Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States; Division of Diabetes, The University of Texas Health Science Center at San Antonio (UTHSCSA), United States; Audie L. Murphy Veterans Administration Medical Center (VAMC), San Antonio, TX, United States; Malcom Randall VAMC, Gainesville, FL, United States.
Divisions of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, United States.
J Hepatol. 2014 Jan;60(1):167-74. doi: 10.1016/j.jhep.2013.07.042. Epub 2013 Aug 20.
BACKGROUND & AIMS: Liver biopsy is the only reliable way of diagnosing and staging NASH but its invasive nature limits its use. Plasma caspase-generated cytokeratin-18 fragments (CK-18) have been proposed as a non-invasive alternative. We studied its clinical value in a large multiethnic NAFLD population and examined its relationship to clinical/metabolic/histological parameters.
424 middle-aged subjects in whom we measured adipose tissue, liver and muscle insulin resistance (IR), liver fat by MRS (n=275) and histology (n=318).
Median CK-18 were elevated in patients with vs. without NAFLD by MRS (209 [IQR: 137-329] vs. 122 [IQR: 98-155]U/L) or with vs. without NASH (232 [IQR: 151-387] vs. 170 [IQR: 135-234]U/L, both p<0.001). Plasma CK-18 raised significantly with any increase in steatosis, inflammation and fibrosis, but there was a significant overlap across disease severity. The CK-18 AUROC to predict NAFLD, NASH or fibrosis were 0.77 (95% CI=0.71-0.84), 0.65 (95% CI=0.59-0.71) and 0.68 (95% CI=0.61-0.75), respectively. The overall sensitivity/specificity for NAFLD, NASH and fibrosis were 63% (57-70%)/83% (69-92%), 58% (51-65%)/68% (59-76%) and 54% (44-63%)/85% (75-92%), respectively. CK-18 correlated most strongly with ALT (r=0.57, p<0.0001) and adipose tissue IR (insulin-suppression of FFA: r=-0.43; p<0.001), less with steatosis, lobular inflammation and fibrosis (r=0.28-0.34, all p<0.001), but not with ballooning, BMI, metabolic syndrome or T2DM.
Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study.
肝活检是诊断和分期 NASH 的唯一可靠方法，但由于其侵袭性，限制了其应用。血浆半胱氨酸蛋白酶生成的细胞角蛋白-18 片段（CK-18）已被提议作为一种非侵入性的替代方法。我们在一个大型多民族非酒精性脂肪性肝病（NAFLD）人群中研究了其临床价值，并研究了其与临床/代谢/组织学参数的关系。
我们测量了 424 名中年受试者的脂肪组织、肝脏和肌肉胰岛素抵抗（IR）、肝脏脂肪的 MRS（n=275）和组织学（n=318）。
与 MRS 检测到的无 NAFLD 患者相比，有 NAFLD 患者的 CK-18 中位数升高（209 [IQR：137-329] vs. 122 [IQR：98-155]U/L），与有 NASH 患者相比，无 NASH 患者的 CK-18 中位数升高（232 [IQR：151-387] vs. 170 [IQR：135-234]U/L，均 p<0.001）。CK-18 随着脂肪变性、炎症和纤维化的任何增加而显著升高，但疾病严重程度之间存在显著重叠。预测 NAFLD、NASH 或纤维化的 CK-18 AUROC 分别为 0.77（95%CI=0.71-0.84）、0.65（95%CI=0.59-0.71）和 0.68（95%CI=0.61-0.75）。NAFLD、NASH 和纤维化的总灵敏度/特异性分别为 63%（57-70%）/83%（69-92%）、58%（51-65%）/68%（59-76%）和 54%（44-63%）/85%（75-92%）。CK-18 与 ALT 相关性最强（r=0.57，p<0.0001）和脂肪组织 IR（胰岛素抑制 FFA：r=-0.43；p<0.001），与脂肪变性、小叶炎症和纤维化相关性较弱（r=0.28-0.34，均 p<0.001），但与气球样变、BMI、代谢综合征或 T2DM 无关。
血浆 CK-18 对 NAFLD 和纤维化具有较高的特异性，但由于其灵敏度有限，不能作为 NASH 分期的筛查试验。将其作为一个与其他生物标志物或临床/实验室检测联合的诊断组合是否有用，需要进一步研究。
