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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The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review

Nutrients, Journal Year: 2020, Volume and Issue: 12(6), P. 1899 - 1899

Published: June 26, 2020

Exercise is an effective strategy for preventing and treating obesity its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution energy substrates, optimization global expenditure, enhancement hypothalamic circuits that control appetite-satiety decreased systemic inflammation insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, osteokines, immune cytokines adipokines are hypothesized to play important role the body’s response exercise. To our knowledge, no review has provided a comprehensive integrative overview these novel molecular players mechanisms involved metabolic fuel during after exercise, weight reduced inflammation. In this review, we explain potential namely such as irisin, IL-6, IL-15, METRNL, BAIBA, myostatin, particular selenoprotein P, fetuin A, FGF21, ANGPTL4, follistatin. We also describe function specifically osteocalcin, leptin, adiponectin, resistin. emphasize pleiotropic mechanisms, pathways, inter-organ crosstalk mass loss, inflammation, healthy induced by

Language: Английский

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Hepatokines and metabolism: Deciphering communication from the liver

Molecular Metabolism, Journal Year: 2020, Volume and Issue: 44, P. 101138 - 101138

Published: Dec. 4, 2020

The liver is a key regulator of systemic energy homeostasis and can sense respond to nutrient excess deficiency through crosstalk with multiple tissues. Regulation by the mediated in part regulation glucose lipid metabolism. Dysregulation either process may result metabolic dysfunction contribute development insulin resistance or fatty disease.The has recently been recognized as an endocrine organ that secretes hepatokines, which are liver-derived factors signal communicate distant liver-centered inter-organ pathways improper ultimately dysfunction. Deciphering mechanisms regulate hepatokine expression communication tissues essential for understanding therapeutic strategies treat dysfunction.In this review, we discuss liver-centric secretion. We highlight hepatokines their roles control, examine molecular each hepatokine, potential targets disease. also important areas future studies signaling under healthy pathophysiological conditions.

Language: Английский

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Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit

Nature Reviews Endocrinology, Journal Year: 2020, Volume and Issue: 16(9), P. 495 - 505

Published: July 6, 2020

Language: Английский

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Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(5), P. 2639 - 2639

Published: March 5, 2021

Adipose, skeletal, and hepatic muscle tissues are the main endocrine organs that produce adipokines, myokines, hepatokines. These biomarkers can be harmful or beneficial to an organism still perform crosstalk, acting through endocrine, paracrine, autocrine pathways. This study aims review crosstalk between Far beyond understanding actions of each biomarker alone, it is important underline these cytokines act together in body, resulting a complex network different tissues, which may have non-beneficial effects on genesis various physiological disorders their respective outcomes, such as type 2 diabetes mellitus (DM2), obesity, metabolic syndrome, cardiovascular diseases (CVD). Overweight individuals secrete more pro-inflammatory adipokines than those healthy weight, leading impaired immune response greater susceptibility inflammatory infectious diseases. Myostatin elevated environments, sharing space with organokines, tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), resistin, chemerin. Fibroblast growth factor FGF21 acts beta-oxidation regulator decreases lipogenesis liver. The mentioned above interfere homeostatic play role potential therapeutic target assist methods diagnosing syndrome CVD.

Language: Английский

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Pathophysiological Implication of Fetuin-A Glycoprotein in the Development of Metabolic Disorders: A Concise Review

Journal of Clinical Medicine, Journal Year: 2019, Volume and Issue: 8(12), P. 2033 - 2033

Published: Nov. 21, 2019

: Alpha 2-Heremans-Schmid glycoprotein, also known as fetuin-A (Fet-A), is a multifunctional plasma glycoprotein that has been identified in both animal and human beings. The protein hepatokine predominantly synthesized the liver, which considered an important component of diverse normal pathological processes, including bone metabolism regulation, vascular calcification, insulin resistance, protease activity control. Epidemiological studies have already consistently demonstrated significant elevated circulating Fet-A course obesity related complications, such type 2 diabetes mellitus, metabolic syndrome, nonalcoholic fatty liver disorder (NAFLD). Moreover, strongly correlated with many parameters to homeostasis dysregulation, sensitivity, glucose tolerance, lipid levels (non-esterified free acids triglycerides), pro- anti-inflammatory factors (C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin (IL)-6). Metabolic-interfering effects thus shown highly exacerbate resistance (IR) through blocking insulin-stimulated transporter 4 (GLUT-4) translocation kinase B (Akt) activation. Furthermore, appeared interfere downstream phosphorylation events receptor substrate signaling. emerging importance for diagnosis therapeutics therefore come attention researchers pharmaceutical industry, prospect developing new therapeutic strategies methods disorders.

Language: Английский

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The metabolic basis of nonalcoholic steatohepatitis

Endocrinology Diabetes & Metabolism, Journal Year: 2020, Volume and Issue: 3(4)

Published: Feb. 24, 2020

Abstract Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic and associated with significant morbidity mortality worldwide, high incidence in Western countries non‐Western that have adopted diet. NAFLD commonly components the metabolic syndrome, type 2 diabetes mellitus cardiovascular disease, suggesting common mechanistic basis. An inability to metabolically handle free acid overload–metabolic inflexibility–constitutes core node for pathogenesis, resulting lipotoxicity, mitochondrial dysfunction cellular stress leading inflammation, apoptosis fibrogenesis. These responses can lead histological phenotype nonalcoholic steatohepatitis (NASH) varying degrees fibrosis, which progress cirrhosis. This perspective review describes key molecular mechanisms NASH, namely an excessive burden carbohydrates acids contribute lipotoxicity hepatocellular injury Understanding extrahepatic dysmetabolic contributors NASH crucial development safe, effective durable treatment approaches this increasingly disease.

Language: Английский

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Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 18, 2023

Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) a key enzyme cysteine catabolism that enriched in liver, whose role NAFLD remains poorly understood. Here, we show exercise induces expression of hepatic Cdo1 via cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout (Cdo1LKO) decreases basal metabolic rate mice and impairs effect against NAFLD, whereas hepatocyte-specific overexpression (Cdo1LTG) increases synergizes with to ameliorate NAFLD. Mechanistically, tethers Camkk2 AMPK by interacting both them, thereby activating signaling. This promotes acid oxidation mitochondrial biogenesis hepatocytes attenuate hepatosteatosis. Therefore, promoting Camkk2-AMPK pathway, acts as important downstream effector combat

Language: Английский

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Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases

Biomedicines, Journal Year: 2024, Volume and Issue: 12(9), P. 2129 - 2129

Published: Sept. 19, 2024

Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in early 1990s. This revelation unveiled dynamic endocrine function adipose tissue, which has expanded further. emerged recent decades multifunctional that plays significant role energy metabolism homeostasis. Currently, it is evident primarily performs its by secreting diverse array signaling molecules known adipokines. Apart from their pivotal expenditure regulation, these adipokines exert influence over multitude biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, insulin sensitivity. Adipokines are regulating numerous processes within facilitating communication between various organs, brain, gut, pancreas, endothelial cells, liver, muscle, more. Dysregulated have been implicated several metabolic diseases, like obesity diabetes, well cardiovascular diseases. In this article, we attempted describe significance developing diseases highlight crosstalk tissues other organs.

Language: Английский

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The wonder exerkines—novel insights: a critical state-of-the-art review

Molecular and Cellular Biochemistry, Journal Year: 2021, Volume and Issue: 477(1), P. 105 - 113

Published: Sept. 23, 2021

Abstract Several benefits can be acquired through physical exercise. Different classes of biomolecules are responsible for the cross-talk between distant organs. The secretome skeletal muscles, and more widely field organokines, is ever-expanding. “Exerkine” has emerged as umbrella term covering any humoral factors secreted into circulation by tissues in response to This review aims at describing most interesting exerkines discovered last 3 years, which paving way both physiological novel insights potential medical strategies. five identified all play a significant role healthy effect Specifically: miR-1192, released muscles myocardium circulation, modulating cardioprotective trained mice; miR-342-5p, located exosomes from vascular endothelial cells, also miRNA young humans; apelin, involved anti-inflammatory pathways muscle regenerative capacity rats; GDF-15, yet unknown source, whose effects observed on multiple organs men after single bout exercise; oxytocin, myoblasts myotubes, with autocrine paracrine functions myotubes. systemic transport vesicles crosstalk deserve deep investigation. Sources, targets, mechanisms, biological roles, population samples, frequency, intensity, time type exercise should considered characterization existing exerkines. “exercise medicine” framework include favor public health.

Language: Английский

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