Portal venous system thrombosis (PVST) is a common and severe complication of liver cirrhosis. The reported prevalence of non-malignant PVST in liver cirrhosis ranges from 10% to 25%. Failure to detect and treat PVST in a timely fashion may not only lead to mesenteric ischemia, but also cause cavernous transformation of portal vein and aggravate portal hypertension.
Thrombophilia has been considered as a major contributor for PVST. However, at present, the utility of thrombophilia work-up in cirrhotic patients with PVST is still controversial. The American College of Gastroenterology (ACG) guideline recommends thrombophilia work-up among patients with liver cirrhosis and PVST, if they have previous history of thrombosis, concomitant thrombosis at unusual sites such as hepatic veins, and family history of thrombosis. But the ACG guideline does not specify which types of thrombophilic conditions are needed to be screened. The European Association for the Study of the Liver (EASL) guideline recommends screening for genetic thrombophilia alone, such as factor V Leiden and prothrombin gene G20210A mutation and methylenetetrahydrofolate reductase C677T mutation, in patients with liver cirrhosis and PVST, but not acquired thrombophilia.
A total of 911 adult (>18 years) patients, who were consecutively admitted to the Department of Gastroenterology of the General Hospital of Northern Theater Command between January 2016 and June 2020 and treated by an attending physician, were retrospectively screened. Finally, 654 patients (219 cirrhotic patients and 435 non-cirrhotic patients) were included in this study. The study protocol was approved by the medical ethical committee of our hospital with an approval number of Y (2020) 032. The requirement for informed consent was waived due to the retrospective nature of this study.
Diagnosis and Assessment
Liver cirrhosis was diagnosed by the history of chronic liver diseases, clinical symptoms and signs, laboratory tests, and abdominal images. If necessary, liver biopsy was performed. The severity of liver disease was estimated according to the Child-Pugh and Model for End-stage Liver Disease (MELD) scoring systems. As previously described, PVST was confirmed by evaluating the patency of portal venous system vessels using contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans or CT portal venography. Portal venous system included left portal vein, right portal vein, main portal vein (MPV), splenic vein, confluence of superior mesenteric vein (SMV) and splenic vein, and SMV.
Hcy level was quantitatively determined using Beckman Coulter AU5821 automated analyzer (Beckman Coulter, America). Reference range was 0 to 20 μmol/L. If Hcy level exceeded 20 μmol/L, HHcy would be diagnosed. aCL and aβ2GPI were qualitatively determined using kits based on enzyme-linked immune sorbent assay from EUROIMMUN Medical Diagnostics (EUROIMMUN, China). aCL and aβ2GPI activity were classified as negative and positive.
Continuous variables were expressed as median (range) and compared by the non-parametric Mann-Whitney U test. Categorical variables were expressed as frequency (percentage) and compared by the Chi-square test or Fisher’s exact test. Hcy level, HHcy proportion, aCL positivity, and aβ2GPI positivity were compared according to the presence of liver cirrhosis (with versus without liver cirrhosis), Child-Pugh classification (Child-Pugh class A versus Child-Pugh class B/C), PVST (with versus without PVST), grade of PVST (MPV thrombosis >50% versus MPV thrombosis <50% and MPV patency), and severity of PVST (with versus without clinically significant PVST).
Liver Cirrhosis Versus No Liver Cirrhosis
Patients with liver cirrhosis were significantly older [56 years (22-90) versus 53 years (16-94); P = 0.001] than those without, but the proportion of male was statistically similar between the 2 groups [151/219 (68.9%) versus 276/435 (63.4%); P = 0.163]. The proportion of positive aβ2GPI was significantly higher in patients with liver cirrhosis than those without [44/108 (40.7%) versus 2/18 (11.1%); P = 0.016]. Median Hcy level [10.16 μmol/L (2.05-56.82) versus 10.25 μmol/L (3.04-96.25); P = 0.273] and proportions of HHcy [29/201 (14.4%) versus 45/395 (11.4%); P = 0.295] and positive aCL [21/108 (19.4%) versus 2/18 (11.1%); P = 0.605] were not significantly different between the 2 groups.
The present study has explored the association of Hcy level, HHcy, aCL, and aβ2GPI with PVST in liver cirrhosis. As for the study design, a major advantage of the present study should be the use of contrast-enhanced CT or MRI or CT portal venography to comprehensively and accurately identify the presence of thrombosis within portal venous system; and another advantage should be that degree of MPV thrombosis and clinically significant PVST are analyzed in order to determine the potential impact of these possible thrombophilia factors on the severity of PVST.
In a study, none had positive aβ2GPI in cirrhotic PVST and non-PVST groups. By comparison, the present study found a relatively high proportion of positive aβ2GPI (39.1% and 40.4% in patients with and without PVST, respectively), but the relationship between positive aβ2GPI and PVST could not be established. Besides, a prospective study demonstrated that the baseline aβ2GPI level could not predict the development of PVST during a 1-year follow-up. Only one previous study had explored the influence of APS on the extension of non-cirrhotic and non-malignant PVST, and did not find any difference in the prevalence of APS between patients with thrombosis within MPV alone and those within MPV and SMV. The present study further found that aCL and aβ2GPI positivity were not significantly associated with MPV thrombosis >50% or clinically significant PVST.
The present study has several major limitations. First, this was a cross-sectional study, so it could not explain the cause-effect association of Hcy, aCL, and aβ2GPI with PVST in liver cirrhosis. Second, multiple measurements of Hcy, aCL, and aβ2GPI were lacking. Third, the titers of aCL and aβ2GPI were not quantitatively measured. Fourth, IgM and IgG types of aCL and aβ2GPI were not clarified. Fifth, lupus anticoagulants, another marker of antiphospholipid antibody, were not measured. Sixth, Hcy level was a component of lipid profile laboratory tests at our hospital, so a majority of our patients underwent Hcy measurement. But only a minority of patients underwent aCL and aβ2GPI measurement.
Positive aβ2GPI may be associated with presence of liver cirrhosis and severity of liver disease, and HHcy may be positively associated with the severity of liver cirrhosis. However, we cannot establish any significant relationship of Hcy, aCL, and aβ2GPI with the presence of PVST, MPV thrombosis >50%, and clinically significant PVST. Therefore, screening for Hcy, aCL, and aβ2GPI should not be considered as routine thrombophilia testing for PVST in liver cirrhosis.