Department of Medicine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States of America.
Department of Gastroenterology, Università Cattolica del Sacro Cuore, Rome, Italy.
Metabolism. 2023 Nov;148:155694. doi: 10.1016/j.metabol.2023.155694. Epub 2023 Sep 25.
The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated.
To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages.
This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited.
We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD.
Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.
代谢/炎症激素系统在与代谢功能障碍相关的脂肪性肝病（MASLD）中的作用仍有待充分阐明。
报告新型总和 H 特异性生长分化因子-15（GDF-15）和其他已建立的激素系统的水平，并描述 MASLD 及其各阶段对照者和患者的激素模式。
这是来自两个胃肠病学-肝病学系（希腊和澳大利亚）和一个减肥代谢外科系（意大利）的多中心研究。总共招募了 n=455 例经活检证实的 MASLD（n=374 例）和对照者（n=81 例）的血清样本。
我们首次报告，总 GDF-15 和 H 特异性 GDF-15 水平在 MASLD、代谢功能障碍相关脂肪性肝炎（MASH）和严重纤维化中高于对照者。此外，在 MASLD 患者中，卵泡抑素样-3（FSTL-3）、游离胰岛素样生长因子-1（IGF-1）、瘦素和胰岛素水平高于对照者，而脂联素水平在 MASLD 患者中低于对照者。与无/轻度纤维化相比，激活素-A、卵泡抑素（FST）、FSTL-3 和胰岛素水平在严重纤维化中显著增加，而游离 IGF-1 减少。此外，无纤维化的患者脂联素水平低于任何纤维化的患者。此外，GDF-15 与 MASLD 和高危 MASH 的发生几率呈正相关，而在调整分析中，FST 和脂联素呈负相关。通过无监督分析揭示了两种不同的高危 MASH 模式（总变异解释=54%）。在我们的样本中最常见的模式（34.3%）的特点是总 GDF-15 和 H 特异性 GDF-15、卵泡抑素和激活素的水平较高，脂联素水平较低。揭示的第二种模式的特点是游离 IGF-1、胰岛素和瘦素水平较高，激活素-A 和脂联素水平较低。在整体 MASLD 中也生成了类似的模式。
随着 MASLD 严重程度的进展，总 GDF-15 和 H 特异性 GDF-15 水平增加。FSTL-3、游离 IGF-1、瘦素和胰岛素水平也较高，而脂联素和激活素-A 水平在 MASLD 组中低于对照组。包括 GDF-15 在内的激素系统不仅可能参与了病理生理学，而且可能对 MASLD 及其各阶段的诊断检查有用，并可能具有治疗价值。
