Wisplinghoff Medical Laboratories, Cologne, Germany.
Clin Chim Acta. 2013 Jun 5;421:126-31. doi: 10.1016/j.cca.2013.02.029. Epub 2013 Mar 15.
Still a challenging medical problem is the non-invasive monitoring of patients with a variety of chronic liver diseases being on risk to develop fibrosis, cirrhosis, and, finally, primary liver cell carcinoma. Previously, we have shown that CTGF/CCN2, a down-stream mediator of TGF-β, in serum might be a promising non-invasive biomarker of fibrosis, which is extended in the following study to cirrhosis and liver cell carcinoma. Healthy individuals (n=56), as well as fibrotic (n=77), cirrhotic (n=17), and HCC-patients (n=72) with chronic hepatitis B (HBV) infection, clinically, biochemically and histopathologically well characterized and classified, were included for the measurements of CTGF-concentrations in serum using a newly developed CTGF-enzyme immunoassay. A statistical significant increase of the mean serum CTGF-concentrations was associated with different stages of fibrosis, ranging from 15.9 μg/L (S0), 20.3 μg/L (S1/2) to 36.9 μg/L (S3/4). The highest CTGF-concentrations were measured in cirrhotic patients (43.6 μg/L), compared to healthy subjects (17.7 μg/L), followed by a decrease in cirrhotic HCC-patients (38.5 μg/L; p=0.001). Of note, HCC patients without underlying cirrhosis (n=8) had CTGF levels (13.5±13.2 μg/L) comparable to those in healthy controls. No statistical relation between CTGF levels and parameters of liver injury (e.g. AST, ALT) was noticed, but CTGF levels are correlated negatively with serum albumin levels (p=0.007) and platelet counts (p=0.0032), respectively. The latter was negatively correlated with the stage of fibrosis (p=0.025). In HCC patients, CTGF concentrations decreased with tumor progression and size, with lower levels in TNM stage II (30.5 μg/L) and stage III (33.6 μg/L) compared to TNM stage I (41.6 μg/L). Our data suggest a valuable diagnostic impact of CTGF in serum for the follow-up of patients suffering from chronic liver diseases developing fibrosis, cirrhosis and finally HCC. CTGF serum levels in HCC are most likely due to underlying fibrosis/cirrhosis but not due to malignancy per se.
目前，临床上仍存在一个具有挑战性的医学问题，即如何对各种慢性肝病患者进行非侵入性监测，这些患者存在发生纤维化、肝硬化，最终发展为原发性肝癌的风险。在此之前，我们已经证明血清中的 CTGF/CCN2（TGF-β 的下游介质）可能是纤维化的一种很有前途的非侵入性生物标志物，在本研究中，我们将其扩展到肝硬化和肝癌。本研究纳入了 77 例纤维化患者、17 例肝硬化患者和 72 例乙型肝炎病毒（HBV）感染的 HCC 患者，以及 56 名健康个体，对他们的临床、生化和组织病理学特征进行了详细分类，并使用新开发的 CTGF 酶免疫测定法测量了血清中 CTGF 浓度。结果发现，与不同纤维化阶段（从 S0 期的 15.9μg/L、S1/2 期的 20.3μg/L 到 S3/4 期的 36.9μg/L）相关的血清 CTGF 浓度呈统计学显著升高。与健康个体（17.7μg/L）相比，肝硬化患者的 CTGF 浓度最高（43.6μg/L），其次是肝硬化合并 HCC 患者（38.5μg/L；p=0.001）。值得注意的是，8 例无基础肝硬化的 HCC 患者的 CTGF 水平（13.5±13.2μg/L）与健康对照组相当。没有观察到 CTGF 水平与肝损伤参数（如 AST、ALT）之间存在统计学关系，但 CTGF 水平与血清白蛋白水平（p=0.007）和血小板计数（p=0.0032）呈负相关，后两者与纤维化阶段呈负相关（p=0.025）。在 HCC 患者中，CTGF 浓度随肿瘤进展和大小而降低，与 TNM Ⅰ期（41.6μg/L）相比，Ⅱ期（30.5μg/L）和Ⅲ期（33.6μg/L）的 CTGF 浓度更低。我们的数据表明，血清 CTGF 对慢性肝病患者纤维化、肝硬化和最终 HCC 的随访具有重要的诊断价值。HCC 患者的 CTGF 血清水平很可能是由于潜在的纤维化/肝硬化所致，而不是由于肿瘤本身所致。
