PEVIVA用于肝脏疾病——细胞凋亡和肝脏损伤
由细胞凋亡引起肝细胞死亡在所有急性和慢性肝脏疾病中都有出现。细胞修复后的应激反应包括炎症和纤维化都可以由细胞凋亡引起。这些生物学效应中，肝纤维化可能是最严重的，最终肝纤维化恶化成肝硬化。
引起肝纤维化的主要原因是病毒性肝炎（比如乙肝病毒和丙肝病毒感染），酒精性脂肪肝（ASH）和非酒精性脂肪肝（NASH）。实验和临床研究表明肝细胞凋亡有助于形成肝纤维化。进来研究也表明肝细胞凋亡与患有慢性HBV、HCV病人和非酒精性脂肪肝的疾病状态有关。
在临床方面，评估肝脏疾病情况和监测慢性肝脏疾病病人一直以来是个大挑战。虽然肝脏活检被认为是评估患病情况的标准方法，但是这种侵入式的技术有一定风险，不适合疾病监测。
因此，在肝脏损伤的血清标记物和治疗反馈中，非常希望提供一种非入侵式方法检测人肝细胞凋亡状况。» Brochure: M30 Apoptosense ELISA – A Serum Apoptosis Marker for Chronic Liver Disease
肝脏细胞凋亡生物标记物Caspase-cleaved K18 (“M30″)
细胞凋亡的最后常规步骤， caspases (特别是caspase-3 和caspase-7)激活。这些特定的细胞内水解酶可以催化世界几种细胞来源的底物，包括角蛋白18 (K18, 也称为细胞角蛋白18 或者CK18), 由干细胞表达的主要中间丝状体蛋白。
M30单抗检测caspase催化水解K18后在Asp396处形成的新表位(Leers et al., 1999; 专利注册1998). M30 Apoptosense® ELISA与该抗体，试剂盒自出用于肿瘤研究 (Hägg et al., 2002, Ueno et al., 2003, Kramer et al., 2004).
接着发现可用M30 Apoptosense® ELISA检测丙肝病毒（HCV）感染引起的肝细胞凋亡 (Bantel et al., 2004).来自肝细胞，由caspase催化水解K18产生的片段可在血液循环中检测到。 M30 Apoptosense® ELISA可用于HCV的预后好监测（见以下内容). Bantel et al. 首次发现使用M30 Apoptosense® ELISA检测肝细胞凋亡胡，其他研究者也发现与肝细胞凋亡相关的其他疾病，血液循环中 caspase-cleaved K18升高。非酒精性脂肪肝(NASH) 是其中一种疾病，M30 Apoptosense® ELISA 可用于确诊该疾病的患病情况 (Wieckowska et al., 2006)。毒素相关的脂肪性肝炎 (TASH; Cave et al., 2010) 严重胆道感染和严重胆汁淤积的病人 (Yagmur et al., 2007; reviewed by Yilmaz, 2009).也有相似结果报道。
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Leers MP et al. (1999). Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol. 1999 187:567-72. |
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Hägg M et al. (2002). A novel high-through-put assay for screening of pro-apoptotic drugs. Invest. New Drugs 20, 253-259. |
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Ueno T et al. (2003). Measurements of an apoptosis product in sera of breast cancer patients. Eur J Cancer 39, 769-74. |
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Kramer G et al. (2004). Differentiation between Cell Death Modes using Measurements of Different Soluble Forms of Extracellular Cytokeratin 18. Cancer Research 64, 1751-1756. |
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Bantel H et al. (2004). Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. Hepatology 40:1078. |
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Wieckowska A et al. (2006). In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44:27 |
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Yagmur E et al. (2007). Elevated apopto- sis-associated cytokeratin 18 fragments (CK18Asp386) in serum of patients with chronic liver diseases indicate hepatic and biliary inflammation. Clin Biochem 40:651–5. |
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Cave M et al. (2010). Toxicant-associated steatohepatitis in vinyl chloride workers. Hepatology 51:474-81. |
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Yilmaz Y (2009). Systematic review: caspase-cleaved fragments of cytokeratin 18 – the promises and challenges of a biomarker for chronic liver disease. Aliment Pharmacol Ther 30:1103-9. 204:468 |
HCV临床的细胞凋亡标记物
大约全世界人口的3%—超过1700万人口—感染了丙肝病毒。大约70%的感染转变成慢性：与恶化成晚期肝脏疾病有关，比如肝硬化和肝细胞癌症（HCC）。慢性HCV感染病人的M30值大部分与常规替代标记物比如转氨酶水平有关。然后，正常ALT病人和患有HCV相关肝纤维化病人的血清中caspase-cleaved 角蛋白18水平提高，表明M30在检测早期肝脏损伤方面是一个更灵敏的标记物。检测血清样品中caspase活性也反映了那些病人肝脏脂肪变性的程度。另外，在检测慢性HBV感染的病人方面，M30也 一个可信的血清标记物。
时下进行的抗病毒治疗中，大概50%的HCV病人治疗没有效果。所以很需要在早期就能检测出这些疾病（这些疾病对抗病毒治疗无效）。进来对315个病人研究，证明在进行抗病毒治疗时治疗有效病人血清中M30水平会下降，但是治疗无效的病人血清中M30的值不会下降。(Sgier et al., 2010).
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Bantel H et al. (2004). Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury. Hepatology. (2004) 40:1078. |
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Kronenberger B et al. (2005). Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C. J Viral Hepat. (2005) 12:307‑14 |
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Seidel N et al. (2005). The extent of liver steatosis in chronic hepatitis C virus infection is mirrored by caspase activity in serum. Hepatology. (2005) 42:113 |
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Volkmann X et al. (2006). Caspase activation is required for antiviral treatment response in chronic hepatitis C virus infection. Hepatology. (2006) 43:1311 |
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Yagmur E et al. (2007). Elevated apoptosis‑associated cytokeratin 18 fragments (CK18Asp386) in serum of patients with chronic liver diseases indicate hepatic and biliary inflammation. |
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Papatheodoridis GV et al. (2008). Serum Apoptotic Caspase Activity As A Marker Of Severity In Hbeag‑Negative Chronic Hepatitis B Virus Infection. Gut. (2008) 57:500‑6 |
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Sgier C et al. (2010). Effect of antiviral therapy on circulating cytokeratin-18 fragments in patients with chronic hepatitis C. J Viral Hepat. 2010, 17:845-50. |
NASH病人中caspase-cleaved K18
非酒精性脂肪肝是一连串的脂肪不正常现象，从脂肪变性到非酒精性脂肪肝。根据观察，HCV感染病人的脂肪变性与M30的血清水平相关，近来研究表明血清中caspase-cleaved K18水平与NAFLD病人肝脏脂肪变性有关。而且，这项研究血清中caspase-cleaved K18检测可以区分简单的NAFLD和NASH，检测患晚期肝脏疾病的风险。
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Wieckowska A, et al., In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. (2006) 44:27 |
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Yilmaz Y, Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol. (2007) 13:837‑44. |
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Younossi Z. et al., A Novel Diagnostic Biomarker Panel for Obesity-related Nonalcoholic Steatohepatitis (NASH).Obes Surg. 2008 Nov;18(11):1430-7 |
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Feldstein et al., Cytokeratin-18 Fragment Levels as Noninvasive Biomarkers for Nonalcoholic Steatohepatitis: A Multicenter Validation Study. Hepatology, Vol. 50, No. 7, 2009 |
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PEVIVA PEVIVA肿瘤及肝病上皮细胞死亡检测试剂盒
