Nonselective β-Blockers May Progress the Thrombosis of Portal Venous System in Cirrhotic Patients: A Retrospective Observational Study

Based on a prospectively collected database in which eligible patients should be diagnosed with liver cirrhosis without malignancy and performed both contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and upper gastrointestinal endoscopy during their hospitalizations, we retrospectively screened the patients admitted between August 2013 and October 2019 and selected the patients who performed contrast-enhanced CT and/or MRI scans again to assess the progression of liver disease at their repeated admission. The exclusion criteria were as follows: (1) patients with a history of liver transplantation, splenectomy, or other abdominal trauma; (2) patients received anticoagulants or antiplatelets during study period; (3) contrast-enhanced CT and/or MRI scans were not well preserved; (4) the information regarding use of NSBBs was unavailable; and (5) the duration between baseline and follow-up contrast-enhanced CT/MRI scans was less than 6 months.

The study was conducted in accordance with the Helsinki Declaration and approved by the Medical Ethical Committee of the General Hospital of Northern Theater Command. Due to the retrospective observational nature of the study, the requirement for patient consent was waived.

Age, gender, etiology of liver cirrhosis, laboratory tests at the first admission, including hemoglobin, platelet count, total bilirubin, serum albumin, alanine aminotransferase, aspartate aminotransferase, serum creatinine, sodium, and international normalized ratio at the last admission were collected for all patients; Child–Pugh score, which is composed of ascites, hepatic encephalopathy, total bilirubin, serum albumin, and international normalized ratio, was calculated; and model for end-stage liver disease (MELD) score, which is composed of total bilirubin, serum creatinine, and international normalized ratio, was also calculated [20]. The type, dosage, frequency, and duration of NSBBs were collected. The presence and severity of PVT at the first and last admissions were evaluated by three physicians (FY, SX, and XQ), who were blinded to the use of NSBBs.

Generally, the dosage and frequency of NSBBs followed the recommendations of current guidelines [12‐14]. The detailed information regarding the type, dosage, duration, and adherence of NSBBs was acquired by telephone follow-up. Patients were divided into NSBBs and no NSBBs groups according to the use of NSBBs during the study period. The reasons why these patients did not take NSBB included: (1) contraindication or intolerance to NSBB, and (2) the use of NSBB was not given at the discretion of their physicians. Notably, only patients who had taken NSBBs for 6 months or more were classified as the NSBBs group; in contrast, patients who had never taken NSBBs or had taken NSBBs for less than 6 months were classified as the no NSBBs group.

Contrast-enhanced CT and/or MRI scans were used to determine the presence of PVT. The degree of PVT was recorded based on the most severe thrombosis in any vessel of the portal venous system, including mural PVT (< 50% occlusion), partial PVT (≥ 50% occlusion), complete PVT (> 80% occlusion), and fibrotic cord. The extension of PVT was recorded as follows, including left portal vein (LPV), right portal vein (RPV), main portal vein (MPV), confluence of superior mesenteric vein (SMV) and splenic vein (SV), SV, and SMV.

Progressing thrombosis was a composite endpoint, which included the development and aggravation of PVT (Fig. 1). The dynamic change of PVT was obtained by comparing the findings of contrast-enhanced CT/MRI scans between baseline and follow-up. The development of PVT was defined as de novo occurrence of a thrombus within the portal venous system in patients without PVT. The aggravation of PVT was defined as either the degree or the extension of the thrombus was aggravated in patients with PVT. To standardize this definition of PVT aggravation, a quantitative scoring system was employed. First, according to the degree of the thrombus at each vessel of the portal venous system, mural thrombus (< 50% occlusion), partial thrombus (≥ 50% occlusion), complete thrombus (> 80% occlusion), and fibrotic cord were assigned to 1, 2, 3, and 4 points, respectively. Then, an accumulative score was calculated by adding the points for each individual patient. Finally, the scores obtained between the last and first admissions were subtracted to evaluate a dynamic change of severity of PVT. A positive value (> 0) indicated the aggravation of PVT; otherwise, the aggravation of PVT would not be considered.

Statistical analysis was performed by using the SPSS 20.0 (IBM, College Station, USA) statistical package. Continuous variables were expressed as median (range) and categorical variables as frequency (percentage). Differences in the continuous variables were evaluated by the Mann–Whitney U test and categorical variables were evaluated by the Chi square test. Univariate and multivariate logistic regression analyses were performed to identify the effect of NSBBs on progressing thrombosis in liver cirrhosis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A P value < 0.05 was considered to be statistically significant.

A total of 43 patients were included in this study, including 16 in the NSBBs group and 27 in the no NSBBs group (Fig. 2). Patient characteristics are summarized in Table 1. The median age was 57 years (range 30–76 years) and 35 (81.4%) patients were male. The most common etiology of cirrhosis was alcohol abuse (22, 51.2%) and hepatitis B viral infection (15, 34.9%). A majority of patients had Child–Pugh class A (22, 52.4%). Median MELD score at admission was 10.51 (range 6.87–21.56).

In the NSBBs group, propranolol was prescribed in 15 patients, and propranolol for 10 months was followed by carvedilol in 1 patient. The median dosage of propranolol was 20 mg (range 10–40 mg) per day, and the median duration of NSBBs was 1.56 years (range 0.58–6.15 years). In the no NSBBs group, 25 had never taken NSBB, 1 had taken NSBB for 1 month, and 1 had taken NSBB for 2 months. Additionally, in the no NSBBs group, 8 did not have previous gastrointestinal bleeding, of whom none had undergone endoscopic variceal treatment before; and 19 had previous gastrointestinal bleeding, of whom 12 had endoscopic variceal treatment and 7 did not have previous endoscopic variceal treatment.

The duration between baseline and follow-up contrast-enhanced CT/MRI scans (P = 0.214), grade of esophageal varices (P = 0.297), history of bleeding (P = 0.911), history of esophageal variceal treatment (P = 0.252), and esophageal variceal treatment at the first admission (P = 0.416) were all not significantly different between the NSBBs and no NSBBs groups.

At the first admission, there were 16 patients diagnosed with PVT, including 8 in the NSBBs group and 8 in the no NSBBs group. The commonest location of PVT was MPV (56.2%) and the confluence of MPV and SV (50.0%), followed by SMV (31.2%), SV (25.0%), LPV (25.0%), and RPV (18.8%). The commonest degree of PVT was partial PVT (62.5%), followed by mural PVT (43.8%), complete PVT (12.5%), and fibrotic cord (6.2%).

Among the 16 patients with PVT at the first admission, 12 still had PVT at the last admission. Among the 27 without PVT at the first admission, 5 patients developed de novo PVT at the last admission (Fig. 3). Therefore, there were 17 patients diagnosed with PVT at the last admission, including 8 in the NSBBs group and 9 in the no NSBBs group. The commonest location of PVT was MPV (82.4%), followed by the confluence of MPV and SV (52.9%), RPV (47.1%), SMV (41.2%), SV (29.4%), and LPV (23.5%). The commonest degree of PVT was mural PVT (64.7%), followed by partial PVT (52.9%), complete PVT (41.2%), and fibrotic cord (23.5%).

Thirteen patients had progressing thrombosis. The incidence of progressing thrombosis was significantly higher in the NSBBs group than in the no NSBBs group [50.0% (8/16) vs. 18.5% (5/27), P = 0.030]. Univariate logistic regression analyses also revealed that the use of NSBBs (OR 4.400, 95% CI 1.107–17.482, P = 0.035) was significantly associated with progressing thrombosis (Table 2). Multivariate logistic regression analyses revealed that the use of NSBBs was not independently associated with progressing thrombosis (OR 4.084, 95% CI 0.488–34.158, P = 0.194) (Table 2).