Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain.
Hepatology. 2019 Aug;70(2):547-562. doi: 10.1002/hep.30319. Epub 2019 Feb 14.
Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low-molecular-weight metabolites by new high-throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19-9 (CA 19-9) and alpha-fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy-proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14-15 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Conclusion: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
早期和无创方法对肝内胆管癌（iCCA）和肝细胞癌（HCC）的鉴别诊断是当前的临床挑战。通过新的高通量技术分析低分子量代谢物是鉴定生物标志物的一种策略。在这里，我们研究了血清代谢组是否可以为 iCCA 和 HCC 的诊断提供有用的生物标志物，并可以区分 iCCA 和 HCC。由于原发性硬化性胆管炎（PSC）是 CCA 的危险因素，因此还比较了 PSC 和 CCA 患者的血清代谢谱。分析 iCCA、HCC 和 PSC 患者与健康个体（每组 20 人）的血清中脂质和氨基酸水平显示出不同的图谱。几种代谢物对 iCCA 与对照、HCC 与对照和 PSC 与对照的诊断具有较高的价值，其受试者工作特征曲线（ROC）下面积（AUC）大于血清中常用的非特异性肿瘤标志物碳水化合物抗原 19-9（CA 19-9）和甲胎蛋白（AFP），分别用于帮助诊断 iCCA 和 HCC。结合甘氨酸、天冬氨酸、SM（42：3）和 SM（43：2）开发的算法可以准确地区分两种类型的肿瘤（经活检证实）的诊断。所提出的模型产生了 0.890 AUC、75%敏感性和 90%特异性。另一种通过组合 PC（34：3）和组氨酸的算法可以准确地区分 PSC 和 iCCA，AUC 为 0.990、100%敏感性和 70%特异性。这些结果在每组 14-15 名患者的独立队列中进行了验证，并与非酒精性脂肪性肝病/非酒精性脂肪性肝炎患者的图谱进行了比较。结论：某些代谢物血清浓度的特定变化有助于区分 iCCA 与 HCC 或 PSC，并有助于这些疾病的早期诊断。
