Fan Hong, Kouvari Matina, Mingrone Geltrude, George Jacob, Papatheodoridis Georgios, Valenzuela-Vallejo Laura, Liu Zhenqiu, Chen Xingdong, Zhang Tiejun, Mantzoros Christos S
Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, China; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Clin Gastroenterol Hepatol. 2025 Jul;23(8):1356-1365.e5. doi: 10.1016/j.cgh.2024.10.018. Epub 2024 Dec 11.
BACKGROUND & AIMS: Lipoprotein(a) (Lp(a)) is an emerging biomarker for cardiometabolic factors. We studied the role of Lp(a) in the full spectrum of metabolic dysfunction-associated steatotic liver disease (MASLD).
Three independent analyses were implemented using a multi-center, cross-sectional, liver biopsy-based study (n = 332) (Study 1) and the UK Biobank prospective study (n = 270,004) (Study 2; median follow-up, 12.47 years). In Study 1, we studied the cross-sectional association between Lp(a) mass and MASLD stages (Analysis A). In Study 2, we studied the prospective association between Lp(a) concentration and MASLD, liver cirrhosis, and hepatocellular carcinoma (Analysis B). Finally, these analyses were accompanied by a prospective analysis using LPA Genetic Risk Score (Analysis C).
In Study 1, an inverse association between Lp(a) and at-risk metabolic dysfunction-associated steatohepatitis (odds ratio, 0.64; 95% confidence interval [CI], 0.42-0.97) was observed. In contrast, when similar associations were examined prospectively (Study 2), subjects with Lp(a) <10.75 nmol/L had a higher risk for cirrhosis (hazard ratio, 1.49; 95% CI, 1.22-1.81) and HCC (hazard ratio, 1.69; 95% CI, 1.12-2.56) compared with subjects with Lp(a) within the 10.75 to 21.5 nmol/L range. Above these levels, the risk increased significantly and positively. Similarly, genetic analysis showed an L-shaped association with LPA Genetic Risk Score.
The inverse association observed in cross-sectional studies should be attributed to reverse causality (ie, the presence of liver disease may decrease Lp(a) levels). Genetically predicted very low Lp(a) levels are also associated with impaired liver health prospectively. Clinical trials evaluating Lp(a)-lowering agents should thus be monitored carefully for adverse liver effects in subjects attaining extremely low concentrations.
脂蛋白(a) [Lp(a)] 是一种新出现的心脏代谢因子生物标志物。我们研究了Lp(a)在代谢功能障碍相关脂肪性肝病（MASLD）全谱中的作用。
使用一项基于肝活检的多中心横断面研究（n = 332）（研究1）和英国生物银行前瞻性研究（n = 270,004）（研究2；中位随访时间为12.47年）进行了三项独立分析。在研究1中，我们研究了Lp(a)质量与MASLD分期之间的横断面关联（分析A）。在研究2中，我们研究了Lp(a)浓度与MASLD、肝硬化和肝细胞癌之间的前瞻性关联（分析B）。最后，这些分析还伴有一项使用LPA基因风险评分的前瞻性分析（分析C）。
在研究1中，观察到Lp(a)与有风险的代谢功能障碍相关脂肪性肝炎之间存在负相关（比值比，0.64；95%置信区间[CI]，0.42 - 0.97）。相比之下，在进行前瞻性研究时（研究2），与Lp(a)在10.75至21.5 nmol/L范围内的受试者相比，Lp(a) <10.75 nmol/L的受试者患肝硬化（风险比，1.49；95% CI，1.22 - 1.81）和肝细胞癌（风险比，1.69；95% CI，1.12 - 2.56）的风险更高。高于这些水平，风险显著且呈正相关增加。同样，基因分析显示与LPA基因风险评分呈L形关联。
横断面研究中观察到的负相关应归因于反向因果关系（即肝病的存在可能会降低Lp(a)水平）。基因预测的极低Lp(a)水平在未来也与肝脏健康受损有关。因此，在评估降低Lp(a)药物的临床试验中，对于达到极低浓度的受试者，应仔细监测其肝脏不良反应。
