Keratin 18-M65: A biomarker for early-stage alcohol-associated liver disease.
Keratin 18-M65: A biomarker for early-stage alcohol-associated liver disease.
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角蛋白 18-M65：早期酒精相关肝病的生物标志物。
DOI：
10.1111/acer.15117
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Vatsalya,Vatsalya
中科院分区：
文献类型：
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作者：
McClain,CraigJ;Kirpich,Irina;Song,Ming;Vatsalya,Vatsalya
角蛋白，以前称为细胞角蛋白，是中间丝蛋白的主要上皮特异性亚群。它们有许多功能，包括保护肝细胞免于凋亡和坏死。K8和K18是成人肝细胞中仅有的角蛋白，K18在细胞死亡时被释放（Ku et al., 2016）。细胞外角蛋白18 （CK18或细胞角蛋白18 - k18）是上皮细胞死亡的标志物，肝细胞死亡后血清水平可显著升高（Vatsalya et al., 2020）。在细胞死亡过程中，细胞膜完整性的丧失导致细胞内蛋白质（包括K18）释放到细胞外隔室。K18也是caspase 3的底物，K18的裂解形式（K18M30）是细胞凋亡的生物标志物。在肝细胞凋亡过程中，活化的半胱天冬酶会切割K18，这可以通过M30 ELISA在血浆中检测到。M65 ELISA检测caspase-cleaved和uncleaved K18。因此，ELISA检测K18既可以量化肝细胞死亡，也可以区分坏死和凋亡（Vatsalya et al., 2020）。一些研究小组已经将K18-M65作为严重酒精相关性肝炎的诊断和预后生物标志物（AH； Atkinson等人，2020；Bissonnette等人，2017；Vatsalya等人，2020；Woolbright等人，2017）。重要的是，K18比常规使用的AST和ALT水平更准确地测量酒精相关性肝病（ALD）中细胞死亡的程度（McClain et al, 2021）。此外，虽然MELD评分反映了疾病的严重程度，但它并不能区分严重的急性炎症/细胞死亡和肝硬化失代偿（McClain et al., 2021）。因此，除了我们目前使用的生物标志物之外，K18测定法还增加了重要的信息。最后，来自STOPAH试验的研究人员表明，M65可以预测谁将从严重AH的类固醇治疗中获益。因此，K18被认为是严重AH的诊断、预后和治疗诊断（Atkinson等，2020；McClain等，2021）。在这期ACER杂志中，Maccioni及其同事评估了血清K18-M65在早期ALD患者的肝脏疾病检测中是否有价值（Maccioni等，2023）。因此，与大多数早期评估K18在严重AH中的研究相反，该团队研究了它在肝损伤谱系的另一端，即早期ALD中的功效。他们前瞻性地评估了两组在康复计划中接受治疗的积极饮酒的酒精使用障碍（AUD）患者（训练[n= 162]和验证[n= 78]以及匹配的健康对照[n= 21]）。所有患者均报告长期饮酒（60克/天）（60克/天），并在入院前一直积极饮酒。既往诊断为显著ALD、肝硬化或既往肝失代偿发作或体征的患者被排除在外。因此，本研究的患者群体相对均匀且特征明确。临床、实验室和影像学数据，包括纤维扫描，用于区分AUD患者单纯性脂肪变性（轻度ALD）和脂肪性肝炎/纤维化（早期ALD）。作者测量了血清K18-M65水平，并评估了其预测早期ALD的能力。他们发现，患有AUD和早期ALD的患者中K18-M65水平较高，而轻度ALD组的水平与健康对照组相似。K18-M65将轻度肝病与早期ALD分离（AUROC= 0.8704; p< 0.0001），最佳临界值为265.9 U/I。该K18-M65截止值在验证队列中检测早期ALD也具有较高的准确性（敏感性86.67%，特异性96.67%）。AST和ALT与K18-M65均有相关性，但AST/ALT与K18-M65无相关性。K18-M65，但是……
Keratins, previously termed cytokeratins, are the major epithelialspecific subgroup of intermediate filament proteins. They have many functions including protecting hepatocytes from apoptosis and necrosis. K8 and K18 are the only keratins found in adult hepatocytes, and K18 is released upon cell death (Ku et al., 2016). Extracellular keratin 18 (CK18 or cytokeratin 18—K18) is a marker for epithelial cell death, and serum levels can be significantly elevated following hepatocyte death (Vatsalya et al., 2020). During cell death, loss of cell membrane integrity results in the release of intracellular proteins, including K18, into the extracellular compartment. K18 is also a substrate for caspase 3, and the cleaved form of K18 (K18M30) is a biomarker for apoptosis. During hepatocyte apoptosis, activated caspases cleave K18, and this can be detected in plasma by the M30 ELISA. The M65 ELISA detects both caspase-cleaved and uncleaved K18. Thus, measurement of K18 by ELISA can both quantify hepatocyte death and can differentiate necrosis from apoptosis (Vatsalya et al., 2020). Several groups have used K18-M65 as both a diagnostic and prognostic biomarker in severe alcohol-associated hepatitis (AH; Atkinson et al., 2020; Bissonnette et al., 2017; Vatsalya et al., 2020; Woolbright et al., 2017). Importantly, K18 more accurately measures the magnitude of cell death in alcohol-associated liver disease (ALD) than the regularly used AST and ALT levels (McClain et al., 2021). Moreover, while the MELD score reflects disease severity, it does not distinguish between severe acute inflammation/cell death and cirrhosis decompensation (McClain et al., 2021). Thus, the K18 assay adds important information in addition to that derived by our currently used biomarkers. Lastly, investigators from the STOPAH trial showed that M65 could predict who would benefit from steroid therapy in severe AH. Thus, K18 has been postulated to be diagnostic, prognostic, and theragnostic in severe AH (Atkinson et al., 2020; McClain et al., 2021). In this ACER issue, Maccioni and coworkers evaluated whether serum K18-M65 was valuable in detecting liver disease in patients with early ALD (Maccioni et al., 2023). Thus, in contrast to most earlier studies that evaluated K18 in severe AH, this team studied its efficacy in the opposite end of the spectrum of liver injury, early ALD. They prospectively evaluated two cohorts of actively drinking patients with alcohol use disorder (AUD) treated in a rehabilitation program (training [n= 162] and validation [n= 78] and matched healthy controls [n= 21]). All patients reported long-term (> 1 year) alcohol consumption (> 60 g/day) and were actively drinking until the day of admission. Patients with a previous diagnosis of significant ALD, cirrhosis, or previous episodes or signs of liver decompensation were excluded. Thus, the patient population in this study was relatively homogeneous and well-characterized. Clinical, laboratory, and imaging data, including Fibroscan, were used to separate AUD patients with simple steatosis (minimal ALD) from steatohepatitis/fibrosis (early ALD). The authors measured serum K18-M65 levels and assessed its ability to predict early ALD. They found high levels of K18-M65 in patients with AUD and early ALD, while levels in the minimal ALD group were similar to those in healthy controls. K18-M65 separated minimal liver disease from early ALD (AUROC= 0.8704; p< 0.0001) with an optimal cutoff at 265.9 U/I. This K18-M65 cutoff also detected early ALD in the validation cohort with high accuracy (sensitivity 86.67%, specificity 96.67%). Both AST and ALT correlated with K18-M65, but the AST/ALT ratio did not. K18-M65, but …