The Role Of Des-gamma-carboxy Prothrombin In Predicting Liver Function And Prognosis Of Patients With Liver Cirrhosis

Background and aimsCirrhosis is a diffuse liver injury caused by long-term or repeated effects of one or more causes and is the terminal stage of various liver diseases.Cirrhosis has become the14th largest cause of death in the world.The major causes of cirrhosis in most developed countries are hepatitis C virus（HCV）,alcohol abuse and more and more non-alcoholic liver disease.In sub-Saharan Africa and some Asian countries,especially in China,the main cause of cirrhosis is hepatitis B virus（HBV）.Once cirrhosis patients develop ascites,hepatic encephalopathy,upper gastrointestinal bleeding,spontaneous bacterial peritonitis and other complications,it becomes the clinical decompensation that lack of the effective treatment and has high mortality.Therefore,looking for serological markers that can accurately reflect the decompensation and prognosis of patients with liver cirrhosis will help to improve the clinical diagnosis and treatment of patients.Des-gamma-carboxy prothrombin（DCP）is an abnormal prothrombin which one or more glutamic acid（Glu）domain of theγ-carboxyglutamic acid（Gla）domain in its molecular structureesidues were not completely carboxylated toγ-carboxyglutamate（Gla）,thus completely losing normal prothrombin function.^[3]In 1968,Ganrot et al.found that the synthesis of normal prothrombin needs vitamin K and vitamin K deficiency in DCP synthesis.Therefore,DCP is also known as vitamin K deficiency-induced prothrombin II,PIVKA II^[4].In contrast to normal prothrombin,one or more glutamic acid residues of DCP in itsgamma-carboxyglutamatestructurearenotfullycarboxylated to gamma-carboxyglutamate resulting in loss of normal coagulation function.In the absence of vitamin K or taking vitamin K antagonists（such as warfarin）,the prothrombin releases into the blood with non-carboxylated form.Since 1984,Liebman et al.found that DCP was significantly increased in primary hepatocellular carcinoma,a large number of studies in recent years confirmed the diagnostic value of DCP in hepatocellular carcinoma,especially in early stage^[6,7,8,9].Recently domestic scholars conducted a large,multicenter retrospective study and confirmed that DCP diagnosis efficacy of early hepatocellular carcinoma is higher than the alpha-fetoprotein（AFP）,and DCP expression increase is associated with the malignant clinical phenotype and adverse prognosis.The efficacy of combination of DCP with AFP is higher than that of AFP in the diagnosis of hepatocellular carcinoma and determining the prognosis of patients with hepatocellular carcinoma^[10].On the other hand,serum DCP also has important predictive value for the recurrence and death of patients with hepatocellular carcinoma after treatment^[11,12].However,the role of DCP in estimating liver function and predicting the diagonosis of the cirrhotic patients has not been reported yet.Therefore,we intend to detect the expression of DCP in cirrhotic patients and to clarify its correlation with liver function and its role in prognosis evaluation.MethodsA total of 137 paitents with liver cirrhosis,whose serum samples were collected from January 2013 to August 2016 in our hospital,were included in the study.Inclusion criteria:at least 18 years old,diagnosed with liver cirrhosis.Exclusion criteria:alcoholic liver diseases（inclouding alcoholic liver cirrhosis）,primary biliary cholangitis,primary hepatocellular carcinoma,acute liver failure,taking warfarin,vitamin K or cephalosporins before testing,chronic cholecystitis,pancreatic and bile duct diseases,chronic renal insufficiency,respiratory insufficiency,heart failure.All patients included were informed of relevant details and signed informed consent before the retention of blood samples.This research was approved by our Hospital Ethics Committee.All patient blood samples were collected on an early morning within 24 hours after admission in the hospital.The blood samples were sent to the hospital laboratory to test biochemical indexes such as PLT count,albumin,ALT,AST,ALP,GGT,TBil,PT and serum creatinine.Abdomen ultrasound,CT,MRI and other imaging studies were also examined.The relevant test results were calculated to get the Child-Pugh score and MELD scores to assess liver function for patients with cirrhosis.Serum samples of all subjects were sent to the Department of Laboratory Medicine,the other hospital for DCP detection by chemiluminescence enzyme immunoassay（CLEIA）（LUMIPULS EG1200,Fujirebio,Tokyo,Japan）.DCP positive Criteria for reference was provided by kit instructions.The case report form for all patients with cirrhosis was established which was approved by the hospital ethics committee.Subsequently,the database of liver cirrhosis in our hospital was searched.The conplications including ascites,hepatic encephalopathy,spontaneous bacterial peritonitis,upper gastrointestinal bleeding,primary hepatocellular carcinoma were further examined through the hospital medical record system and telephone follow-up.Follow-up time was not less than 6 months.ResultsThis study included 137 patients with cirrhosis.In the group of patients with cirrhosis,73 were males and 64 were females.The average age was 56.80 years（56.80±11.76）.Child-Pugh classification of A,B,C were 55,52 and 30 cases,respectively.The mean MELD score was 8.61（8.61±5.34）.The MELD scores for Child-Pugh A,B,C grade were5.72,8.49 and 14.11,respectively.There is 55 cases of decompensated cirrhosis and 82cases of decompensated cirrhosis.A total of 113 patients with cirrhosis were followed up,including 60 males and 53 females,with a mean age of 57.04 years（57.04±11.80）.The Child-Pugh grade of A,B,C in these follow up patients was 45,42 and 26 cases,respectively,and the mean MELD score was 8.74（8.74±5.54）.MELD scores for Child-Pugh A,B and C grade was 5.93,8.43 and 13.62,respectively.Among them,45patients with compensated cirrhosis and 68 patients with decompensated cirrhosis.The MELD score of decompensation and decompensation was 5.93 and 10.59,respectively.One hundred thirty-seven patients enrolled were divided into two groups at a normal cut-off value of DCP of 40 mAU/mL,of whom 118 were DCP negative（≤40 mAU/mL）and 19 were DCP positive（>40 mAU/mL）.There was no significant difference between the two groups in age and gender.Using a cut-off value of 40 mAU/mL as normal value for DCP,1.82%（1/55）was positive in patients with Child-Pugh A class;21.15%（11/52）was positive in Child-Pugh B,and 23.33%was positive in Child-Pugh C.Mann-Whitney U test showed that patients with DCP≥40 mAU/ml had a lower level of albumin and higher levels of bilirubin,prothrombin time and international standardization ratio as compared with patients with DCP<40 mAU/ml,suggesting that DCP level was negatively correlated with liver function in cirrhotic patients.Sperman correlation test showed a significant positive correlation between DCP levels and MELD scores（r=0.259,P=0.021）in patients with Child-Pugh B and C.Further study found that the patients with DCP≥40 mAU/mL developed more ascites（χ²=5.744,P=0.022）and spontaneous bacterial peritonitis（χ²=97.636,P=0.019）in compared with the patients with DCP value<40 mAU/mL,suggesting that serum DCP levels were positively related to the development of ascites and spontaneous bacterial peritonitis（SBP）in patients with cirrhosis.4.Relationship between DCP and the prognosis of patients with cirrhosisThrough regular follow-up of patients with cirrhosis,we found that DCP expression was significantly associated with clinical decompensation in compensated patients and was significantly associated with liver-related mortality in patients with cirrhosis.Conclusion1.Serum DCP can be used as an indicator of liver function in cirrhotic patients.2.Serum DCP level is closely related to the occurrence of cirrhosis-related complications and can be used as an index to predict the occurrence of cirrhosis complications.3.DCP can reflect the severity of patients with cirrhosis to some extent,and has certain clinical significance for the assessment of the prognosis of patients with cirrhosis.