Smoking Aggravates Inflammation, Fibrogenesis, Angiogenesis and Cancer Risk in Patients With Cirrhosis

Background and Aims Smoking induces a proinflammatory state, yet its role in advanced chronic liver disease (ACLD) remains understudied. This study evaluated its impact on disease‐driving mechanisms and clinical outcomes in ACLD patients. Methods ACLD patients undergoing hepatic venous pressure gradient measurements from 2017 to 2021 were included. The association of smoking with biomarkers of inflammation, fibrogenesis, angiogenesis and the incidence of hepatocellular carcinoma (HCC), extrahepatic malignancies and mortality was examined. Results Among 339 ACLD patients (66.1% men, median age: 56.8 years, MELD: 11, HVPG: 17 mmHg), 62% ( n = 210) were ever‐smokers ( n = 78 former, n = 132 active). Compared to never/former smokers, active smokers exhibited significantly higher white blood cell counts (5.49 vs. former: 4.74 vs. never: 4.25 G/L; p < 0.001) and C‐reactive protein levels (CRP: 0.36 vs. former: 0.29 vs. 0.21 mg/dL; p = 0.035). Active smokers showed upregulated fibrogenic (TIMP‐1: 364 vs. former: 324 vs. never: 278 ng/mL, p < 0.001; P3NP: 20.9 vs. former: 15.6 vs. never: 17.2 μg/L, p = 0.008) and angiogenic (PLGF: 21.7 vs. former: 18.2 vs. never: 19.0 pg/mL, p = 0.004) activity markers. Over a median follow‐up of 30.4 months, ever‐smokers exhibited a higher incidence of extrahepatic malignancies (SHR: 11.30; p = 0.019) and numerically higher HCC incidence (SHR: 2.27 p = 0.150; mostly evident in Child‐Pugh A patients: SHR: 7.44, p = 0.053). All‐cause or liver‐related mortality risk did not differ significantly between ever‐smokers and never‐smokers. Conclusion Smoking is linked to an upregulation of inflammatory, fibrogenic and angiogenic processes in ACLD and increases the risk of extrahepatic malignancies. These findings underscore the importance of strategies supporting smoking cessation in ACLD patients.