In chronic hepatitis C virus (HCV) infection, host-related and environmental factors influence fibrosis progression.1 In morphological studies, the presence of venous lesions suggestive of intrahepatic thrombotic events have led to the postulation that thrombosis might play a key role in the pathogenesis of fibrosis and cirrhosis.2 We investigated the association between the most common genetic risk factor for venous thrombosis, activated protein C (APC) resistance owing to the factor V Leiden (FV Leiden)3, and cirrhosis in patients with chronic HCV infection.
Consecutive patients with HCV infection undergoing liver biopsy were included. Biopsy samples smaller than 10 mm were excluded. Biopsies were evaluated according to METAVIR scoring.4 APC resistance was assessed by the APC-resistance modified test, which is highly sensitive and specific for the identification of the FV Leiden carriers.5 Odds ratio (OR) and 95% confidence interval (95% CI) were calculated by logistic regression and adjusted for the factors known to influence fibrosis progression. The reported P values were corrected for multiple imputation.
Among the 559 patients with chronic HCV infection studied, 75 were cirrhotic and 484 were noncirrhotic (15 F0, 273 F1, 138 F2, and 58 F3 fibrosis score). Median age was 54 years (range, 32-77) in the cirrhotic group and 44 (20-78) in the noncirrhotic group. Median age at infection and median duration of infection were 26 and 22 years, respectively, in the cirrhotic group and 22 and 19 years, respectively, in the noncirrhotic group. Alcohol intake above 50 g/day was more frequent among cirrhotic than noncirrhotic patients (28% vs. 16%). One third of each patient group had previously received antiviral therapy. APC resistance was found in 8/75 (10.6%) patients with cirrhosis and 14/484 (2.9%) without cirrhosis. The overall OR for cirrhosis in the presence of APC resistance was 4.0 (P = .003). After adjustment for gender, age at infection, duration of infection, alcohol intake, and previous antiviral treatment, the presence of APC resistance was associated with an adjusted OR for cirrhosis of 3.6 (P = .01) (Table 1).
|Odds Ratio (95% CI)||P Value||Adjusted Odds Ratio (95% CI)||P Value|
|Female||0.6 (0.4–1.1)||.087||0.6 (0.3–1.1)||.100|
|Age at infection (years)|
|20–30||1.3 (0.6–2.8)||.484||1.8 (0.7–4.1)||.200|
|>30||2.6 (1.3–5.0)||.011||4.1 (1.9–9.0)||.001|
|Duration of infection (years)|
|15–30||1.3 (0.6–2.7)||.555||1.5 (0.7–3.3)||.300|
|>30||2.9 (1.2–7.0)||.015||5.3 (2.0–13.6)||.001|
|>50 g/day||2.0 (1.1–3.7)||.018||2.0 (1.0–3.9)||.038|
|Yes||1.3 (0.8–2.2)||.357||1.1 (0.6–1.9)||.834|
|APC resistance (FV Leiden)|
|Yes||4.0 (1.6–9.9)||.003||3.6 (1.4–8.9)||.010|
In patients with chronic HCV infection, carriers of APC resistance (FV Leiden) were at approximately a fourfold increased risk for development of cirrhosis compared with noncarriers. Wright et al.6 recently reported that possession of the FV Leiden mutation was associated with an OR of 3.28 for fast progression to cirrhosis in HCV infection. It is tempting to speculate that APC resistance (FV Leiden) is a risk factor for cirrhosis because it is a thrombosis risk factor. Recent studies have emphasized the involvement of a clotting process in liver fibrosis:morphological observations of fibro-obliterative lesions of small portal and hepatic veins suggesting thrombotic events in extensive fibrosis2 and stimulation of hepatic stellate cells by thrombin.7
In conclusion, definition of APC resistance (FV Leiden), the most common genetic risk factor for venous thrombosis, as an independent risk factor for cirrhosis is highly important to a better understanding of the pathogenesis of disease progression and to define new therapeutic approaches.