NHHR、HOMA-IR与VFA在代谢功能障碍相关脂肪性肝病中的作用机制及临床价值

The Mechanistic Roles and Clinical Value of NHHR, HOMA-IR, and VFA in Metabolic Dysfunction-Associated Steatotic Liver Disease

摘要: 代谢功能障碍相关脂肪性肝病(MASLD)已成为全球高发的慢性肝脏疾病，可进展为脂肪性肝炎、肝纤维化、肝硬化及肝癌，并显著增加心血管疾病风险。传统诊断手段(肝穿刺活检有创、超声灵敏度有限、常规血脂及肝功能预测效能低)难以满足早期筛查与精准分层需求。非高密度脂蛋白胆固醇/高密度脂蛋白胆固醇比值(NHHR)、稳态模型胰岛素抵抗指数(HOMA-IR)与内脏脂肪面积(VFA)作为三类无创、简易的代谢标志物，可从脂质代谢、胰岛素抵抗与体脂分布维度反映机体代谢紊乱。现有研究表明，VFA过度堆积、胰岛素抵抗与NHHR异常升高三者均与MASLD的发生与进展密切相关。中介分析证实，脂质指标可介导体重指数与MASLD的关联，非传统脂质标志物的介导效应优于常规血脂参数。HDL-C水平下降、非HDL-C及NHHR水平升高均可增加MASLD风险。大量横断面及队列研究证实：VFA、HOMA-IR、NHHR单项指标均与MASLD患病风险呈显著正相关(如NHHR最高四分位数组新发MASLD风险增加134%，HOMA-IR最高四分位数组风险为最低组的7.055倍，VFA最高四分位组女性风险达最低组18.91倍)，且与肝脂肪变性程度(CAP值)及肝纤维化风险密切相关。NHHR预测MASLD的效能优于传统血脂指标，HOMA-IR可独立预测肝纤维化进展。临床应用方面，三者均依托常规体检，适合大规模早期筛查，可用于高危人群风险分层、治疗疗效监测及合并症(2型糖尿病、心血管疾病)综合管理。他汀类药物可能通过降低NASH和纤维化风险对MASLD具有潜在益处。当前研究仍以横断面为主，缺乏统一截断值及干预靶点的随机对照试验。未来需前瞻性队列与机制研究加以验证。三者联合应用有望提升MASLD无创诊断效能，为精细化临床管理提供新策略。

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a highly prevalent chronic liver disease worldwide, which can progress to steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma, and significantly increases the risk of cardiovascular disease. Conventional diagnostic approaches—such as invasive liver biopsy, limited sensitivity of ultrasonography, and low predictive performance of routine blood lipids and liver function tests—are inadequate for early screening and precise risk stratification. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR), the homeostatic model assessment of insulin resistance (HOMA-IR), and visceral fat area (VFA), as three noninvasive and simple metabolic markers, can reflect metabolic disturbances from the dimensions of lipid metabolism, insulin resistance, and body fat distribution. Existing studies indicate that excessive accumulation of VFA, insulin resistance, and abnormally elevated NHHR are all closely associated with the development and progression of MASLD. Mediation analysis has confirmed that lipid indices can mediate the association between body mass index and MASLD, and the mediating effects of non-traditional lipid markers are superior to those of conventional blood lipid parameters. Decreased HDL-C levels and increased non-HDL-C and NHHR levels can all increase the risk of MASLD. A large body of cross-sectional and cohort studies has confirmed that VFA, HOMA-IR, and NHHR, used as individual markers, are significantly positively correlated with the risk of MASLD (e.g., the highest NHHR quartile was associated with a 134% increased risk of incident MASLD; the highest HOMA-IR quartile had a 7.055-fold risk compared to the lowest quartile; and for VFA, women in the highest quartile had an 18.91-fold risk compared to the lowest quartile). They are also closely related to the degree of hepatic steatosis (assessed by controlled attenuation parameter [CAP]) and the risk of liver fibrosis. NHHR outperforms conventional lipid indices in predicting MASLD, and HOMA-IR can independently predict the progression of liver fibrosis. In clinical application, all three markers are based on routine physical examination data, making them suitable for large-scale early screening. They can be utilized for risk stratification in high-risk populations, monitoring of treatment efficacy, and comprehensive management of comorbidities such as type 2 diabetes and cardiovascular disease. Statins may have potential benefits for MASLD by reducing the risk of steatohepatitis (NASH) and fibrosis. Current studies remain predominantly cross-sectional, and there is a lack of standardized cut-off values and randomized controlled trials with defined intervention targets. Future prospective cohort and mechanistic studies are needed for validation. The combined use of these three markers is expected to enhance the noninvasive diagnostic performance for MASLD, thereby providing new strategies for refined clinical management.