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

Hepatology, Год журнала: 2023, Номер 77(5), С. 1797 - 1835

Опубликована: Фев. 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

Язык: Английский

---

Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites

Gut, Год журнала: 2020, Номер 70(4), С. 761 - 774

Опубликована: Июль 21, 2020

Objective Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary cholesterol in driving NAFLD–HCC through modulating gut microbiota and its metabolites. Design High-fat/high-cholesterol (HFHC), high-fat/low-cholesterol or normal chow diet was fed to C57BL/6 male littermates for 14 months. Cholesterol-lowering drug atorvastatin administered HFHC-fed mice. Germ-free mice were transplanted with stools from different diets determine direct modulated-microbiota NAFLD–HCC. Gut analysed by 16S rRNA sequencing serum metabolites liquid chromatography–mass spectrometry (LC–MS) metabolomic analysis. Faecal microbial compositions 59 hypercholesterolemia patients 39 healthy controls. Results High led sequential progression steatosis, steatohepatitis, fibrosis eventually HCC mice, concomitant insulin resistance. Cholesterol-induced formation associated dysbiosis. The composition clustered distinctly along stages steatohepatitis HCC. Mucispirillum, Desulfovibrio, Anaerotruncus Desulfovibrionaceae increased sequentially; while Bifidobacterium Bacteroides depleted which corroborated human hypercholesteremia patients. Dietary induced bacterial alteration including taurocholic acid decreased 3-indolepropionic acid. gavaged HFHC manifested hepatic lipid accumulation, inflammation cell proliferation. Moreover, restored cholesterol-induced dysbiosis completely prevented development. Conclusions drives inducing Cholesterol inhibitory therapy manipulation may be effective strategies prevention.

Язык: Английский

---

NAFLD and cardiovascular diseases: a clinical review

Clinical Research in Cardiology, Год журнала: 2020, Номер 110(7), С. 921 - 937

Опубликована: Июль 21, 2020

Abstract Non-alcoholic fatty liver DISEASE (NAFLD) is the most common chronic disease in Western countries and affects approximately 25% of adult population. Since NAFLD frequently associated with further metabolic comorbidities such as obesity, type 2 diabetes mellitus, or dyslipidemia, it generally considered hepatic manifestation syndrome. In addition to its potential cause liver-related morbidity mortality, also subclinical clinical cardiovascular (CVD). Growing evidence indicates that patients are at substantial risk for development hypertension, coronary heart disease, cardiomyopathy, cardiac arrhythmias, which clinically result increased mortality. The natural history variable vast majority will not progress from simple steatosis fibrosis end stage disease. However, progressive forms NAFLD, including non-alcoholic steatohepatitis (NASH) and/or advanced fibrosis, well concomitant types highest CVD. This review describes underlying pathophysiological mechanisms linking CVD, discusses role a dysfunction factor, focuses on manifestations patients.

Язык: Английский

---

Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy

Antioxidants, Год журнала: 2021, Номер 10(2), С. 174 - 174

Опубликована: Янв. 26, 2021

Oxidative stress (OxS) is considered a major factor in the pathophysiology of inflammatory chronic liver diseases, including non-alcoholic disease (NAFLD). Chronic impairment lipid metabolism closely related to alterations oxidant/antioxidant balance, which affect metabolism-related organelles, leading cellular lipotoxicity, peroxidation, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Increased OxS also triggers hepatocytes pathways, inflammation fibrogenesis, contributing progression steatohepatitis (NASH). The antioxidant response, regulated by Nrf2/ARE pathway, key component this process counteracts oxidative stress-induced damage, restoration normal metabolism. Therefore, modulation response emerges as an interesting target prevent NAFLD development progression. This review highlights link between disturbed context NAFLD. In addition, emerging potential therapies based on effects their likely molecular targets are discussed.

Язык: Английский

---

RETRACTED ARTICLE: Role of the gut microbiome in chronic diseases: a narrative review

European Journal of Clinical Nutrition, Год журнала: 2021, Номер 76(4), С. 489 - 501

Опубликована: Сен. 28, 2021

Язык: Английский

---

Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2021, Номер 18(12), С. 835 - 856

Опубликована: Сен. 10, 2021

Язык: Английский

---

Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits

Journal of Hepatology, Год журнала: 2022, Номер 77(4), С. 1136 - 1160

Опубликована: Июнь 22, 2022

Язык: Английский

---

Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health—Pathophysiology and Therapeutic Strategies

Gastroenterology, Год журнала: 2020, Номер 160(2), С. 573 - 599

Опубликована: Ноя. 27, 2020

Язык: Английский

---

Role of Insulin Resistance in MAFLD

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(8), С. 4156 - 4156

Опубликована: Апрель 16, 2021

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as dysfunction-associated (MAFLD). Metabolic this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and syndrome, with insulin resistance common pathophysiology. Imbalance between energy intake expenditure results various tissues alteration gut microbiota, resulting fat accumulation liver. The role genetics also been revealed hepatic fibrosis. In process liver, intracellular damage well further potentiates inflammation, fibrosis, carcinogenesis. Increased lipogenic substrate supply from other tissues, zonation Irs1, factors, including ER stress, play crucial roles increased de novo lipogenesis MAFLD resistance. Herein, we provide an overview factors contributing systemic local progression MAFLD.

Язык: Английский

---

MASLD: a systemic metabolic disorder with cardiovascular and malignant complications

Gut, Год журнала: 2024, Номер unknown, С. gutjnl - 330595

Опубликована: Янв. 16, 2024

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic globally and is currently estimated to affect up 38% of global adult population. NAFLD a multisystem where systemic insulin resistance related metabolic dysfunction play pathogenic role in development its relevant liver-related morbidities (cirrhosis, failure hepatocellular carcinoma) extrahepatic complications, such as cardiovascular (CVD), type 2 diabetes mellitus, kidney disease, certain types cancers. In 2023, three large multinational associations proposed that dysfunction-associated steatotic (MASLD) should replace term NAFLD; name chosen non-alcoholic steatohepatitis was (MASH). Emerging epidemiological evidence suggests an excellent concordance rate between MASLD definitions—that is, ~99% individuals with meet criteria. this narrative review, we provide overview literature on (a) recent data risk developing CVD malignant (b) underlying mechanisms by which (and factors strongly linked MASLD) may increase these complications (c) diagnosis assessment potential treatments reduce people or MASH.

Язык: Английский

---