The Potential of Angiogenesis Soluble Markers in Chronic Hepatitis C *

Abstract

Angiogenesis, the formation of new vessels, has been reported to play a significant pathogenic role in liver damage-associated hepatitis C virus infection. Most of our current knowledge derives from immunohistochemical studies of hepatic biopsy samples obtained from chronic hepatitis C (CHC) patients. We evaluated whether CHC is associated with elevated serum levels of angiogenesis markers and whether these are modulated by therapy. Vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and soluble Tie-2 (sTie-2) were determined in the serum of 36 CHC patients, before and after receiving antiviral combination therapy with pegylated interferon alpha-2b plus ribavirin, and in 15 healthy controls. CHC patients showed elevated baseline VEGF and Ang-2 levels. After treatment, both factors were decreased, whereas antiangiogenic sTie-2 was increased, indicating a shift toward an "anti-angiogenic" profile of serum markers in CHC patients. In conclusion, this suggests that serum VEGF, Ang-2, and sTie-2 levels could be useful as noninvasive, mechanistically based markers of response to therapy and disease progression in CHC. (HEPATOLOGY 2005;42: 696-701.)

The Effect of Interferon/Ribavirin Therapy on the Levels of Angiopoetin-2 andTIE-2 in Chronic Hepatitis C Patients.

“…Also, Wada et al (2007) (19) reported that interferon alpha treatment decreased the level of Ang-2 in hepatocellular carcinoma patients although it was combined with 5-fluorouracil and concluded that this combination has anti-proliferative and anti-737 angiogenic effects, which we can say also for our combination therapy regardless the virological response; this can be powered by the fact that also, IFN-alpha has been successfully used in patients with pulmonary hemangiomatosis, (20) angioblastomas (21) and hemangioendotheliomas (22) which was via its anti-proliferative and anti-angiogenic effects by decreasing Ang-2 level. On the other hand, in our study, we found that combined therapy by IFN/RBV raised the level of serum sTie-2 from baseline levels to end of treatment levels (17.7 ± 2.1 and 31.2 ± 1.04) respectively; this finding is similar to that mentioned by Salcedo et al (17) where he found a low level of the Ang-2 inhibitor sTie-2 receptor in 36 CHC patients were comparable to the 15 healthy controls which was markedly increased after combination therapy by IFN/RBV. However, in our study, serum Ang-2 and sTie-2 didn't express statistically significant change between responders and non-responders at 48 weeks, while Salcedo et al (17) demonstrated a close relationship between variations in serum levels of angiogenesis markers and response to therapy in CHC patients; this may be due to the smaller number of their patients or differences in samples.…”

“…On the other hand, in our study, we found that combined therapy by IFN/RBV raised the level of serum sTie-2 from baseline levels to end of treatment levels (17.7 ± 2.1 and 31.2 ± 1.04) respectively; this finding is similar to that mentioned by Salcedo et al (17) where he found a low level of the Ang-2 inhibitor sTie-2 receptor in 36 CHC patients were comparable to the 15 healthy controls which was markedly increased after combination therapy by IFN/RBV. However, in our study, serum Ang-2 and sTie-2 didn't express statistically significant change between responders and non-responders at 48 weeks, while Salcedo et al (17) demonstrated a close relationship between variations in serum levels of angiogenesis markers and response to therapy in CHC patients; this may be due to the smaller number of their patients or differences in samples. As regards the relation between the angiogenic factors and viremia, we found that high level of viremia was associated with increased serum levels of Ang-2 and is inversely related to level of sTie-2 Vice versa; while in a study conducted by Helaly and Abou Shamaa (23) who studied the Influence of hepatitis C virus infection on circulating levels of VEGF (another angiogenic factor similar in action to Ang-2) in patients with hepatitis C and hepatocellular carcinoma (HCC), they found a weak correlation between the level of viremia and VEGF.…”

“…In our study, there was a baseline elevated level of serum Angiopoetin-2 (Ang-2) in all patients (544.7 ± 64.1 in patients who achieved EVR, and 553.9 ± 24.9 in those who didn't achieve EVR at 12 weeks of therapy). Similarly, Salcedo et al (2005) (17) found that the serum level of Ang-2 is a significantly higher in chronic hepatitis C (CHC) group compared to a control group, which indicated that Ang-2 may be more relevant to the pathophysiology of the disease; also in another study (18) it was reported that the mean levels of sAng-2 were significantly elevated in HCV, HBV and HCC patients when compared to that in the healthy control subjects. Regarding the response to the combination therapy with interferon and ribavirin in our study, there was a marked reduction in the serum marker Ang-2 before and after therapy at week 48 (545.1 ± 66.8 and 332.6 ± 75.7) respectively; more interestingly, the same reduction was observed also between patients who achieved ETR and those who didn't achieve it (540.7 ± 26.1 and 312.3 ± 33.8) respectively.Similarly, Salcedo et al (2005) (17) founded that antiviral combination therapy markedly decreased Ang-2 levels in CHC patients.…”

“…Similarly, Salcedo et al (2005) (17) found that the serum level of Ang-2 is a significantly higher in chronic hepatitis C (CHC) group compared to a control group, which indicated that Ang-2 may be more relevant to the pathophysiology of the disease; also in another study (18) it was reported that the mean levels of sAng-2 were significantly elevated in HCV, HBV and HCC patients when compared to that in the healthy control subjects. Regarding the response to the combination therapy with interferon and ribavirin in our study, there was a marked reduction in the serum marker Ang-2 before and after therapy at week 48 (545.1 ± 66.8 and 332.6 ± 75.7) respectively; more interestingly, the same reduction was observed also between patients who achieved ETR and those who didn't achieve it (540.7 ± 26.1 and 312.3 ± 33.8) respectively.Similarly, Salcedo et al (2005) (17) founded that antiviral combination therapy markedly decreased Ang-2 levels in CHC patients. Also, Wada et al (2007) (19) reported that interferon alpha treatment decreased the level of Ang-2 in hepatocellular carcinoma patients although it was combined with 5-fluorouracil and concluded that this combination has anti-proliferative and anti-737 angiogenic effects, which we can say also for our combination therapy regardless the virological response; this can be powered by the fact that also, IFN-alpha has been successfully used in patients with pulmonary hemangiomatosis, (20) angioblastomas (21) and hemangioendotheliomas (22) which was via its anti-proliferative and anti-angiogenic effects by decreasing Ang-2 level.…”

Hepatic fibrosis developing in morbid obesity independent of steatohepatitis: new mechanism or the Rube Goldberg machine?

“…The association between hepatic inflammation and angiogenesis is not unique to NAFLD. In persons with chronic hepatitis C, serum levels of proangiogenic markers, VEGF and angiopoietin-2, were elevated at baseline and decreased after interferon-based therapy [14].…”