The Significance Of CK18in Post Hepatitis B Cirrhosis,Hepatocellular Carcinoma And Surgery-associated Liver Injury

BackgroundChronic hepatitis B had been a great threat to Chinese people’s health. Reccurent liver imflammation induces fibrosis, leading to irreversible cirrhosis, and then hepatocellular carcinoma emerges. There are up to100million chronic hepatitis B carriers in China, and the deaths caused by post chronic hepatitis cirrhosis is24.5/106per year; the deaths caused by hepatocellular carcinoma is14.5/106per year. The prevalence of hepatitis B had decreased remarkbly, as a result of the great improvement of vaccination coverage. Nevertheless, it is still in a high level, especially in some rural areas. The cirrhosis and hepatocellular carcinoma turn up in an asymptomatic way, the are often in a relatively late stage when diagnosed. Therefore, the early diagnosis of cirrhosis and hepatocellular carcinoma in of great importance.The combination of serum AFP and US had been widely used in surveillence of hepatocellular carcinoma, yet the exploration for better biomarkers is still going on. Recently, GP-73, GPC-3, AFP-L3had seemed promising.Howerver, the early diagnosis of liver cirrhosis remains a tough case. Experimental and clincal studies provided detailed knowledge of the pathogenesis of liver cirrhosis, bringing many kinds of biomarkers like PⅢNP、HA、LN, into our sight. Nevertheless, even the relatively best and most extensively evaluated ones do not meet the criteria of an ideal marker. Recently, the gold standard of diagnosing liver cirrhosis is still biopsy, which is invasive and unfit for surveillance. Better biomarkers for early diagnosis of liver cirrhosis is an strong and urgent need.CK18belongs to the cytokeratin superfamily, it is a component of cytoskeleton. Several kinds of epithelial cells express CK18. It has been noticed that serum CK18is elevated in cirrhosis and HCC patient, yet the significance of CK18for the pathogenesis and diagnosis of liver cirrhosis and HCC remains unknown.CK18is a component of cytoskeleton, it can be released into plasma when hepatocytes are damaged. We assume that HCC and surgery-associated liver injury could be estimated by the elevation of serum CK18level. Meanwhile, the significance of the dynamic changes of serum CK18level, for the evaluation of surgery-associated liver injury and postoperation recovery had not been reported, it is a study of great clinical value.Objective(1) Based on the significance of CK18in post hepatitis B cirrhosis and hepatocellular carcinoma, our study aims first to determining whether serum CK18elevate in patients with liver cirrhosis and hepatocellular carcinoma in the background of chronic hepatitis B;(2) Most of the chronic hepatitis B patients in China manifests different stages of liver fibrosis and cirrhosis, it is important to clarify the roles that cirrhosis and hepatocellular carcinoma played in causing the elevation of serum CK18;(3) CK18is a component of cytoskeleton, the damages by surgery would definitely lead to breakage of hepatocytes and release of CK18. It is reasonable to assume that surgery-associated liver injury could be estimated by the elevation of serum CK18level. Our study is to find whether CK18can be a serum marker for surgery-associated liver injury, and the evaluation of postoperation recovery.(4) Operation causes acute damage to hepatocytes, which is different from chronic damage in mechanism. By comparing the degrees of serum CK18elevation caused by operation and cirrhosis/HCC, we can put some insight to the mechanism of acute and chronic liver injury, which can be used for evaluating the progress and prognosis of disease in treating cirrhosis and HCC patients.MethodsDuring December2013and June2014, sequential patients with a diagnosis of HCC and liver carnevous hemangioma were recruited to the study at Liver Surgery Department of Peking Union Medical College Hospital. HCC patients had no anti-tumor therapy within4weeks. Clinical data collected included age, sex, Child-Pugh score, serum AFP, tumor size, Barcelona stage. Peripheral venous blood was drawn in before and day1, day3, day5after operation. M65and M30ELISA were used to test serum level of total CK18and CK18fragments.ResultsCK18significantly elevated in patients with liver cirrhosis and hepatocellular carcinoma in the background of chronic hepatitis B than in control group (total CK18:262.9±130.0U/L, control158.7±44.5U/L, P=0.038; CK18fragments:145.1±69.6U/L, control81.6±15.2U/L, P=0.005). Serum CK18went down close to normal value in day5after operation (total CK18:311.9±158.8U/L, control180.8±54.1U/L, P=0.078; CK18fragments:103.5±32.0U/L, control82.9±8.0U/L, P=0.012). It is difficult to tell the influence of cirrhosis and HCC, because the sample is too small.CK18paralleled ALT changes before and after operation:peak value occured in day1after operation and then gradualy went down, close to the level of before operation in day5. Correlation analysis of the serum CK18released by hepatocyte necrosis and ALT showed a correlation coefficient of0.659in cancer group and0.922in control group. Meanwhile, the serum level of ALT in day5after operation is still higher than before operation (cancer group ALT before operation:19.8±8.0U/L, day5after operation:188.1±119.4U/L, P=0; control group ALT before operation:11.6±3.0U/L day5after operation:99.0±70.4U/L, P=0.01), suggesting CK18may have a shorter half life than ALT, which is the first time reported. The total CK18(before operation:262.9±130.1U/L, day1after operation:1286.9±984.3U/L, P=0.005) and CK18released by hepatocyte necrosis(before operation:117.8±117.2U/L, day1after operation:1065.6±831.9U/L, P=0.002) in day1after operation are remarkbly higher than before operation in a large extent, suggesting the acute liver damage caused by operation can lead to a rather bigger change of serum CK18than chronic liver damage caused by cirrhosis and HCC.Conclusion(1) Serum CK18significantly elevated in patients with liver cirrhosis and hepatocellular carcinoma in the background of chronic hepatitis B, which fit the expected result; the effect of chronic hepatitis B is also considered:studies found that the serum CK18level in chronic hepatitis B carrier without activities of liver inflammatory is rather close to normal value, that is why we believe the elevation of serum CK18is most of the consequence of cirrhosis and hepatocellular carcinoma.(2) Hepatocellular carcinoma may have played a more important role in the elevation of serum CK18than cirrhosis, which is first reported by us; yet we need more cases of patients to make a certain conclusion.(3) This study is the first to find that surgery-associated liver injury can lead to the elevation of serum CK18, which is in line with the significance of CK18in hepatocyte damage. We also found discovered that serum CK18can decrease down to the level before operation in day5after that; while ALT is still higher than before operation. This suggests CK18may have a shorter halflife than ALT, which had not been reported. We can assume that the consistant damage of hepatocytes maintained the elevated level of CK18, and if the damage were reduced, serum CK18level should decrease remarkbly. This is of great importance of the surveillance for chronic liver diseases and the judgement of therapies.(4) The acute liver damage caused by operation can lead to a rather bigger change of serum CK18than chronic liver damage caused by cirrhosis and HCC, suggesting acute liver injury may lead to more severe hepatocyte breakage. Further study can be used for evaluating the progress and prognosis of disease in treating cirrhosis and HCC patients.