Sato-Espinoza Karina, Vierkant Robert A, Chotiprasidhi Perapa, Vairo Filippo Pinto E, Tian Shulan, Ma Jun, O'Brien Daniel, Lazaridis Konstantinos N, Dlugosch Carola, Scheider Carolin, Allen Alina M, Wangensteen Kirk J
Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Department of Quantitative Health Sciences, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
Liver Int. 2025 Oct;45(10):e70300. doi: 10.1111/liv.70300.
BACKGROUND & AIMS: Steatotic liver disease (SLD) is characterised by liver fat accumulation exceeding 5%. Lean body weight (BMI ≤ 25 kg/m) with non-alcoholic SLD is a rare phenotype, and the balance of risks related to metabolic conditions or genetic predisposition, or the risk of progressive liver disease, is not known. This study evaluates clinical and genetic predictors of non-alcoholic SLD and advanced liver disease in lean individuals.
We used International Classification of Disease codes, radiology and pathology review to identify 177 lean non-alcoholic SLD cases (47 cryptogenic, 130 MASLD), 677 matched lean controls, and 3090 overweight/obese SLD cases in the Mayo Clinic Biobank and Tapestry databases. We performed case-control and cross-sectional comparisons of clinical and genetic factors between these groups, using univariable and multivariable analyses.
Lean individuals with non-alcoholic SLD exhibited metabolic and genetic profiles that were intermediate between those of lean controls without SLD and overweight/obese SLD individuals, including intermediate rates of diabetes, hypertension, hyperlipidaemia and of homozygosity for the risk allele of PNPLA3. Multivariable analysis indicated that diabetes was an independent predictor of SLD among lean individuals. Among lean individuals with non-alcoholic SLD, those with metabolic-associated SLD (MASLD), as compared to those with cryptogenic SLD (without metabolic risk factor), were more likely to be homozygous for risk alleles in GCKR. The Fib-4 score, a tool for screening advanced liver disease in SLD, accurately predicted advanced fibrosis among lean individuals with non-alcoholic SLD.
Diabetes serves as a primary predictor of non-alcoholic SLD in lean individuals. These results support the recommendation to screen for SLD in patients with diabetes, regardless of BMI. The GCKR risk allele is associated with MASLD in lean individuals, and the risk factors for cryptogenic SLD remain unclear.
脂肪性肝病（SLD）的特征是肝脏脂肪堆积超过5%。非酒精性SLD且体重正常（BMI≤25kg/m）是一种罕见的表型，与代谢状况或遗传易感性相关的风险平衡，或进展性肝病的风险尚不清楚。本研究评估了体重正常个体中非酒精性SLD和晚期肝病的临床及遗传预测因素。
我们使用国际疾病分类代码、放射学和病理学检查，在梅奥诊所生物样本库和Tapestry数据库中识别出177例体重正常的非酒精性SLD病例（47例隐源性，130例代谢相关脂肪性肝病[MASLD]）、677例匹配的体重正常对照以及3090例超重/肥胖SLD病例。我们采用单变量和多变量分析，对这些组之间的临床和遗传因素进行病例对照和横断面比较。
非酒精性SLD的体重正常个体表现出的代谢和遗传特征介于无SLD的体重正常对照和超重/肥胖SLD个体之间，包括糖尿病、高血压、高脂血症的发生率以及PNPLA3风险等位基因纯合性的发生率均处于中间水平。多变量分析表明，糖尿病是体重正常个体中SLD的独立预测因素。在非酒精性SLD的体重正常个体中，与隐源性SLD（无代谢危险因素）个体相比，代谢相关SLD（MASLD）个体更可能是GCKR风险等位基因的纯合子。Fib-4评分是一种用于筛查SLD中晚期肝病的工具，能准确预测非酒精性SLD体重正常个体中的晚期纤维化。
糖尿病是体重正常个体中非酒精性SLD的主要预测因素。这些结果支持对糖尿病患者进行SLD筛查的建议，无论其BMI如何。GCKR风险等位基因与体重正常个体中的MASLD相关，而隐源性SLD的危险因素仍不清楚。
