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

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NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Nature, Год журнала: 2021, Номер 592(7854), С. 450 - 456

Опубликована: Март 24, 2021

Abstract Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1–5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification patients optimal response to therapy unmet need 6,7 Here we report the progressive accumulation exhausted, unconventionally activated CD8 + PD1 T cells in NASH-affected livers. In preclinical models NASH-induced therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded within tumours did not lead tumour regression, which indicates that immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led increase incidence NASH–HCC and number size nodules, correlated with increased hepatic CXCR6 , TOX TNF cells. The HCC triggered by prevented depletion neutralization, suggesting help induce NASH–HCC, rather than invigorating executing surveillance. We found similar phenotypic functional profiles from humans NAFLD NASH. A meta-analysis three randomized phase III clinical trials tested inhibitors PDL1 (programmed death-ligand 1) more 1,600 advanced revealed improve survival two additional cohorts, NASH-driven who received anti-PDL1 showed reduced overall compared other aetiologies. Collectively, these data show particularly might be less responsive immunotherapy, probably owing NASH-related aberrant cell activation causing tissue damage leads impaired Our provide a rationale according underlying aetiology studies as primary adjuvant treatment.

Язык: Английский

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GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Nature Reviews Endocrinology, Год журнала: 2021, Номер 17(10), С. 592 - 607

Опубликована: Авг. 11, 2021

Язык: Английский

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Impact of non-invasive biomarkers on hepatology practice: Past, present and future

Journal of Hepatology, Год журнала: 2022, Номер 76(6), С. 1362 - 1378

Опубликована: Май 16, 2022

Язык: Английский

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Current therapies and new developments in NASH

Gut, Год журнала: 2022, Номер 71(10), С. 2123 - 2134

Опубликована: Июнь 16, 2022

Non-alcoholic steatohepatitis is becoming the most important aetiology for advanced liver disease. There has been progress in field recent years and complexity of pathophysiology NASH better understood. Multiple non-invasive circulating imaging biomarkers have tested. The importance lifestyle recognised several drugs are being tested clinical trials. This review addresses challenges that healthcare professionals face management patients.

Язык: Английский

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Discovery of farnesoid X receptor and its role in bile acid metabolism

Molecular and Cellular Endocrinology, Год журнала: 2022, Номер 548, С. 111618 - 111618

Опубликована: Март 11, 2022

Язык: Английский

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CXCR2 inhibition enables NASH-HCC immunotherapy

Gut, Год журнала: 2022, Номер 71(10), С. 2093 - 2106

Опубликована: Апрель 27, 2022

Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor sensitise ICI therapy. Neutrophil infiltration was characterised in human and mouse models of HCC. Late-stage intervention anti-PD1 and/or performed murine NASH-HCC. The tumour microenvironment by imaging mass cytometry, RNA-seq flow cytometry. Neutrophils expressing CXCR2, receptor crucial neutrophil recruitment acute-injury, are highly represented In lacking response ICI, the combination antagonist suppressed burden extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation CD8+ T numbers which anti-tumoural immunity, this confirmed loss therapeutic effect on genetic impairment myeloid recruitment, neutralisation XCR1-ligand XCL1 or depletion cells. Therapeutic benefit accompanied an unexpected increase tumour-associated (TANs) switched from protumour anti-tumour progenitor-like phenotype. Reprogrammed TANs were found direct contact cells clusters enriched for cytotoxic protease granzyme B. reprogramming not observed circulation indicative selectively influencing TANs. CXCR2-inhibition induces promotes

Язык: Английский

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GDF15 promotes weight loss by enhancing energy expenditure in muscle

Nature, Год журнала: 2023, Номер 619(7968), С. 143 - 150

Опубликована: Июнь 28, 2023

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, most individuals, usually not maintained partly due to physiological adaptations suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment rodents fed high-fat diet recombinant growth differentiating factor 15 (GDF15) reduces obesity improves glycaemic control through glial-cell-derived neurotrophic family receptor α-like (GFRAL)-dependent suppression food intake4-7. Here we find that, addition suppressing appetite, GDF15 counteracts compensatory reductions eliciting greater (NAFLD) compared caloric alone. This effect maintain expenditure during calorie requires GFRAL-β-adrenergic-dependent signalling axis increases acid oxidation calcium futile cycling skeletal muscle mice. These data indicate therapeutic targeting GDF15-GFRAL pathway may be useful maintaining restriction.

Язык: Английский

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Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia

Cell Metabolism, Год журнала: 2022, Номер 34(6), С. 919 - 936.e8

Опубликована: Июнь 1, 2022

Язык: Английский

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Transcriptomics Identify Thrombospondin‐2 as a Biomarker for NASH and Advanced Liver Fibrosis

Hepatology, Год журнала: 2021, Номер 74(5), С. 2452 - 2466

Опубликована: Июнь 9, 2021

NAFLD is the most common liver disease worldwide. NASH, progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes. We searched for their noninvasive biomarkers.Global RNA sequencing tissue from 98 patients biopsy-proven was performed. Unsupervised hierarchical clustering well distinguished NASH nonalcoholic fatty (NAFL), exhibited molecular abnormalities reflecting pathological features. Transcriptomic analysis identified proteins up-regulated in and/or (stage F3-F4), including matricellular glycoprotein thrombospondin-2 (TSP-2), encoded by thrombospondin 2 (THBS2) gene. The intrahepatic THBS2 expression level showed highest areas under receiver operating characteristic curves (AUROCs) 0.915 0.957 diagnosing fibrosis, respectively. positively correlated inflammation ballooning according to activity score, serum aspartate aminotransferase hyaluronic acid (HA) levels, Fibrosis Score (NFS). extracellular matrix collagen biosynthesis, platelet activation, caspase-mediated cleavage cytoskeletal proteins, immune cell infiltration. Serum TSP-2 measured 213 significantly higher than NAFL, increased parallel stage. AUROCs predicting were 0.776 0.856, respectively, which comparable Fibrosis-4 index, HA level, NFS diagnosis. count independent predictors fibrosis. levels could stratify risk hepatic complications, cancer decompensated cirrhotic events.TSP-2 may be a useful biomarker diagnosis NAFLD.

Язык: Английский

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