The use of β-blockers is associated with a lower risk of developing hepatocellular carcinoma in patients with cirrhosis

Herrera, Iván; Pascual, Sonia; Zapater, Pedro; Carnicer, Fernando; Bellot, Pablo; Palazón, José M.

doi:10.1097/meg.0000000000000677

Cited by 21 publications

(17 citation statements)

References 17 publications

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“…Other potential effects of beta-blockers upon cirrhotic patients: To further investigate the haemodynamically independent effects of beta-blockade in patients with cirrhosis, Thiele et al[42] performed a meta-analysis of 23 RCTs on 2618 patients finding a reduced incidence of hepatocellular carcinoma (HCC) in patients receiving NSBBs [risk difference 0.026, 95% CI 0.052-0.001, number needed to treat (NNT) 38 patients]. Recently, Herrera et al[43] prospectively evaluated 173 patients included in the early HCC detection program for a median follow-up time of 11 years. The cumulative incidence of HCC was significantly lower in NSBB users compared to non-users (6% vs 19% at 10 years, 16% vs 24% at 15 years), with beta-blockade being the only parameter inversely correlated with HCC development on multivariate analysis.…”

Section: Currently-used Medicationsmentioning

confidence: 99%

Current and future pharmacological therapies for managing cirrhosis and its complications

Kockerling

Nathwani

Forlano

et al. 2019

WJG

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Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis, and may impede hepatic fibrogenesis and decompensation. Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management, nutritional optimisation and patient education.

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Section: Currently-used Medicationsmentioning

confidence: 99%

Current and future pharmacological therapies for managing cirrhosis and its complications

Kockerling

Nathwani

Forlano

et al. 2019

WJG

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“…Some studies reported that NSBB was not associated with increased mortality among decompensated cirrhotic patients with ascites [6][7][8][9], whereas Kalambokis GN, et al [10] found that an increased mortality was observed in Child-Pugh C cirrhotic patients with ascites if using NSBB for more than six months. Moreover, NSBB could reduce cancer risk [11,12], including hepatocellular carcinoma (HCC) [13,14]. The issue about the use of NSBB on the prognosis in compensated cirrhotic patients without major complications has seldom been reported.…”

Section: Introductionmentioning

confidence: 99%

The Role of Non-Selective β-Blockers in Compensated Cirrhotic Patients without Major Complications

et al. 2019

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Background and Objectives: Non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in cirrhotic patients with clinically significant portal hypertension (CSPH), but remained uncertain for compensated cirrhotic patients without major complications. We aimed to compare the clinical outcomes between propranolol users and non-users of a CC group without major complications. Material and Methods: We conducted this population-based cohort study by using the Taiwanese Longitudinal Health Insurance Database 2000. Propranolol users (classified as cumulative defined daily dose (cDDD)) and non-PPL users were matched with a 1:1 propensity score in both cohorts. Results: This study comprised 6896 propranolol users and 6896 non-propranolol users. There was no significant impact on the development of spontaneous bacterial peritonitis between the two groups (aHR: 1.24, 95% confidence interval (CI): 0.88~1.75; p = 0.2111). Male gender, aged condition, and non-liver related diseases (peripheral vascular disease, cerebrovascular disease, dementia, pulmonary disease, and renal disease) were the independent risk factors of mortality. PPL users had significantly lower incidence of HCC development than non-users (aHR: 0.81, p = 0.0580; aHR: 0.80, p = 0.1588; and aHR: 0.49, p < 0.0001 in the groups of 1–28, 29–90, and >90 cDDD, respectively). Conclusion: The current study suggested that high cumulative doses of propranolol could decrease the risk of hepatocellular carcinoma among compensated cirrhotic patients without major complications. Further large-scale prospective studies are still required to confirm the findings in this study. Results: It remained uncertain whether non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in compensatory cirrhotic patients without major complications. This study aimed to compare the clinical outcomes between propranolol users and non-users of the CC group without major complications.

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“…One potential explanation for this effect is the reduction in gastrointestinal bleeding by β receptor blockers; another possible explanation is a reduction in the incidence of liver cancer ( 18 ). It was also demonstrated that propranolol reduced the 10-year cumulative incidence of liver cancer in patients with hepatitis C-associated cirrhosis ( 19 ). Liver cancer in patients in China primarily develops from hepatitis B virus (HBV)-associated liver cirrhosis and is frequently accompanied by an increase in α-fetoprotein levels ( 20 – 22 ).…”

Section: Discussionmentioning

confidence: 99%

Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells

et al. 2018

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An increasing amount of evidence indicates that the inhibition of β adrenergic signaling can result in the inhibition of tumor growth. However, the role of propranolol in liver cancer and the underlying mechanism remain to be elucidated. The present study aimed to investigate the role of propranolol in liver cancer cell lines and provide evidence for further clinical study. Propranolol was added at different concentrations to HepG2 and HepG2.2.15 liver cancer cells and HL-7702 normal human liver cells. The proliferation of the cell lines was monitored by live-cell imaging at a range of time intervals. Immunofluorescence using DAPI and Hoechst 33342/propidium iodide (PI) staining, Annexin V-FITC/PI double-staining flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction were used to investigate the effect of propranolol on liver cancer cell apoptosis. The proliferation of HepG2 and HepG2.2.15 cells was inhibited by 40 and 80 µmol/l propranolol. However, the proliferation of HL-7702 cells was not affected by <160 µmol/l propranolol. Propranolol treatment decreased the expression of adrenergic receptor β-2 to a greater extent than adrenergic receptor β-1, and induced apoptosis in the liver cancer cells. The apoptotic rates of HepG2 and HepG2.2.15 cells increased following treatment with propranolol, while the apoptotic rate of HL-7702 cells was not affected. Propranolol promoted poly (ADP-ribose) polymerase cleavage and decreased the expression of full-length caspase-3 in liver cancer cell lines; it induced S-phase arrest in HepG2 and HepG2.2.15 cell lines, while HL-7702 cells were arrested at the G0/G1 phase of the cell cycle. Thus, it was demonstrated that propranolol inhibited proliferation, promoted apoptosis and induced S-phase arrest in HepG2 and HepG2.2.15 cells.

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The use of β-blockers is associated with a lower risk of developing hepatocellular carcinoma in patients with cirrhosis

Abstract: Cirrhotic patients treated with BB have a lower cumulative probability of developing HCC during the 10 years after the diagnosis of cirrhosis.

Cited by 21 publications

References 17 publications

Current and future pharmacological therapies for managing cirrhosis and its complications

Current and future pharmacological therapies for managing cirrhosis and its complications

The Role of Non-Selective β-Blockers in Compensated Cirrhotic Patients without Major Complications

Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells

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