Export Background and Aims: Phenotypic heterogeneity among patients with NAFLD is poorly understood. We aim to identify clinically important phenotypes within NAFLD patients and assess the long-term outcomes among different phenotypes. Methods: We analyzed the clinical data of 2311 participants from the Third National Health and Nutrition Examination Survey (NHANES III) and their linked mortality data through December 2019. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other liver diseases and excess alcohol use. A 2-stage cluster analysis was applied to identify clinical phenotypes. We used Cox proportional hazard models to explore all-cause and cause-specific mortality between clusters. Results: We identified 3 NAFLD phenotypes. Cluster 1 was characterized by young female patients with better metabolic profiles and lower prevalence of comorbidities; Cluster 2 by obese females with significant insulin resistance, diabetes, inflammation, and advanced fibrosis and Cluster 3 by male patients with hypertension, atherogenic dyslipidemia, and liver and kidney damage. In a median follow-up of 26 years, 989 (42.8%) all-cause mortality occurred. Cluster 1 patients presented the best prognosis, whereas Cluster 2 and 3 had higher risks of all-cause (Cluster 2—adjusted HR: 1.48, 95% CI: 1.16–1.90; Cluster 3—adjusted HR: 1.29, 95% CI: 1.01–1.64) and cardiovascular (Cluster 2—adjusted HR: 2.01, 95% CI: 1.18–3.44; Cluster 3—adjusted HR: 1.75, 95% CI: 1.03–2.97) mortality. Conclusions: Three phenotypically distinct and clinically meaningful NAFLD subgroups have been identified with different characteristics of metabolic profiles. This study reveals the substantial disease heterogeneity that exists among NAFLD patients and underscores the need for granular assessments to define phenotypes and improve clinical practice.

The development of an easy-to-use noninvasive model to screen nonalcoholic fatty liver disease (NAFLD) is warranted. This study aimed to develop and validate a simple noninvasive NAFLD risk score (NARS). We used the National Health and Nutrition Examination Survey 2017 to March 2020 cycle data. The sample size of derivation and validation cohort were 4056 and 2502, separately. The NAFLD was determined by FibroScan® measured controlled attenuation parameter scores of >285 dB/m in the absence of excessive alcohol use, steatogenic medications use, and viral hepatitis. The NARS was derived from a multivariable logistic regression model and variables were selected based on Boruta analysis. The performance of NARS was internally validated and compared with previous models using receiver-operating characteristics curve and C-statistics. The NARS was established using waist circumference, triglycerides, alanine aminotransferase, and fasting glucose, and the total score ranges from 0 to 8, with an increasing risk of NAFLD. NARS demonstrated ideal discrimination in the validation cohort, with C-statistics of 0.832 (95% confidence interval, 0.801–0.824), and was not inferior to any existing models. The optimal cutoff point for predicting NAFLD was obtained at 4 scores with a sensitivity of 82% and specificity of 69%. We reported the derivation and internal validation of a novel and easy-to-use risk score for detecting the presence of NAFLD. NARS demonstrated ideal discrimination performance and was practical in clinical practice for selecting individuals at higher risk of NAFLD for further examination or intervention.