Wernberg Charlotte Wilhelmina, Indira Chandran Vineesh, Lauridsen Mette Munk, Skytthe Maria Kløjgaard, Hansen Camilla Dalby, Hansen Johanne Kragh, Grønkjær Lea Ladegaard, Jacobsen Birgitte Gade, Di Caterino Tina, Detlefsen Sönke, Thiele Maja, Guiliani Alejandro Mayorca, Villesen Ida Falk, Leeming Diana Julie, Karsdal Morten, Graversen Jonas Heilskov, Krag Aleksander
Fibrosis, Fatty Liver and Steatohepatitis Research Center Odense (FLASH), Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark.
Institue for Regional Health Science, Liver Research Group, Department of Gastroenterology and Hepatology, University Hospital of South Denmark, Esbjerg, Denmark.
JHEP Rep. 2025 Apr 22;7(8):101432. doi: 10.1016/j.jhepr.2025.101432. eCollection 2025 Aug.
BACKGROUND & AIMS: Diet and weight loss remain the primary treatment for most patients with metabolic dysfunction-associated fatty liver disease (MASLD), with one recent drug therapy approved for severe cases. However, a significant need remains for non-invasive tests (NITs) that can assist clinicians in evaluating treatment response. We aimed to explore the ability of several NITs to reflect a change of at least one point in histologic non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS).
This study explores biomarkers reflecting treatment response in 173 patients from secondary care with type 2 diabetes or severe obesity, all of whom underwent repeated liver biopsies and blood samples. We measured soluble triggering receptor expressed on myeloid cells 2 (TREM2), collagen markers PRO-C3, PRO-C4, PRO-C6, PRO-C8, and PRO-C18L and liver stiffness measured by FibroScan, FAST-score, and homeostatic model assessment of insulin resistance (HOMA-IR). We studied biomarker changes and their capacity to reflect liver biopsy alterations in two distinct cohorts, using comparative paired analyses and multivariable logistic regression to evaluate the results.
Mean age was 52 years (±12), 38% male, 52% had NAS ≥3 at baseline (90/173), 70% had F0-F1 fibrosis, and 23% (39/173) had metabolic dysfunction-associated steatohepatitis. Significant differences were seen in sTREM2, PRO-C3, HOMA-IR, and FAST-score levels by NAS changes (worsened, no-change, improved) ( = 0.0001). In multivariable analysis, sTREM2 + PRO-C3 and HOMA-IR predicted NAS improvement (AUROC >0.75), with an odds ratio of 1.13 for each unit decrease ( = 0.001, 95% CI 1.04-1.21). FIB-4 and non-alcoholic fatty liver disease fibrosis score (NFS) did not reflect NAS improvement (AUROC <0.60, OR <1.05, >0.5).
sTREM2, PRO-C3, and HOMA-IR indicate NAS improvement and warrant further investigation as surrogate markers for gauging intervention response.
Non-invasive tests (NITs) will play a crucial role in monitoring treatment responses in metabolic dysfunction-associated steatotic liver disease, providing a viable alternative to liver biopsies. Our study investigates whether NITs reflect histological responses based on changes in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) in patients with type 2 diabetes mellitus or obesity. We used non-invasive markers, some corresponding to different biological aspects of disease severity. We found that reductions in certain NIT levels correlate well with NAS reduction and composite histological improvements (lobular inflammation and ballooning). Combining soluble triggering receptor expressed on myeloid cells 2, PRO-C3, or homeostatic model assessment of insulin resistance enhances the potential for monitoring NAS improvement.
ClinicalTrials.gov (NCT03068078; NCT03535142).
饮食和体重减轻仍然是大多数代谢功能障碍相关脂肪性肝病（MASLD）患者的主要治疗方法，最近有一种药物疗法被批准用于严重病例。然而，对于能够帮助临床医生评估治疗反应的非侵入性检测（NITs）仍有很大需求。我们旨在探索几种NITs反映组织学非酒精性脂肪性肝病（NAFLD）活动评分（NAS）至少变化1分的能力。
本研究探索了173例来自二级医疗机构的2型糖尿病或严重肥胖患者中反映治疗反应的生物标志物，所有患者均接受了重复肝活检和血液样本采集。我们测量了髓系细胞2上表达的可溶性触发受体（TREM2）、胶原标志物PRO-C3、PRO-C4、PRO-C6、PRO-C8和PRO-C18L，以及通过FibroScan测量的肝脏硬度、FAST评分和胰岛素抵抗稳态模型评估（HOMA-IR）。我们在两个不同队列中研究了生物标志物变化及其反映肝活检改变的能力，使用比较配对分析和多变量逻辑回归来评估结果。
平均年龄为52岁（±12），38%为男性，52%在基线时NAS≥3（90/173），70%有F0-F1纤维化，23%（39/173）有代谢功能障碍相关脂肪性肝炎。根据NAS变化（恶化、无变化、改善），sTREM2、PRO-C3、HOMA-IR和FAST评分水平存在显著差异（P = 0.0001）。在多变量分析中，sTREM2 + PRO-C3和HOMA-IR预测NAS改善（AUROC>0.75），每降低一个单位的比值比为1.13（P = 0.001，95%CI 1.04-1.21）。FIB-4和非酒精性脂肪性肝病纤维化评分（NFS）未反映NAS改善（AUROC<0.60，OR<1.05，P>0.5）。
sTREM2、PRO-C3和HOMA-IR表明NAS改善，作为衡量干预反应的替代标志物值得进一步研究。
非侵入性检测（NITs）在监测代谢功能障碍相关脂肪性肝病的治疗反应中将发挥关键作用，为肝活检提供了可行的替代方法。我们的研究调查了NITs是否基于2型糖尿病或肥胖患者非酒精性脂肪性肝病（NAFLD）活动评分（NAS）的变化反映组织学反应。我们使用了非侵入性标志物，其中一些对应于疾病严重程度的不同生物学方面。我们发现某些NIT水平的降低与NAS降低和综合组织学改善（小叶炎症和气球样变）密切相关。结合髓系细胞2上表达的可溶性触发受体、PRO-C3或胰岛素抵抗稳态模型评估可增强监测NAS改善的潜力。
ClinicalTrials.gov（NCT03068078；NCT03535142）
