Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.
Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Egypt.
BMC Med. 2020 Nov 12;18(1):336. doi: 10.1186/s12916-020-01784-7.
Keratins (Ks) represent tissue-specific proteins. K18 is produced in hepatocytes while K19, the most widely used ductular reaction (DR) marker, is found in cholangiocytes and hepatic progenitor cells. K18-based serum fragments are commonly used liver disease predictors, while K19-based serum fragments detected through CYFRA21-1 are established tumor but not liver disease markers yet. Since DR reflects the severity of the underlying liver disease, we systematically evaluated the usefulness of CYFRA21-1 in different liver disease severities and etiologies.
Hepatic expression of ductular keratins (K7/K19/K23) was analyzed in 57 patients with chronic liver disease (cohort i). Serum CYFRA21-1 levels were measured in 333 Austrians with advanced chronic liver disease (ACLD) of various etiologies undergoing hepatic venous pressure gradient (HVPG) measurement (cohort ii), 231 French patients with alcoholic cirrhosis (cohort iii), and 280 hospitalized Germans with decompensated cirrhosis of various etiologies (cohort iv).
(i) Hepatic K19 levels were comparable among F0-F3 fibrosis stages, but increased in cirrhosis. Hepatic K19 mRNA strongly correlated with the levels of other DR-specific keratins. (ii) In ACLD, increased serum CYFRA21-1 associated with the presence of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) (OR = 5.87 [2.95-11.68]) and mortality (HR = 3.02 [1.78-5.13]; median follow-up 22 months). (iii) In alcoholic cirrhosis, elevated serum CYFRA21-1 indicated increased risk of death/liver transplantation (HR = 2.59 [1.64-4.09]) and of HCC (HR = 1.74 [1.02-2.96]) over the long term (median follow-up 73 months). (iv) In decompensated cirrhosis, higher serum CYFRA21-1 predicted 90-day mortality (HR = 2.97 [1.92-4.60]) with a moderate accuracy (AUROC 0.64), independently from established prognostic scores.
Hepatic K19 mRNA and serum CYFRA21-1 levels rise in cirrhosis. Increased CYFRA21-1 levels associate with the presence of CSPH and reliably indicate mortality in the short and long term independently of conventional liver biochemistry markers or scoring systems. Hence, the widely available serum CYFRA21-1 constitutes a novel, DR-related marker with prognostic implications in patients with different settings of advanced liver disease.
角蛋白（Ks）代表组织特异性蛋白。K18 由肝细胞产生，而 K19 是最广泛使用的胆管反应（DR）标志物，存在于胆管细胞和肝祖细胞中。基于 K18 的血清片段通常被用作肝病预测指标，而基于 CYFRA21-1 的血清片段则被确定为肿瘤标志物，而不是肝病标志物。由于 DR 反映了潜在肝病的严重程度，我们系统地评估了 CYFRA21-1 在不同肝病严重程度和病因中的有用性。
在 57 名患有慢性肝病的患者中分析了胆管角蛋白（K7/K19/K23）的肝表达（队列 i）。在接受肝静脉压力梯度（HVPG）测量的 333 名患有不同病因的晚期慢性肝病（ACLD）的奥地利人（队列 ii）、231 名患有酒精性肝硬化的法国患者（队列 iii）和 280 名患有不同病因失代偿性肝硬化的住院德国患者（队列 iv）中测量了血清 CYFRA21-1 水平。
（i）在 F0-F3 纤维化阶段，肝 K19 水平相当，但在肝硬化中增加。肝 K19 mRNA 与其他 DR 特异性角蛋白的水平强烈相关。（ii）在 ACLD 中，血清 CYFRA21-1 水平升高与存在临床显著门静脉高压（CSPH；HVPG≥10mmHg）（OR=5.87[2.95-11.68]）和死亡率（HR=3.02[1.78-5.13]）相关；中位随访 22 个月）。（iii）在酒精性肝硬化中，血清 CYFRA21-1 升高表明死亡/肝移植（HR=2.59[1.64-4.09]）和 HCC（HR=1.74[1.02-2.96]）的风险增加，长期随访（中位随访 73 个月）。（iv）在失代偿性肝硬化中，较高的血清 CYFRA21-1 预测 90 天死亡率（HR=2.97[1.92-4.60]），具有中等准确性（AUROC 0.64），独立于既定的预后评分。
肝硬化时肝 K19 mRNA 和血清 CYFRA21-1 水平升高。CYFRA21-1 水平升高与 CSPH 相关，并可独立于常规肝功能生化标志物或评分系统，可靠地预测短期和长期死亡率。因此，广泛可用的血清 CYFRA21-1 是一种新的与 DR 相关的标志物，在不同晚期肝病患者中具有预后意义。
