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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American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings

Endocrine Practice, Journal Year: 2022, Volume and Issue: 28(5), P. 528 - 562

Published: May 1, 2022

Language: Английский

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NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications

Gut, Journal Year: 2020, Volume and Issue: 69(9), P. 1691 - 1705

Published: April 22, 2020

Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to third of the world's adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) associated with higher risk all-cause mortality and leading causes death among patients are cardiovascular diseases (CVDs), followed by extrahepatic malignancies liver-related complications. A growing body evidence also indicates strongly an increased major CVD events other cardiac complications (ie, cardiomyopathy, valvular calcification arrhythmias), independently traditional factors. This narrative review provides overview literature on: (1) for association between cardiovascular, arrhythmic complications, (2) putative pathophysiological mechanisms linking (3) current pharmacological treatments might benefit or adversely affect CVD.

Language: Английский

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The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD)

Journal of Diabetes Research, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 16

Published: Aug. 4, 2020

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, vice versa. This complex intricate association is supported mediated insulin resistance (IR). In this review, we discuss NAFLD immunopathogenesis, connection IR T2DM, role screening noninvasive tools, mostly impact current antidiabetic drugs on steatosis new potential therapeutic targets.

Language: Английский

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Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus

Nature Reviews Endocrinology, Journal Year: 2021, Volume and Issue: 17(8), P. 484 - 495

Published: June 15, 2021

Language: Английский

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EASL–EASD–EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 81(3), P. 492 - 542

Published: June 7, 2024

Language: Английский

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Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited After a Decade

Hepatology, Journal Year: 2020, Volume and Issue: 73(2), P. 833 - 842

Published: Aug. 12, 2020

Nonalcoholic fatty liver disease (NAFLD) is an epidemic disease, affecting approximately one quarter of the entire population in world.(1) This encompasses a broad spectrum clinical phenotypes ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrotic NASH, advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Although inflammation NAFLD appears less prognostically relevant when compared fibrosis,(2) latter may be cumulative result former.(3) Noninvasive assessment fibrosis (e.g., by transient elastography) has reduced need for invasive procedures such as biopsy,(4) although late-stage trials still require histologic endpoints. The plays crucial role glucose lipid metabolism. frequently present obesity reflects risk factor many metabolic diseases type 2 diabetes (T2D).(5) In turn, T2D associated with up 90% patients. been linked various extrahepatic disorders cardiovascular complications(6) chronic kidney disease.(7) Furthermore, not only major HCC but also increased rate malignancies gastrointestinal gynecological malignancies.(4) cancer seems even higher than itself.(8) As such, prototypic systemic disorder targeting organs throughout body. pathophysiology underlying this complex incompletely understood. A decade ago, we proposed multiple parallel hits hypothesis which lipotoxicity adipose tissue (AT) alterations gut microbial functions contribute evolution NAFLD.(9) Progress over last was substantial that AT inflammation(10) microbiome (and related metabolites) evolved players pathogenesis NAFLD.(11, 12) dietary components other proinflammatory potential have identified. Finally, genetic pathways play manifestation; several hits, patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, membrane-bound O-acyltransferase 7, hydroxysteroid 17-beta dehydrogenase 13, are involved especially metabolism.(13) review, will discuss pathophysiological factors focusing on intricate triangular interplay between tract, AT, liver. Normal composed adipocytes, fibroblasts, endothelial cells, resident macrophages cells immune system collectively regulate host metabolism energy storage.(14) White depots comprise visceral (VAT) subcutaneous (SAT), which, together liver, participate acid health, communicates control homeostasis.(15) obesity, characterized cytokine chemokine expression infiltration example, leukocytes, serve fuel local inflammation. inflammatory state contributes inflammation, deteriorate insulin resistance, exemplifying aspects AT–liver axis.(9, 10) hallmarks influx macrophages, cluster differentiation 4–positive (CD4+) CD8+ T dendritic natural killer (NK) cytokines/chemokines.(16) Primary cues remain poorly explored arguably involve diet-induced stress subsequently induces response cell infiltration. initial fueled self-maintained tissue-infiltrating cells. For recruitment (ATMs) dependent chemokines C-C motif ligand (CCL2), expressed obese animals patients.(17) Adaptive immunity cells) recruited antigen-presenting precedes ATM accumulation.(18) Expression (besides CCL2) CCL5 (also known regulated upon activation, normal expressed, secreted) or CCL13 patients.(19) Importantly, most these cytokines tumor necrosis alpha (TNFα), interleukin 1-beta (IL-1β), IL-6. TNFα first described adipokine obesity-related resistance murine models, its human obesity.(20) Similarly, preclinical evidence indicated key IL-1β IL-1α-deficient, IL-1β-deficient, 1 IL-1 receptor–deficient mice protected against high-fat diet–induced resistance(21); expression.(22) IL-37, anti-inflammatory family member, highly subjects able improve experimental models.(23, 24) IL-6 produced mostly ATMs adipocytes.(25) importance SAT source circulating convincingly demonstrated, 15%-35% being derived tissue.(26) Both VAT produce large amounts disorders, both sources biologically affect sensitivity.(27) We investigated morbidly patients undergoing bariatric surgery. TNFα, IL-1β, IL-6, strongly after successful weight loss.(23, 28) adiponectin leptin (prototypic immunomodulatory adipokines) critically disorders.(29) Collectively, studies highlight cellular, cytokine, adipokine. networks (see Fig. 1). Clinical provide cellular molecular correlate degree disease. Du Plessis colleagues studied transcriptomic profiles VAT, functional characteristics ATMs, severity 113 surgery.(30) They found genes comparing NASH. NASH exhibited number CD11c+CD206+ (C-C motif) receptor–positive accompanied release chemokines. Most importantly, directly correlated inflammation.(30) study investigating 3,197 participants observed independently obesity.(31) no proof concept NAFLD, they clearly link light (mechanistic) report axis disorders. Insulin hallmark NAFLD,(32) occurs tissues muscle, AT.(33) While it commonly conceived emerges consequent recent demonstrated through monocyte chemoattractant protein 1–regulated leukocyte recruitment.(34) These findings interesting accelerates lipolysis mitogen-activated kinase (MAPK) signaling, results activation ß3-adrenergic receptor.(35) Lipolysis enhanced free export promoting potentially NAFLD. line this, correlates (especially fibrosis); improvement pioglitazone, peroxisome proliferator–activated receptor-gamma agonist, resulted decrease hepatocyte ballooning patients.(36) Indeed, NAFLD.(37) study, authors established macrophage measuring soluble CD183, proposing acids might involved. support crosstalk aforementioned notable, descriptive can indirect mammals. Bijnen transplanted lean, obese, ATM-depleted lean Ldr−/− mice.(38) transplantation injury pronounced AT. Liver paralleled numbers neutrophils, effect mainly attributed synthesis neutrophil chemotaxis proteins (C-X-C ligands 14 16 ATM.(38) previously hypothesized tissue-specific knockout (KO) models AT-specific KO mice) would reveal numerous reported took advantage adipocyte-specific mouse models; few discussed here. deletion receptor and/or insulin-like growth severe lipodystrophy progressive resembling dysplastic nodules at week 52.(39) Lipid peroxidation critical mechanism model.(39) deficiency hormone-sensitive lipase causes increase lipodystrophy, impaired synthesis, resistance.(40) contrast, lipoprotein angiopoietin-like 4 (which controls metabolism) attenuates steatosis, atherosclerosis.(41) shown I interferon worsens perturbation, gain, intolerance.(42) However, did impact our model. indicate specific hubs deserve dissected more detail. Various impinge gut–liver axis. shaped metabolites hormones system.(43) section made deciphering intestinal microbiota identification NASH-associated signature,(44) preceded smaller NAFLD.(45) abundance Proteobacteria, Enterobacteriaceae, Escherichia coli differed microbiomes(45); association Bacteroidetes simple healthy controls.(46) Boursier histology-proven 57 patients.(47) Bacteroides depending while Prevotella decreased. convincing example signature comes Loomba colleagues.(44) 86 histologically defined identified 37 bacterial species, allowed them distinguish mild versus fibrosis. Advanced Proteobacteria Firmicutes Faecalibacterium prausnitzii. Such prevalent case cirrhosis.(48) An important bacteria-derived endotoxin disease-contributing had claimed already 20 years ago.(49) confirmed presence livers. Patients concentrations similar accumulation hepatocytes, toll-like macrophages.(50) Further intrahepatic another reporting portal tract.(51) Experimental endotoxin-producing strains Enterobacter cloacae B29, PY102, Klebsiella pneumoniae A7 promoted germ-free diet.(52) Moreover, ethanol-producing isolated caused oral gavaging.(53) Due space constraints, do barrier NAFLD.(54) Vice versa, modulate susceptibility excellently reviewed recently(55) conclusion, overwhelming underpins very exciting rapidly evolving topic (i.e., AT) blood) expands beyond dysbiosis Bacterial 16S ribosomal DNA indeed detected blood, diabetes,(56) blood NAFLD.(57) tissue, material taxa two cohorts NAFLD.(51) Sookoian colleagues(51) severely (similar microbiome). different including solid cancers,(58) T2D, obesity.(59) reminiscent omental, SAT, subjects.(60) Schierwagen central, hepatic, venous peripheral cirrhosis receiving transjugular portosystemic shunt(61); some bacteria could cultivated sites. and, cases, live circulation diseased liver/AT. implications health describe compelling window opportunity research were considered sterile. Metagenomic sequencing metabolite screens (metabolomics) allow insight into repertoire communities. metabolomics recently.(12) Hoyles plasma urine metabolome, fecal metagenome bacteria), transcriptome transcriptional profile) women.(62) phenylacetate) steatosis. Fecal transfer women high-grade feeding phenylacetate mice.(62) search vein dysfunction, Koh discovered imidazole propionate, microbially histidine-derived metabolite.(63) metabolite, propionate affected signaling p38 MAPK phosphorylation p62, finally mechanistic target rapamycin.(63) Levels N,N,N-trimethyl-5-aminovaleric acid, bacteria, serum NAFLD; deteriorated steatosis.(64) Other 3-(4-hydroxphenyl)lactate discriminated without unknown.(65) combination 10 showed powerful discriminatory effects detecting greater diagnostic accuracy Fibrosis-4 index.(66) increasingly recognized intestine, Future fascinating insights bears therapeutic) use. Besides pathways, interactions. Colonic sensitivity under diet.(67) By generating macrophage-specific epithelium–specific mice, decreased colonic permeability, improved tolerance, highlighting gut–AT axis.(67) Interestingly, products commensal L-lactate acetate enterocyte altered storage oxidation.(68) distal effects, influencing lipid-driven atherosclerosis Many exert development NAFLD.(69) Dietary metabolism(70) act microbiome, referred "dysbiosis."(71) so far damage Western diet high fat consumption intake alcohol, salt, refrained grains, fructose, red processed meat developing progressing NAFLD.(69, 72) volunteers endotoxemia low-grade inflammation.(73) Trans-fatty unsaturated vegetables enriched snack foods, fried margarines. Intake trans-fat negatively all-cause mortality coronary heart mortality.(74) well studied. Trans-fat single function tests index.(75) Preclinical data propose trans-fats promote cholesterogenesis,(76) trans-fat-induced if trans-fatty deleted pool, exact mechanisms elusive.(77) Fructose fibrosis.(78) triggers de novo lipogenesis process involves microbiota-derived acetate.(79) subjects, however, excess isocaloric fructose 8 weeks detrimental liver.(80) raises doubts whether damages Wheat amylase trypsin inhibitors, common wheat component, activates macrophages(81) aggravates inflammation.(82) converts nutrients choline carnitine trimethylamine, metabolized flavin monooxygenases trimethylamine N-oxide (TMAO),(83) discontinuation TMAO levels within weeks.(84) Numerous diseases.(85) relationship trial 60 biopsy-proven lower betaine betaine/choline ratio.(86) Administration diet, involving bile farnesoid X antagonism.(87) Therefore, food thereby initiate processes outside tract. oppose above-described pool metabolites. indole, tryptophan derivate microbiota, improves mice; low NAFLD.(88) interventional using either low-sugar diet,(89) carbohydrate-restricted diet,(90) Mediterranean diet(91) beneficial defined. intervention promising strategy treat future.(69) decade, tract emerged drivers Despite fact pathogenesis, randomized controlled specifically lacking. Altered involving, NAFLD.(92) Interactions bidirectional, experiments transgenic exemplified plethora define loss behind metabolism.(33, 54, 93) corroborated 2010 hypothesis,(9) forming based gained animal trials. better understanding translation novel therapeutics endemic gratefully acknowledge Austrian Federal Ministry Science, Research, Economy National Foundation Technology, Development. All contributions discussion content wrote, edited article.

Language: Английский

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Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis

Gut, Journal Year: 2020, Volume and Issue: 71(1), P. 156 - 162

Published: Dec. 10, 2020

Objective Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney (CKD). However, whether this changes with increasing severity NAFLD remains uncertain. We performed meta-analysis observational studies to quantify the magnitude incident CKD. Design systematically searched PubMed, Web Science Scopus from January 2000 August 2020 using predefined keywords identify follow-up duration ≥1 year, in which was diagnosed by blood biomarkers/scores, International Classification Diseases codes, imaging techniques or biopsy. Data selected were extracted, random-effects modelling. Results 13 1 222 032 individuals (28.1% NAFLD) 33 840 cases CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2 , without accompanying overt proteinuria) over median 9.7 years included. associated moderately (n=10 studies; HR 1.43, 95% CI 1.33 1.54; I =60.7%). All risks independent age, sex, obesity, hypertension, diabetes other conventional factors. Sensitivity analyses did not alter these findings. Funnel plot reveal any publication bias. Conclusion This large updated indicates that is significantly a~1.45-fold long-term ≥3. Further are needed examine

Language: Английский

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MAFLD and risk of CKD

Metabolism, Journal Year: 2020, Volume and Issue: 115, P. 154433 - 154433

Published: Nov. 16, 2020

Language: Английский

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The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

Biomolecules, Journal Year: 2020, Volume and Issue: 10(2), P. 347 - 347

Published: Feb. 24, 2020

Chronic kidney disease (CKD) is one of the fastest growing causes death worldwide, emphasizing need to develop novel therapeutic approaches. CKD predisposes acute injury (AKI) and AKI favors progression. Mitochondrial derangements are common features both mitochondria-targeting therapies under study as nephroprotective agents. PGC-1α a master regulator mitochondrial biogenesis an attractive target. Low levels decreased transcription its gene targets have been observed in preclinical (nephrotoxic, endotoxemia, ischemia-reperfusion) experimental human CKD, most notably diabetic nephropathy. In mice, deficiency was associated with subclinical predisposition while overexpression tubular cells protected from diverse causes. Several strategies may increase activity successfully tested animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, anti-TWEAK antibodies. conclusion, low appears be feature recent characterization approaches that pave way for potentially effective CKD.

Language: Английский

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