Noninvasive Biomarker of Variceal Bleeding in HCV Cirrhosis

Portal hypertension is a consequence of cirrhosis that is defined by a hepatic vein pressure gradient of >5 mmHg, with a gradient of >10 mmHg indicating clinically significant portal hypertension.¹ Early detection of portal hypertension is critical for the optimal management of related complications. Although hepatic vein pressure gradient measurement represents the most accurate method for evaluation of portal hypertension, it is invasive and not widely available.

In the search for noninvasive markers of portal hypertension, researchers have demonstrated the predictive values of ascites, low platelet count, caput medusa, splenomegaly, and liver stiffness.^2,3 However, these measures may not be applicable to early portal hypertension or compensated cirrhosis, and their utility in predicting variceal bleeding is unknown.

Previous findings have suggested a potential role for von Willebrand factor antigen (vWF-Ag), an indicator of endothelial cell activation, as a predictor of variceal bleeding.⁴ Researchers at Alexandra University in Egypt further explored this possibility in a new prospective study published in the European Journal of Gastroenterology and Hepatology.¹

Researchers compared mean levels of serum vWF-Ag and the VITRO score (defined as the vWF-Ag/platelet ratio) among 3 groups of participants: patients with cirrhosis secondary to hepatitis C virus (HCV) infection and no history of variceal bleeding (n=25), those with HCV-related cirrhosis and upper gastrointestinal bleeding as a result of variceal rupture (n=25), and 80 healthy controls.

The results showed that both measures were higher in patients with variceal bleeding compared with controls and patients without variceal bleeding (P <.001). Researchers found that vWF-Ag levels predicted bleeding with a sensitivity and specificity of 92% and 99.9% at a cutoff level of 100.1ng/mL (area under the curve [AUC]=0.982). The VITRO score predicted bleeding with a sensitivity and specificity of 80% and 68% at a cutoff level of 0.732 (AUC=0.843). In addition, vWF-Ag levels were positively correlated with the grade of esophageal varices in both the group with variceal bleeding and in all patients.

The study authors explained that the increased vWF-Ag in the variceal bleeding group may be caused by “maximal shear strain applied on endothelial cells [which can] be considered an inducing factor for variceal rupture through microthrombi formation, which may occlude vasa vasora supplying submucosal veins that form [esophageal varices], leading to their wall ischemia and rupture.”¹

Based on these findings, the study authors concluded that the use of vWF and the VITRO score as noninvasive biomarkers of variceal bleeding risk in cirrhosis “will help to avoid potentially harmful preventive treatments in patients who will never bleed and to intervene early in patients with a high risk for bleeding.” They noted that additional research is needed on interactions between endothelial dysfunction, procoagulant imbalance, and inflammation in these patients.

For further discussion regarding the predictive value of vWF-Ag in predicting variceal bleeding in this population, Infectious Disease Advisor spoke with one of the study authors, Sameh Lashen, MD, PhD, lecturer of clinical hepatology, gastroenterology, and endoscopy at Alexandria University. In addition, Infectious Disease Advisorconsulted with Sean G. Kelly, MD, assistant clinical professor of

gastroenterology and transplant hepatology at the Ohio State University Wexner Medical Center.

Infectious Disease Advisor: What is the general significance of these study results?

Dr Lashen: Our study focused on the value of measuring vWF in patients with HCV-related liver cirrhosis with portal hypertension. We found that vWF levels can predict the first attack of variceal rupture and bleeding with high sensitivity and specificity. Early identification of these patients will help with early treatment of high-risk varices and prevention of the first attack. This will reduce mortality and morbidity and will also help to prevent unnecessary screening for another group of patients who may never bleed, thus maximizing resources and avoiding complications.

Dr Kelly: Variceal bleeding is the most common, deadly manifestation of cirrhosis. Therefore, predicting the risk for variceal hemorrhage is a very important topic. Noninvasive laboratory tests that accurately estimate bleeding risk would be a major advance. The vWF-Ag and VITRO score appear to be promising laboratory measurements.

Infectious Disease Advisor: What are the key treatment implications for clinicians?

Dr Lashen: We recommend that vWF should be used as a noninvasive marker for early intervention by endoscopy in patients with clinically significant portal hypertension.

Dr Kelly: While these are encouraging data, the data are not yet strong enough to warrant a change clinical practice. The vWF-Ag levels correlated with the presence of ascites. Patients with ascites clearly have portal hypertension, and upper endoscopy is a high priority for them. Although it is helpful to know which patients have the highest risk for bleeding, the more valuable laboratory test would be one with a strong negative predictive value. Knowing the patients who have an extremely low risk for variceal bleeding could prevent unnecessary procedures.

Infectious Disease Advisor: What should be the focus of future research, on this or related topics?

Dr Lashen: We suggest that vWF, as a procoagulant protein, may be involved in portal vein thrombosis, veno-occlusive disorders, and hepatocellular cancer in this group of patients. Future research should explore these relationships.

Dr Kelly: This was a single-center study in patients with HCV-related cirrhosis. These findings will need to be validated in multicenter studies among patients with various causes of cirrhosis.

References

1. Ibrahima EH, Marzoukb SA, Zeid AE, Lashen SA, Taher TM. Role of the von Willebrand factor and the VITRO score as predictors for variceal bleeding in patients with hepatitis C-related cirrhosis. Eur J Gastroenterol Hepatol. 2019;31(2):241-247.
2. Snowdon VK, Guha N, Fallowfield JA. Noninvasive evaluation of portal hypertension: emerging tools and techniques. Int J Hepatol. 2012;2012:691089.
3. Carrión JA, Navasa M, Bosch J, Bruguera M, Gilabert R, Forns X. Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl. 2006;12:1791-1798.
4. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53-61.