Predictive and Prognostic Value of Von Willebrand Factor in Patients with Cirrhosis and Esophageal Varices

Background and study aim: Von Willebrand factor (vWF) is released by activated endothelial cells and plays a crucial role in the development of portal hypertension. vWF levels correlate with liver function and venous hepatic pressure gradient (VHPG) and independently predict clinical outcome. The aim was to evaluate serum vWF levels as a predictor for esophageal varices and prognosis in patients with liver cirrhosis. 
Patients and Methods: Sixty two patients with liver cirrhosis, divided into two groups according to presence (group I) or absence (group II) of varices were included, In addition, twenty healthy persons served as control group (group III). All patients were submitted to full history taking, clinical examination, laboratory investigations and abdominal ultrasonography. The severity of liver disease was estimated by Modified Child-Pugh and Model for End Stage Liver Disease (MELD) scores. All patients were underwent upper gastrointestinal endoscopy and vWF assay. 
Results: vWF values were significantly higher in group I (p1=0.001), than controls (p2=0.000), but no significant difference between group II and control group (p3= 0.59). Receiver operating characteristics (ROC) curve analysis of vWF revealed that, vWF at cutoff value of 173.8 µg/ml; the sensitivity for detection of esophageal varices was 80.8%, specificity 76.0%, positive predictive value (PPV) was 93.9%, negative predictive value (NPV) was 55.6%; area under the curve was 86.6.There was significant positive correlation between vWF and Child, MELD, esophageal varices grade and severity of portal hypertensive gastropathy. 
Conclusion: vWF is a good predictor for development of esophageal varices and correlated well with prognosis in patients with cirrhosis.


INTRODUCTION
Clinically, cirrhosis has been regarded as an end-stage disease that invariably leads to death.Unless liver transplantation is done, the only preventive strategies available are the screening for early detection of esophageal varices and hepatocellular carcinoma.Lately, this perception has been challenged, because 1-year mortality in cirrhosis varies widely, from 1% to 57%, depending on the occurrence of clinical decompensating events [1].
Portal hypertension (PH) accounts for the major complications of liver cirrhosis, such as ascites, variceal hemorrhage and decompensation.Early diagnosis of PH is essential for the management of patients with cirrhosis.
In previous studies, it has been shown that early diagnosis, leading to adequate treatment, can significantly reduce the mortality rate of PH-related complications [2, 3].Endothelial dysfunction is considered as an important determinant of the increased intrahepatic vascular resistance in cirrhotic livers [4].
Von Willebrand factor is a large adhesive protein released by activated endothelial cells and represents an indicator of endothelial cell activation [5].VWF is a noninvasive predictor of portal hypertension, esophageal varices and portal hypertensive gastropahty (PHG) in patients with cirrhosis.Increased levels of vWF in liver tissues may lead to the elevation of vWF in plasma [6].vWF increases with every Child-Pugh stage.As vWF is a valuable noninvasive marker in patients with liver cirrhosis [7].So, the aim of this study was to evaluate the predictive power of serum levels of vWF in patients with cirrhosis and esophageal varices.

PATIENTS AND METHODS
Patients.This is a case control study which was carried out on eighty-two subjects.Sixty-two patients with liver cirrhosis were divided into two groups according to presence (group I) or absence (group II) of esophageal varices attended or admitted to Hepatology, Gastroenterology and Infectious Diseases Department, Benha University Hospital, within the period between January and May 2016, after approval by the scientific committee of Benha Faculty of Medicine, in addition to twenty persons served as control group (group III).
Patients with cirrhosis were diagnosed by clinical manifestations, laboratory investigations and ultrasonography.Patients were classified according to presence or absence of varices which was diagnosed by upper gastrointestinal endoscopy.Patients with congestive heart failure, renal failure, lung disease, malignancy, hepatic encephalopathy, gastrointestinal bleeding, portal vein thrombosis, pregnancy, transjagular intrahepatic portosystemic shunt (TIPS), cholestatic liver disease, treatment with vasoactive drugs (beta-blockers), statin, aspirin, antioxidants in previous two weeks were excluded from this work at the time of study Methods.All patients were subjected to full history taking thorough clinical examination and routine laboratory tests including liver biochemical profile as serum bilirubin (total, direct), serum albumin, prothrombin time, international normalized ratio and serum creatinine, viral markers: Hepatitis C virus antibody (HCVAb) and Hepatitis B virus surface antigen (HBsAg).Each patient was assigned a score and a grade reflecting the severity of liver affection according to:  The numerical system of Child

Characteristics of the studied patients
Sixty two patients with liver cirrhosis were included in this study.The cases were divided into two groups according to presence or absence of esophageal varices (OV), cases with esophageal varices (group 1) were fifty three while the other nine cases had no varices (group 2).The mean age was 55.6±7.6 in patients of (group 1) compared to 54.5±6.1inpatients of (group 2).There was no statistically significant difference between groups as regards to the age.The varices were more common in males than females (males were 42 cases and females were 11cases) (Table 1).
There was no statistical significant difference between the studied groups as regards the frequencies of HCV and HBV infections.Most cases of group were in advanced Child grade, when compared to cases group with statistical significance.
MELD score was significantly higher in group I, when compared to group II.By ultrasonography; Ascites, collaterals and periportal fibrosis (PPF) were predominate in group I with statistical significance (Table 1).

Endoscopic findings
In the present study, sixty two cases with liver cirrhosis were included; fifty three of them (85.5%) had esophageal varices and nine patients (14.5%) had no esophageal varices.Portal hypertensive gastropathy (PHG) was predominant in group I with significant difference.The most of OV cases were OV grade III (Table 2).

Serum vWF values in the studied groups
Concerning Serum vWF value, it was significantly higher in group I (330.5)pg/ml (p1=0.001),than in group II (155) pg/ml, higher in group I than controls (155) pg/ml (p2=0.000),but no significant difference between group II and control group (p3=0.59)(Table 3).

Serum vWF as a predictor for esophageal varices
Concerning vWF as a predictor for esophageal varices at cutoff value of 173.8 µg/ml; the sensitivity for detection of esophageal varices was 80.8%, specificity 76.0%, positive predictive value (PPV) was 93.9%, negative predictive value (NPV) was 55.6%; area under the curve was 86.6 denoting good prediction of vWF in prediction of esophageal varices (Table 4 and  Figure1).

vWF and severity of liver disease
There was significant positive correlation between vWF and Child score, MELD score, OV grade and PHG severity (Table 5).

DISCUSSION
Results of the present study revealed that vWF values were significantly higher in group I than group II and controls but no significant difference between group II and control group.
These results are supported by that obtained by Ferlitsch et al. who reported that vWF was significantly higher in patients with PH, compared to patients without PH.VWF values were higher in patients with esophageal varices and history of ascites, compared to patients without, higher vWF levels were significantly associated with varices Odds Ratio (OR) = 3.27; P<0.001) and ascites (OR = 3.93; P < 0.001) [12].vWF is released by activated endothelial cells and therefore represents an indicator of endothelial cell activation and plays a crucial role in high shear stress depending on primary hemostasis.The endothelium plays a crucial role in many vascular diseases and endothelial dysfunction is a fundamental component of the increased hepatic vascular tone of cirrhotic livers [4,18].

Reuken et al. mentioned that an imbalance of increased vWF levels associated with systemic inflammation superimposed on advanced cirrhosis
Activation of thrombocytes and endothelium finally leads to platelet aggregation and, probably, to microthrombotic events.Those events lead to increased portal pressure and furthermore might lead to worsening of fibrosis.As vWF is elevated in liver disease, it might be a key player in establishing liver fibrosis [19].
ROC curve analysis of vWF revealed that, at a cutoff value of 173.8 µg/ml; the sensitivity for detection of esophageal varices was 80.8%, specificity 76.0%, positive predictive value (PPV) was 93.9%, negative predictive value (NPV) was 55.6%; area under the curve was 86.6  There was significant positive correlation between vWF and Child, MELD, OV grade and PHG.These results are comparable to those reported by Lisman et al. who reported that, when patients were classified according to MELD score, they also observed a strong correlation between vWF levels and severity of the disease as assessed by the MELD score (r= 0.448, P<0.001) [7].Lisman et al. also reported that, they added vWF levels were substantially elevated in Child A (488%), child B (711%) and child C (735%) cirrhosis, where in the reference group, the median vWF propeptide levels was 89% (p<0.001).They added, there was positive correlation between vWF and Child classification [7].
Results of the present study are also in agreement with Wu et al. who reported that, linear correlations were observed between levels of vWF in liver tissues with portal hypertensive gastropathy and esophageal varices severity [6].Consistent with these findings, Mura and colleagues documented that elevated vWF levels were able to predict clinical endpoints even after adjustment for HVPG and liver dysfunction.Also, levels of vWF are increased in patients with cirrhosis and correlate with the severity of liver disease [5].

CONCLUSION
VWF is significantly increased in cirrhotic patients with esophageal varices; it had a good power of prediction for development of esophageal varices.vWF correlated will with severity of liver cirrhosis assessed by Child and MELD scores as well as OV grade and PHG.

Conflicts of interest: None
Ethical Approval: A written informed consent was taken from all included patients, and the study was approved by the Ethical Committee of our institution.

Figure ( 1 ):
Figure (1): Receiver operative curve analysis of vWF as a predictor for esophageal varices [13].It was explained by the fact that, chronic liver disease (CLD) with portal hypertension promotes bacterial translocation and subsequent inflammation leading to endothelium activation [14, 15].There is increasing evidence that the deregulated inflammatory response in advanced cirrhosis itself further aggravates portal hypertension in a vicious circle [16, 17] and despite an overall correlation of the hepatovenous pressure gradient (HVPG) with vWF [12].

Table (
1): Demographic features of the studied patient groupsCharacteristicsGroup I (

Table ( 2
): Endoscopic features of the studied patients

Table ( 5
): Correlations between vWF and different parameters in the studied patients Willebrand factor; * , significant; PHG, portal hypertensive gastropathy; MELD, Model for end stage liver disease.
denoting good predictive value of vWF in prediction of esophageal varices.These results are comparable to those reported by Ferlitsch et al. who reported that, the most important finding of their study is that a vWF cutoff at 315 can clearly stratify patients with compensated and decompensated liver cirrhosis [12].