incidence rates due viral falling many countries. Meanwhile, prevalence obesity syndrome are on rise, as NAFLD-related incidence. Asia Africa have highest In multiethnic countries, racial ethnic minorities experience disparities well mortality, representing an essential area improvement terms healthcare inequity.Interventions minimize aim reduce implement effective treatment etiology comprehensive programs

Language: Английский

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Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11629 - 11629

Published: Oct. 27, 2021

Obesity is now a worldwide epidemic ensuing an increase in comorbidities' prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes death world. Several studies provide evidence for association between MAFLD atherosclerosis cardio-metabolic disorders, including CVDs coronary heart stroke. Therefore, combination MAFLD/NASH associated with vascular risk progression, but underlying mechanisms linking are still under investigation. may probably be involved, hepatic/systemic atherogenic dyslipidemia, well pro-atherogenic, pro-coagulant, pro-inflammatory mediators released from steatotic/inflamed liver. strongly which involved its pathogenesis progression to NASH. Insulin resistance major factor subjects without diabetes. However, T2D has been considered most common link CVD. This review summarizes obesity MAFLD, NASH, CVD, considering pathophysiological molecular these diseases. We also discuss NASH development structural functional cardiac alterations, pharmacological strategies treat prevention.

Language: Английский

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Are there outcome differences between NAFLD and metabolic‐associated fatty liver disease?

Hepatology, Journal Year: 2022, Volume and Issue: 76(5), P. 1423 - 1437

Published: April 1, 2022

Given the association of NAFLD with metabolic risks, a name change to MAFLD is proposed. We compared long-term outcomes and MAFLD.We included patients fatty liver disease (FLD) from NHANES III 2017-2018 (FLD defined as moderate severe hepatic steatosis by ultrasound for having controlled attenuation parameter ≥285 dB/m 2017-2018). was FLD without other diseases excess alcohol use. Metabolic-associated (MAFLD) dysfunction per criteria. All participants had linked mortality data through December 31, 2015.NHANES (n = 12,878): mean age 43.1 years old; 49.5% male; 20.3% FLD, 16.5% NAFLD, 18.1% MAFLD. 4328): 48.0 49.1% 36.8% 34.2% 36.3% Excellent concordance noted between diagnosis in both sets (kappa coefficient 0.83-0.94). Except components each definition (e.g., use MAFLD), no major differences clinical characteristics were noted. During up 27 follow-up (median 22.8 years), cumulative all-cause cause-specific In addition stage fibrosis, insulin resistance predictor alcohol-associated (ALD) MAFLD.MAFLD have similar profiles outcomes. The increased liver-related among driven resistance, primarily ALD.

Language: Английский

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Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002–2033: the ITA.LI.CA database

Gut, Journal Year: 2021, Volume and Issue: 72(1), P. 141 - 152

Published: Dec. 21, 2021

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum diseases associated to metabolic disorders. The main objective this study was compare patients with MAFLD and non-MAFLD hepatocellular carcinoma (HCC) included in nationally representative cohort.We analysed 6882 consecutive HCC enrolled from 2002 2019 by 23 Italian Liver Cancer centres epidemiological future trends three subgroups: pure, single aetiology (S-MAFLD); mixed (metabolic others, M-MAFLD); HCC.MAFLD diagnosed majority (68.4%). proportion both total S-MAFLD significantly increased over time (from 50.4% 3.6% 2002-2003, 77.3% 28.9% 2018-2019, respectively, p<0.001). In Italy is expected overcome M-MAFLD about 6 years. Patients were older, more frequently men less cirrhotic clinically relevant portal hypertension surveillance-related diagnosis. They had large tumours extrahepatic metastases. After weighting, compared non-MAFLD, showed lower overall (p=0.026, p=0.004) HCC-related (p<0.001, for both) risk death. higher non-HCC-related death (p=0.006).The prevalence rapidly increasing cover HCC. Despite favourable cancer stage at diagnosis, have death, suggesting reduced aggressiveness.

Language: Английский

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Potential screening indicators for early diagnosis of NAFLD/MAFLD and liver fibrosis: Triglyceride glucose index–related parameters

Frontiers in Endocrinology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 2, 2022

Importance Homeostatic model assessment for insulin resistance (HOMA-IR) and triglyceride glucose (TyG) index–related parameters [TyG index, glucose–waist circumference (TyG-WC), glucose–waist-to-height ratio (TyG-WHtR), glucose–body mass index (TyG-BMI)] are gradually considered as convenient alternative indicators in various metabolic diseases, but the specific diagnostic capacity comparison of non-alcoholic fatty liver disease (NAFLD), metabolic-associated (MAFLD), fibrosis remain uncertain. Objective To comprehensively assess compare accuracy above NAFLD, MAFLD, identify appropriate indicators. Methods A total 1,727 adults were enrolled from 2017–2018 National Health Nutrition Examination Surveys. Logistic regressions used to significantly associated with fibrosis; receiver operating characteristic (ROC) curves evaluate their capacity. Subgroup analyses conducted validate concordance, optimal cutoff values determined according Youden’s indexes. Results Significant differences observed between quartile-stratified HOMA-IR TyG across ( P &lt; 0.05). All variables predictive different states The top three AUC TyG-WC, TyG-WHtR, TyG-BMI AUCs 0.815, 0.809, 0.804 NAFLD. 822.34, 4.94, 237.77, respectively. Similar same trend indexes could be MAFLD fibrosis. showed consistent results primary research, despite some heterogeneity. Conclusions can early screening NAFLD MAFLD. These more suitable assessing risks monitoring progression patients

Language: Английский

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Metabolic dysfunction-associated fatty liver disease and implications for cardiovascular risk and disease prevention

Cardiovascular Diabetology, Journal Year: 2022, Volume and Issue: 21(1)

Published: Dec. 3, 2022

The newly proposed term "metabolic dysfunction-associated fatty liver disease" (MAFLD) is replacing the old "non-alcoholic (NAFLD) in many global regions, because it better reflects pathophysiology and cardiometabolic implications of this common disease. change terminology from NAFLD to MAFLD not simply a single-letter an acronym, since defined by set specific positive diagnostic criteria. In particular, definition specifically incorporates within classification recognized cardiovascular risk factors. Although convincing evidence supports significant association between both MAFLD, with increased CVD morbidity mortality, neither nor have received sufficient attention Cardiology community. fact, there paucity scientific guidelines focusing on burdensome disease professional societies. This Perspective article discusses rationale clinical relevance for Cardiologists definition.

Language: Английский

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The intersection between alcohol-related liver disease and nonalcoholic fatty liver disease

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2023, Volume and Issue: 20(12), P. 764 - 783

Published: Aug. 15, 2023

Language: Английский

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An international multidisciplinary consensus statement on MAFLD and the risk of CVD

Hepatology International, Journal Year: 2023, Volume and Issue: 17(4), P. 773 - 791

Published: May 19, 2023

Language: Английский

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Metabolic dysfunction-associated steatotic liver disease increases the risk of incident cardiovascular disease: a nationwide cohort study

EClinicalMedicine, Journal Year: 2023, Volume and Issue: 65, P. 102292 - 102292

Published: Oct. 28, 2023

The various subcategories under the overarching term of steatotic liver disease (SLD) have been recently proposed by nomenclature consensus group and endorsed international academic societies. Our aim was to investigate association between each subtype SLD incident cardiovascular (CVD) in a nationwide Korean cohort.

Language: Английский

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