amino - terminal pro - peptide of type iii pro - collagen ( piiinp ) , collagen iv ( civ ) , laminin ( ln ) , and hyaluronic acid ( ha ) are 4 major serum markers for the non - invasive assessment of liver fibrosis [ 14 ] . some examples have been shown as follows . in 1996 , murawaki et al . demonstrated a close relationship of elevated ha with the severity of liver fibrosis in patients with chronic viral liver diseases . in 2000 , plevris et al . found that ha alone could reliably identify the presence of liver cirrhosis in patients with chronic liver diseases of mixed etiologies . in 2000 , the consensus interferon study group also found that ha alone may be effective in non - invasively assessing the degree of liver fibrosis and cirrhosis in patients with chronic hepatitis c virus infection . in 2001 , murawaki et al . suggested the usefulness of piiinp and ha for staging liver fibrosis in chronic hepatitis c . in 2002 , xie et al . confirmed the relationship of ha and civ with the degree of hepatic fibrosis in patients with chronic viral hepatitis . in 2004 , patel et al . found that ha in combination with tissue inhibitor of matrix metalloproteinase 1 and alpha 2-macroglobulin can reliably differentiate between moderate / severe and no / mild fibrosis in patients with chronic hepatitis c infection . in 2004 , the european liver fibrosis group reported that ha and piiinp in combination with age and tissue inhibitor of matrix metalloproteinase 1 can accurately identify the absence of liver fibrosis . in 2005 , cale et al . reported that ha in combination with platelet count , prothrombin index , aspartate aminotransferase , alpha 2-macroglobulin , urea , and age can predict the presence of clinically significant fibrosis in patients with viral hepatitis ; ha in combination with prothrombin index , alpha 2-macroglobulin , and age could predict the presence of clinically significant fibrosis in patients with alcoholic liver diseases ; ha in combination with gamma - glutamyltransferase , bilirubin , platelet count , and apolipoprotein a1 could predict the area of fibrosis in patients with viral hepatitis ; and ha in combination with prothrombin index , alpha 2-macroglobulin , and platelets could predict the area of fibrosis in patients with alcoholic liver diseases . in 2011 , seven et al . confirmed the correlation of piiinp , civ , ln , and ha with advanced fibrosis in patients with chronic hepatitis b and d . in 2015 , el - mezayen et al . found that civ and ln in combination with aspartate aminotransferase - to - platelet ratio index and albumin can be used to identify a very low risk of significant fibrosis in patients with chronic hepatitis c virus infection . theoretically , the grade of liver fibrosis is positively associated with the severity of liver dysfunction , thereby influencing the survival conditions . however , it remains unclear whether serum liver fibrosis markers can predict the prognosis of patients with liver cirrhosis . this was a prospective observational study , which was registered with clinicaltrials.gov ( nct02335073 ) . the study protocol was written by xsq , discussed with our study group , and approved by the medical ethics committee of our hospital . the written informed consent was signed by every participant before liver fibrosis tests were performed . inclusion criteria were : 1 ) patients were admitted to our department ; 2 ) patients were diagnosed with liver cirrhosis ; and 3 ) patients signed the informed consent and agreed to testing of serum liver fibrosis markers ( piiinp , civ , ln , and ha ) . major exclusion criteria were : 1 ) non - cirrhotic patients ; 2 ) malignancy ; and 3 ) repeated admission . the participants were prospectively enrolled by our study group ( zmc n=1 , yh n=17 , xyl n=1 , hl n=2 , xl n=22 , lnr n=14 , dw n=6 , hzw n=2 , jlw n=2 , cyw n=10 , ylz n=3 , xz n=3 , ygz n=18 , and jjz n=7 ) . three researchers ( yp , hd , and ffh ) recorded the regular clinical and laboratory data of participants from the electronic medical charts of our hospital in the printed case report forms . the primary data at admissions were : age , sex , hepatic encephalopathy , ascites , hydrothorax on chest x ray or ct scans , etiology of liver cirrhosis , red blood cell ( rbc ) , hemoglobin ( hb ) , white blood cell ( wbc ) , platelets count ( plt ) , total bilirubin ( tbil ) , albumin ( alb ) , alanine aminotransferase ( alt ) , aspartate aminotransferase ( ast ) , alkaline phosphatase ( alp ) , gamma - glutamine transferase ( ggt ) , blood urea nitrogen ( bun ) , creatinine ( cr ) , prothrombin time ( pt ) , international normalized ratio ( inr ) , potassium ( k ) , and sodium ( na ) . survival condition at the 6 month was obtained by collecting the re - admission and outpatient information in the electronic medical charts and telephone follow - up . three researchers ( xyw , ffh , and xsq ) were responsible for the telephone follow - up . as previously mentioned , a 3-ml fasting venous blood sample was obtained from every participant and then centrifuged . two laboratory researchers ( jc and clx ) tested the piiinp , civ , ln , and ha levels by using the chemiluminescent immunoassay in the lumo microplate luminometer equipment at the lab of our department . the diagnostic kits for the piiinp , civ , ln , and ha were provided by the autobio diagnostics co. , ltd . ( zhengzhou , henan province , china ) . according to the directions of diagnostic kits , the reference values were : piiinp < 15 ng / ml , civ < 95 ng / ml , ln < 130 ng / ml , and ha < 120 ng / ml . statistical analyses were performed by using the spss and medcalc software . spearman non - parametric tests were employed to test the correlation of piiinp , civ , ln , and ha levels with clinical and laboratory data . logistic regression analysis was used to test the statistically significant prognostic factors . between january and june 2015 , 108 cirrhotic patients were included in this prospective observational study . patient characteristics are shown in table 1 . a majority of included patients had hepatitis b virus infection and alcohol abuse as the major etiology of liver cirrhosis . eighty - four percent of patients had child - pugh classes a and b. meld score could be calculated in 104 of them . ascites , rbc , wbc , tbil , alb , alt , ast , ggt , na , pt , inr , child - pugh score , and meld score significantly correlated with civ level ( table 3 ) . ln level . ascites , wbc , tbil , alb , alt , ast , alp , ggt , na , inr , child - pugh score , and meld score significantly correlated with ln level ( table 4 ) . ascites , hydrothorax , rbc , plt , tbil , alb , pt , inr , child - pugh score , and meld score significantly correlated with ha level ( table 5 ) . the logistic regression univariate analysis of factors associated with the 6-month mortality included the absence of ascites ( or=0.184 , 95%ci=0.0380.899 , p=0.037 ) and increased rbc ( or=0.355 , 95%ci=0.1590.795 , p= 0.012 ) , tbil ( or=1.023 , 95%ci=1.0081.039 , p=0.003 ) , ha ( or=1.00003 , 95%ci=1.0000041.000056 , p=0.022 ) , child - pugh score ( or=1.561 , 95%ci=1.1132.152 , p=0.007 ) , and meld score ( or=1.29 , 95%ci=1.1221.483 , p<0.001 ) ( table 6 ) . the auc of child - pugh score , meld score , and ha level for predicting the 6-month mortality was 0.692 ( 95%ci=0.5870.783 , p=0.0276 ) , 0.803 ( 95%ci=0.7070.878 , p=0.0002 ) , and 0.612 ( 95%ci=0.5080.709 , p=0.1531 ) , respectively ( figure 1 ) . there was a statistically significant difference between child - pugh score and ha level ( p=0.0124 ) , but there was not a statistically significant difference between child - pugh score and ha level ( p=0.3421 ) . between january and june 2015 , 108 cirrhotic patients were included in this prospective observational study . patient characteristics are shown in table 1 . a majority of included patients had hepatitis b virus infection and alcohol abuse as the major etiology of liver cirrhosis . eighty - four percent of patients had child - pugh classes a and b. meld score could be calculated in 104 of them . ascites , rbc , wbc , tbil , alb , alt , ast , ggt , na , pt , inr , child - pugh score , and meld score significantly correlated with civ level ( table 3 ) . ln level . ascites , wbc , tbil , alb , alt , ast , alp , ggt , na , inr , child - pugh score , and meld score significantly correlated with ln level ( table 4 ) . ha level . ascites , hydrothorax , rbc , plt , tbil , alb , pt , inr , child - pugh score , and meld score significantly correlated with ha level ( table 5 ) . the logistic regression univariate analysis of factors associated with the 6-month mortality included the absence of ascites ( or=0.184 , 95%ci=0.0380.899 , p=0.037 ) and increased rbc ( or=0.355 , 95%ci=0.1590.795 , p= 0.012 ) , tbil ( or=1.023 , 95%ci=1.0081.039 , p=0.003 ) , ha ( or=1.00003 , 95%ci=1.0000041.000056 , p=0.022 ) , child - pugh score ( or=1.561 , 95%ci=1.1132.152 , p=0.007 ) , and meld score ( or=1.29 , 95%ci=1.1221.483 , p<0.001 ) ( table 6 ) . the auc of child - pugh score , meld score , and ha level for predicting the 6-month mortality was 0.692 ( 95%ci=0.5870.783 , p=0.0276 ) , 0.803 ( 95%ci=0.7070.878 , p=0.0002 ) , and 0.612 ( 95%ci=0.5080.709 , p=0.1531 ) , respectively ( figure 1 ) . there was a statistically significant difference between child - pugh score and ha level ( p=0.0124 ) , but there was not a statistically significant difference between child - pugh score and ha level ( p=0.3421 ) . the first objective was to validate our previous retrospective observational study regarding the correlation of the 4 serum liver fibrosis markers with the severity of liver dysfunction 17 . first , our previous study demonstrated that civ ( coefficient r : 0.2361 , p=0.0006 ) , ln ( coefficient r : 0.2445 , p=0.0004 ) , and ha ( coefficient r : 0.1612 , p=0.0203 ) levels significantly correlated with child - pugh score , but not piiinp level ( coefficient r : 0.02665 , p=0.7031 ) . similarly , the present prospective observational study confirmed that civ ( coefficient r : 0.658 , p<0.001 ) , ln ( coefficient r : 0.450 , p<0.001 ) , and ha ( coefficient r : 0.325 , p=0.001 ) levels significantly correlated with child - pugh score , but not piiinp level ( coefficient r : 0.081 , p=0.414 ) . second , our previous study also demonstrated that civ ( coefficient r : 0.1795 , p=0.0108 ) and ln ( coefficient r : 0.2588 , p=0.0002 ) levels significantly correlated with meld score , but not piiinp ( coefficient r : 0.04573 , p=0.5191 ) or ha ( coefficient r : 0.07926 , p=0.2633 ) level . in contrast , the present study showed that civ ( coefficient r : 0.368 , p<0.001 ) , ln ( coefficient r : 0.343 , p<0.001 ) , and ha ( coefficient r : 0.282 , p=0.004 ) levels significantly correlated with meld score , but not piiinp ( coefficient r : 0.090 , p=0.363 ) level . the possible causes for such a discrepancy could be : 1 ) the patient characteristics were different between the 2 studies ; 2 ) pearson chi - square test was used in the previous study , but spearman non - parametric test was used in the present study ; and 3 ) the correlation of ha level with meld score might be unstable . the second objective was to explore the effect of the 4 serum liver fibrosis markers on the survival of liver cirrhosis patients . logistic regression analysis showed that only ha level , but not piiinp , civ , or ln level , was significantly associated with the 6-month mortality in cirrhotic patients . however , this association was very weak . when we used the roc analysis to evaluate the effect of ha level for the predicting the 6-month mortality , the significance disappeared . indeed , the prognostic value of ha level may be inferior to those of the traditional prognostic models ( i.e. , child - pugh and meld scores ) . therefore , we do not recommend the prognostic values of the 4 serum liver fibrosis markers in liver cirrhosis . first , the in - hospital mortality was very low ( 0.9% , 1/108 ) , and the logistic regression analysis of factors associated with the in - hospital mortality was not performed . second , the information on 6-month mortality was missing in 11 patients ( 10.1% , 11/108 ) . civ , ln , and ha levels significantly correlated with the severity of liver dysfunction , but they could not predict the 6-month mortality rate of cirrhotic patients . therefore , the current evidence does not recommend the prognostic value of serum liver fibrosis markers in liver cirrhosis patients .
backgroundthe prognostic role of serum liver fibrosis markers in cirrhotic patients remains unclear . 
 we performed a prospective observational study to evaluate the effect of amino - terminal pro - peptide of type iii pro - collagen ( piiinp ) , collagen iv ( civ ) , laminin ( ln ) , and hyaluronic acid ( ha ) on the prognosis of liver cirrhosis.material/methodsall patients who were diagnosed with liver cirrhosis and admitted to our department were prospectively enrolled . 
 piiinp , civ , ln , and ha levels were tested.resultsoverall , 108 cirrhotic patients were included . 
 correlation analysis demonstrated that civ ( coefficient r : 0.658 , p<0.001 ; coefficient r : 0.368 , p<0.001 ) , ln ( coefficient r : 0.450 , p<0.001 ; coefficient r : 0.343 , p<0.001 ) , and ha ( coefficient r : 0.325 , p=0.001 ; coefficient r : 0.282 , p=0.004 ) levels , but not piiinp level ( coefficient r : 0.081 , p=0.414 ; coefficient r : 0.090 , p=0.363 ) , significantly correlated with child - pugh and meld scores . 
 logistic regression analysis demonstrated that ha ( odds ratio=1.00003 , 95% confidence interval [ ci]=1.0000041.000056 , p=0.022 ) was significantly associated with the 6-month mortality . 
 receiver operating characteristics analysis demonstrated that the area under the curve ( auc ) of ha for predicting the 6-month mortality was 0.612 ( 95%ci=0.5080.709 , p=0.1531).conclusionsciv , ln , and ha levels were significantly associated with the severity of liver dysfunction , but might be inappropriate for the prognostic assessment of liver cirrhosis .