Non‐hemodynamic effects: Repurposing of nonselective beta‐blockers in cirrhosis? Article Swipe

To the Editor: Liver cirrhosis (LC), the end-stage condition of chronic liver disease, results in >1,300,000 annual deaths worldwide. Meanwhile, the global incidence of decompensated cirrhosis is rising yearly.1 Following clinically significant portal hypertension (CSPH) in the late compensated stage of LC, as the disease progresses to the decompensated stage, ascites, gastroesophageal variceal bleeding, hepatic encephalopathy (HE), and other severe complications present. Nonselective beta-blockers (NSBBs) have currently served as the first-line therapy for primary and secondary prophylaxis of portal-hypertensive gastrointestinal bleeding, as recommended by practice guidelines.2 Moreover, recent recommendations have extended the use of NSBBs to compensate LC patients with CSPH.2 In addition to the hemodynamic effect of lowering the risk of variceal bleeding, NSBBs have recently been shown to exert non-hemodynamic effects through a reduction in intestinal mucosal permeability and intestinal bacterial translocation.3 Thereby, the incidence of non-bleeding cirrhotic complications, including spontaneous bacterial peritonitis (SBP), HE, and hepatocellular carcinoma (HCC), has significantly reduced, which may defer the progression to decompensation.3 However, few studies have discussed the important effects that may lead to the repurposing of NSBBs. In this paper, we summarized the pathophysiological basis of NSBBs in the progression of SBP, HE, HCC, ascites, and acute-on-chronic liver failure (ACLF). Furthermore, we briefly reviewed the effects of NSBBs based on high-quality evidence derived from randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large-scale observational studies, aiming to provide balanced insights to enrich the therapeutic strategy of LC. SBP is the most prevalent bacterial infection among patients with decompensated LC. NSBBs can effectively accelerate small intestinal transit and decrease intestinal bacterial translocation. They may also ameliorate portal hypertension (PHT)-induced mesenteric blood congestion, thus decreasing the incidence of SBP.3 A nationwide, population-based, retrospective study conducted in Denmark suggested that propranolol could substantially lower the risk of SBP in patients with decompensated cirrhosis.4 Moreover, two recent meta-analyses reported the effectiveness of NSBBs in preventing SBP in cirrhosis patients with ascites,5, 6 although one found a nonsignificant reduced incidence of SBP in the NSBB group5 (Table 1). 1. NSBBs versus non-NSBBs 2. Hemodynamic responders versus non-responders Propranolol: 80 mg/d Carvedilol: 18.8 mg/d Carvedilol: 12.5 mg/d Propranolol: 100 mg/d Carvedilol: 12.5 mg/d Carvedilol: 12.5 mg/d HCC is the third leading cause of cancer mortality globally. The incipient symptoms of HCC are usually latent and atypical. A screening program to improve prognosis through early diagnosis is essential as it may lead to curative therapeutic interventions for early stage HCC.12 The therapeutic potential of NSBBs on HCC can be explained by the following mechanisms. First, widespread pathological bacterial translocation in cirrhosis patients with PHT results in endothelial dysfunction and systemic inflammation; the latter is considered a key driver of the malignant transformation of hepatocytes. Second, the antiangiogenic properties of NSBBs may suppress catecholamine-driven cancer cell migration, as well as inhibit tumor angiogenesis, invasion, and proliferation, thus arresting tumor growth.12 From the clinical perspective, based on Cerner's Health Facts database, Wijarnpreecha et al. retrospectively analyzed 107,428 cirrhosis patients and reported that the use of either carvedilol or propranolol was associated with a significant reduction in HCC risk, regardless of cirrhosis severity and complications, while the use of NSBBs reduced the absolute risk of HCC by 25%–39%.13 Another retrospective study performed in large tertiary medical centers in Taiwan, China suggested that propranolol can effectively reduce the incidence of HCC in patients with alcoholic cirrhosis.12 However, recently published meta-analyses and RCTs draw mixed conclusions; the meta-analyses concluded that NSBBs were able to prevent HCC, whereas the RCTs did not support this conclusion7-9 (Table 1). HE is a neuropsychiatric disorder that develops in patients with end-stage chronic liver disease; it is usually caused by severely impaired liver function and/or a portosystemic shunt. Up to 80% of cirrhosis patients may suffer from HE during disease progression. In addition to hyperammonemia, systemic inflammation, intestinal barrier dysfunction, and alteration of intestinal microbiota have been implicated in HE development. An NSBB-related reduction in intestinal permeability and mitigation of inflammation may reduce the occurrence of HE.3, 14 Nevertheless, studies by Labenz and colleagues indicated that NSBBs may increase the risk of developing an HE episode. Specifically, they reported that NSBBs affect cognitive and memory function through an increase in the plasma concentration of ammonia. Therefore, NSBBs may be associated with the onset of subclinical HE and aggravation of overt HE in patients with decompensated LC.14 Clinical trials on the effect of NSBBs in preventing HE were also inconclusive; one RCT indicated that carvedilol may delay the first episode of HE, but two other RCTs did not confirm the significant preventive effect7, 8, 10 (Table 1). In addition to the aforementioned non-bleeding complications, a recent retrospective study nested in a large-scale prospective cohort of decompensated cirrhosis patients demonstrated that NSBB treatment was associated with improved ACLF in terms of chronic liver failure consortium (CLIF-C) ACLF scores and short-term mortality.15 It was hypothesized that the underlying mechanism was that the sustainable use of NSBBs can alleviate the severity of systemic inflammation, which is remarkably elevated in ACLF patients.11 However, to date, there has only been one published RCT addressing this issue, which revealed that carvedilol reduced the 28-day mortality and improved the ACLF grades for up to 2 weeks; of note, the actual incidence of ACLF in patients on NSBBs compared with that in patients on placebo remains unknown11 (Table 1). Further high-quality studies are needed to determine this. Ascites is the most common clinical manifestation of early decompensation of LC, with an annual incidence of 10% in compensated LC patients. Although NSBBs prevent ascites mainly via hemodynamic mechanisms by reducing portal pressure, recent evidence has indicated that non-hemodynamic mechanisms may also be involved. In this context, NSBBs have been reported to improve intestinal permeability and inhibit the release of pro-inflammatory cytokines to exert anti-inflammatory activities.16 Unfortunately, only non-randomized retrospective studies have reported that non-hemodynamic biomarkers of NSBBs are independent protective factors of further decompensation, including ascites.16, 17 Therefore, high-quality data addressing this important non-bleeding complication are expected in the future. In summary, NSBBs serve as a basic medication to decelerate the progression of LC in the compensated stage through the combination of hemodynamic and non-hemodynamic effects. For patients in the decompensated stage, NSBBs have the potential to prevent further decompensation and thereby improve the long-term prognosis.3 However, establishing a new indication of NSBBs based on non-hemodynamic effects requires two lines of further investigation. First, the underlying mechanisms of NSBBs in preventing decompensation events such as SBP, HCC, and HE remain unclear and require further investigation. Moreover, the improvements of non-hemodynamic effects have not been widely verified in clinical practice, especially in RCT studies. Nonsignificant and conflicting results were observed in real-world observations.14 Second, although some studies found that non-hemodynamic indicators were partly correlated with those of the hemodynamic response, non-hemodynamic benefits could be achieved by different types of NSBBs at various doses, as summarized in Table 1.16 Accordingly, the optimal dose and type of NSBB for optimal non-hemodynamic effects remains unknown, and a standardized prescription has not been established. To provide reliable and precisive treatment guidance, additional well-designed clinical trials, and prospective follow-up studies are highly warranted in the future to explore the effect of NSBBs in cirrhosis patients at different disease stages and with various complications. Yi Yang, Mingkai Li, and Xing Wang planned and designed the study. Yi Yang, Mingkai Li, Jinni Luo, Hongsheng Yu, and Xing Wang performed the literature review. Hong Tian and Xing Wang provided administrative and material support for the study, and critically reviewed the manuscript. All authors wrote the manuscript and approved this version of submitted manuscript. None. This study was supported by grants from the National Natural Science Foundation of China (No. 82070574). The authors declare no conflict of interest. All data relevant to the study have been included in the published paper. All data relevant to the study have been included in the published paper.