The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review

Hepatology, Journal Year: 2023, Volume and Issue: 77(4), P. 1335 - 1347

Published: Jan. 3, 2023

Background and Aims: NAFLD is a leading cause of liver-related morbidity mortality. We assessed the global regional prevalence, incidence, mortality using an in-depth meta-analytic approach. Approach Results: PubMed Ovid MEDLINE were searched for population-based studies from 1990 to 2019 survey year (last published 2022) per Preferred Reporting Items Systematic Reviews Meta-Analyses (PRISMA). Meta-analysis was conducted random-effects models. Bias risk assessment Joanna Briggs Institute. Of 2585 reviewed, 92 (N=9,361,716) met eligibility criteria. Across study period (1990–2019), pooling prevalence estimates ultrasound-defined yielded overall 30.05% (95% CI: 27.88%–32.32%) 30.69% (28.4–33.09), respectively. Global increased by +50.4% 25.26% (21.59–29.33) in 1990–2006 38.00% (33.71–42.49) 2016–2019 ( p <0.001); +38.7% 25.16% (19.46–31.87) 34.59% (29.05–40.57) =0.029). The highest Latin America 44.37% (30.66%–59.00%), then Middle East North Africa (MENA) (36.53%, 28.63%–45.22%), South Asia (33.83%, 22.91%–46.79%), South-East (33.07%, 18.99%–51.03%), (31.20%, 25.86%–37.08%), (29.71%, 25.96%–33.76%), Pacific 28.02% (24.69%–31.60%), Western Europe 25.10% (20.55%–30.28%). Among cohort diagnosed without liver biopsy, pooled rate 1000 PY 12.60 (6.68–23.67) all-cause mortality; 4.20 (1.34–7.05) cardiac-specific 2.83 (0.78–4.88) extrahepatic cancer-specific 0.92 (0.00–2.21) liver-specific Conclusions: 30% increasing which requires urgent comprehensive strategies raise awareness address all aspects on local, regional, levels.

Language: Английский

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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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Global burden of liver disease: 2023 update

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 516 - 537

Published: March 27, 2023

Liver disease accounts for two million deaths annually and is responsible 4% of all (1 out every 25 worldwide); approximately two-thirds liver-related occur in men. Deaths are largely attributable to complications cirrhosis hepatocellular carcinoma, with acute hepatitis accounting a smaller proportion deaths. The most common causes worldwide related viral hepatitis, alcohol, non-alcoholic fatty liver disease. Hepatotropic viruses the aetiological factor cases but drug-induced injury increasingly significant cases. This iteration global burden an update 2019 version focuses mainly on areas where new information available like alcohol-associated disease, carcinoma. We also devote separate section Africa, area world typically neglected such documents.

Language: Английский

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Global incidence and prevalence of nonalcoholic fatty liver disease

Clinical and Molecular Hepatology, Journal Year: 2022, Volume and Issue: 29(Suppl), P. S32 - S42

Published: Dec. 15, 2022

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of worldwide. The estimated global incidence NAFLD 47 cases per 1,000 population and higher among males than females. prevalence adults 32% (40%) compared to females (26%). has increased over time, from 26% in studies 2005 or earlier 38% 2016 beyond. varies substantially by world region, contributed differing rates obesity, genetic socioeconomic factors. exceeds 40% the Americas South-East Asia. projected increase significantly multiple regions 2030 if current trends are left unchecked. In this review, we discuss future projections.

Language: Английский

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Global Epidemiology and Genetics of Hepatocellular Carcinoma

Gastroenterology, Journal Year: 2023, Volume and Issue: 164(5), P. 766 - 782

Published: Feb. 2, 2023

Language: Английский

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Changing epidemiology, global trends and implications for outcomes of NAFLD

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(3), P. 842 - 852

Published: May 10, 2023

Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common globally, currently estimated to affect 38% of global population. A minority patients with NAFLD will progress cirrhosis or hepatocellular carcinoma, but total number this vast population that risk such severe outcomes is increasing. Worryingly, persons are affected by at an earlier age, suggesting they have longer time develop complications. With considerable changes in diet composition and urbanization, obesity type 2 diabetes among population, particular developing countries, proportion projected be further Yet, there large geographical discrepancies prevalence rates its inflammatory component non-alcoholic steatohepatitis (NASH). Such differences partly related differing socio-economic milieus, also genetic predisposition.This narrative review discusses recent epidemiology NASH from regional perspectives, as well special populations. We discuss consequences these can on hepatic extra-hepatic events.

Language: Английский

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Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 391(4), P. 299 - 310

Published: June 8, 2024

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy safety of tirzepatide, an agonist the glucose-dependent insulinotropic polypeptide glucagon-like peptide-1 receptors, in patients MASH moderate or severe fibrosis unclear.

Language: Английский

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Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach

Clinical and Molecular Hepatology, Journal Year: 2022, Volume and Issue: 28(4), P. 841 - 850

Published: Sept. 19, 2022

Background/Aims: Due to increases in obesity and type 2 diabetes, the prevalence of nonalcoholic fatty liver disease (NAFLD) has also been increasing. Current forecast models may not include non-obese NAFLD. Here, we used Bayesian approach NAFLD through year 2040.Methods: Prevalence data from 245 articles involving 2,699,627 persons were with a hierarchical 2040. Subgroup analyses performed for age, gender, presence metabolic syndrome, region, smoking status. Sensitivity analysis was conducted clinical setting study quality.Results: The forecasted 2040 55.7%, three-fold increase since 1990 43.2% 2020 38.9%. estimated average yearly 2.16%. For those aged <50 years ≥50 years, significantly different (56.7% vs. 61.5%, <i>P</i>=0.52). There significant difference by sex (males: 60% 50%) but trend steeper females (annual percentage change: 2.5% 1.5%, <i>P</i>=0.025). no trends overtime region (<i>P</i>=0.48). rate higher without syndrome (3.8% 0.84%, <i>P</i>=0.003) smokers (1.4% 1.1%, <i>P</i>=0.011). clinical/community (<i>P</i>=0.491) or quality (<i>P</i>=0.85).Conclusion: By 2040, over half adult population is have largest are expected occur women, smokers, syndrome. Intensified efforts needed raise awareness determine long-term solutions addressing driving factors disease.

Language: Английский

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Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma

JHEP Reports, Journal Year: 2021, Volume and Issue: 3(4), P. 100305 - 100305

Published: May 11, 2021

The prevalence of hepatocellular carcinoma (HCC) is increasing worldwide, whereas that most other cancers decreasing. Non-alcoholic fatty liver disease (NAFLD), which has increased with the epidemics obesity and type 2 diabetes, increases risk HCC. Interestingly, NAFLD-associated HCC can develop in patients or without cirrhosis. A lack awareness about NAFLD-related led to delays diagnosis. Therefore, a large number are diagnosed advanced-stage low 5-year survival. In this context, NAFLD may lead earlier diagnosis more effective interventions.

Language: Английский

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Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 287 - 295

Published: April 9, 2023

Language: Английский

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