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Cigarette smoking and liver diseases

  • David Marti-Aguado
    Affiliations
    Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, Valencia, Spain

    Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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  • Ana Clemente-Sanchez
    Affiliations
    Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Liver Unit and Digestive Department, Hospital General Universitario Gregorio Marañon, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
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  • Ramon Bataller
    Correspondence
    Corresponding author. Address: Center of Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, 201.19 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
    Affiliations
    Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Published:February 03, 2022DOI:https://doi.org/10.1016/j.jhep.2022.01.016

      Summary

      Cigarette smoking is a preventable risk factor for premature morbidity and mortality. A history of smoking is observed in approximately 40% of patients with liver disease, while a growing number of studies are investigating the potential impact of smoking in chronic liver diseases. This review discusses the effects of smoking on liver diseases, at multiple levels, with a focus on its potential causal role. Clinical evidence indicates that cigarette smoking negatively impacts the incidence and severity of fatty liver disease, fibrosis progression, hepatocellular carcinoma development, and the outcomes of patients with advanced liver disease. The underlying mechanisms are complex and involve different pathophysiological pathways including oxidative stress and oncogenic signals. Importantly, smoking promotes cardiovascular disease and extrahepatic cancers in patients with steatohepatitis and in transplant recipients. We discuss how promoting smoking cessation could improve the rates of treatment response (in clinical trials) and fibrosis regression, while reducing the risk of hepatocellular carcinoma and improving liver transplant outcomes. Finally, we discuss current challenges such as the referral of smokers to specialised units for smoking cessation.

      Keywords

      Introduction

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      Table 1Causal-relationship criteria supporting a deleterious effect of cigarette smoking in liver diseases.
      Causality criteriaDefinitionExample
      StrengthMagnitude of the associationCurrent smokers attributable risk fraction for HCC
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      Biological gradientDose-response curve and reversibilityIncreased fibrosis severity in NAFLD and PBC
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      CoherenceConsistent with existent knowledgeProfibrogenic effect of tobacco in different organs
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      AnalogySimilarities with other associationsNAFLD and smoking are linked to metabolic syndrome features
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      AMPK, AMP-activated protein kinase; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; PBC, primary biliary cholangitis.

      Smoking and fatty liver disease

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      All patients with liver disease who are active cigarette smokers should be advised and assisted to quit smoking.
      The most convincing evidence supporting a link between smoking and NAFLD comes from large studies that included histological analysis of liver tissue. Ancillary studies from the non-alcoholic steatohepatitis (NASH) Clinical Research Network database have evaluated the association of smoking with the severity and progression of liver disease .
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      Figure thumbnail gr1
      Fig. 1Effects of cigarette smoking across the spectrum of liver disease reported in different investigation-related settings.
      Summary of cigarette smoking outcomes in particular disease groups (e.g. those with fatty liver disease, fibrosis and hepatocellular carcinoma, including liver transplant recipients). Evidence was evaluated from population-based, disease-based and longitudinal studies. AlcHep, alcoholic hepatitis; ALD, alcohol-related liver disease; CVD, cardiovascular disease; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; LSM, liver stiffness measurement; MHE, minimal hepatic encephalopathy; NAFLD, non-alcoholic fatty liver disease; PBC, primary biliary cholangitis.
      Patients with alcohol misuse are 3-fold more likely to smoke heavily than the general population. Likewise, the prevalence of alcohol abuse is about 4-fold higher among people with nicotine dependence than in the general population.
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      It is unclear if cigarette smoking aggravates the clinical course of alcohol-related liver disease (ALD). Smoking may exacerbate the pathogenic effects of alcohol on the liver and heavy cigarette smoking aggravates the deleterious effect of alcohol abuse in humans, suggesting that these factors may have a synergistic effect.
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      There is a clear need to perform both retrospective and prospective large cohort studies to explore this particular association. The impact of smoking in liver transplant recipients with ALD is discussed in a later section.
      Experimental studies in mice have also investigated the underlaying mechanisms of NAFLD development and fibrosis progression (Fig. 2). Studies aimed at investigating the role of smoke exposure in standard diet-fed mice have shown: (i) an increase in hepatic lipogenesis through deregulation of genes involved in the modulation of 5′-AMP-activated protein kinase (AMPK) and sterol response element binding protein-1 activity, which are both critical in fatty acid synthesis, and (ii) a reduction of cholesterol clearance due to an imbalance in bile acid synthesis.
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      Cigarette smoking exposure breaks the homeostasis of cholesterol and bile acid metabolism and induces gut microbiota dysbiosis in mice with different diets.
      Nicotine exposure exacerbates diet-induced hepatic steatosis through AMPK inactivation and activation of its downstream target acetyl-coenzyme A-carboxylase.
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      • Choi K.C.
      • et al.
      Mainstream cigarette smoke accelerates the progression of nonalcoholic steatohepatitis by modulating Kupffer cell-mediated hepatocellular apoptosis in adolescent mice.
      Cigarette smoking increases de novo liver steatosis and further exacerbates NASH-related liver injury.
      • Savari F.
      • Mard S.A.
      • Badavi M.
      • Rezaie A.
      • Gharib-Naseri M.K.
      A new method to induce nonalcoholic steatohepatitis (NASH) in mice.
      These experimental studies strongly suggest that smoking acts as a co-factor in NAFLD progression, modulating several pathways that regulate hepatocyte cell death and fibrogenesis. Importantly, the deleterious effect of smoking is higher in heavy smokers and is not observed after a short exposure in both animal and human studies, suggesting a dose-response.
      • Azzalini L.
      • Ferrer E.
      • Ramalho L.N.
      • Moreno M.
      • Domínguez M.
      • Colmenero J.
      • et al.
      Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats.
      ,
      • Park S.
      • Kim J.W.
      • Yun H.
      • Choi S.J.
      • Lee S.H.
      • Choi K.C.
      • et al.
      Mainstream cigarette smoke accelerates the progression of nonalcoholic steatohepatitis by modulating Kupffer cell-mediated hepatocellular apoptosis in adolescent mice.
      ,
      • Kim J.W.
      • Zhou Z.
      • Yun H.
      • Park S.
      • Choi S.J.
      • Lee S.H.
      • et al.
      Cigarette smoking differentially regulates inflammatory responses in a mouse model of nonalcoholic steatohepatitis depending on exposure time point.
      Further research with standardised models is needed to elucidate the underlying mechanisms of smoking-induced NAFLD exacerbation.
      Figure thumbnail gr2
      Fig. 2Potential mechanisms of liver disease induced by cigarette smoke.
      The effect of cigarette smoking on postulated mechanisms for the development and progression of hepatic steatosis, fibrogenesis and hepatocarcinogenesis are schematically illustrated. 4-ABP, 4-aminobiphenyl; ACC, acetyl-coenzyme A-carboxylase; AKT, protein kinase B; AMPK, AMP-activated protein kinase; EMT, epithelial to mesenchymal transition; ERK, extracellular signal regulated kinase; FAS, fatty acid synthase; IL, interleukin; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PAH, polycyclic aromatic hydrocarbons; SREBP, sterol response element binding protein; TGF, transforming growth factor; TH1, T helper 1; TLR, toll-like receptor; TNF, tumour necrosis factor; VEGF vascular endothelial growth factor.
      In conclusion, mounting evidence suggests that smoking may negatively impact on the incidence and severity of NAFLD (Fig. 3). This evidence has implications for the design of future clinical trials in patients with NAFLD. Consensus recommendations (i.e. Liver Forum) for reporting standardised baseline parameters in NASH clinical trials should include current smoking as an important parameter to be recorded and evaluated.
      • Patel Y.A.
      • Imperial J.C.
      • Muir A.J.
      • Anstee Q.M.
      • DeBrota D.
      • Dimick-Santos L.
      • et al.
      Baseline parameters in clinical trials for nonalcoholic steatohepatitis: recommendations from the liver forum.
      ,
      • Byrne C.D.
      • Targher G.
      NAFLD: a multisystem disease.
      Currently, few phase II clinical trials provide information on this essential lifestyle comorbidity (Fig. 4).
      • Ampuero J.
      • Romero-Gomez M.
      Stratification of patients in NASH clinical trials: a pitfall for trial success.
      To ensure the reliability of clinical trials, an adequate stratification including comorbidities like smoking, alcohol consumption and metabolic factors seems mandatory.
      Figure thumbnail gr3
      Fig. 3Traffic light system to depict the magnitude of the association between cigarette smoking and liver disease according to each causal-relationship criterion.
      Association was critically appraised for fatty liver disease, advanced fibrosis, HCC and clinical outcomes. Green circles represent a strong association, yellow circles represent a weak association, and red circles represent absence of association. HCC, hepatocellular carcinoma.
      Figure thumbnail gr4
      Fig. 4Prevalence of reported smoking status in literature in different liver disease-related studies.
      Smoking data was only reported in 10% of the 10 reviewed clinical trials on NASH drugs,
      • Ampuero J.
      • Romero-Gomez M.
      Stratification of patients in NASH clinical trials: a pitfall for trial success.
      23% of the 13 reviewed studies on liver-related events in biopsy-confirmed NAFLD,
      • Taylor R.S.
      • Taylor R.J.
      • Bayliss S.
      • Hagström H.
      • Nasr P.
      • Schattenberg J.M.
      • et al.
      Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      and 2% of the 118 reviewed studies on prognostic indicators of survival in viral and alcohol-related cirrhosis.
      • D'Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

      Smoking in the progression of other chronic liver diseases

      Hepatic fibrosis is a major determinant of morbidity and mortality in patients with chronic liver disease.
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
      ,
      • Ampuero J.
      • Aller R.
      • Gallego-Durán R.
      • Crespo J.
      • Calleja J.L.
      • García-Monzón C.
      • et al.
      Significant fibrosis predicts new-onset diabetes mellitus and arterial hypertension in patients with NASH.
      ,
      • Vilar-Gomez E.
      • Calzadilla-Bertot L.
      • Wai-Sun Wong V.
      • Castellanos M.
      • Aller-de la Fuente R.
      • Metwally M.
      • et al.
      Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multinational cohort study.
      Understanding the individual risk of progression to fibrosis is crucial for personalised clinical management. Among the environmental factors that exacerbate liver fibrosis across all aetiologies, major evidence suggests that cigarette smoking could play a profibrogenic role. Well-designed studies are needed to unravel the specific role of smoking and distinguish it from other confounding factors (Fig. 3). There is a well-known association between smoking and alcohol consumption, another important profibrogenic habit. Therefore, it is feasible that the co-existence of both lifestyle habits could explain the different rates of fibrosis progression among patients with similar degrees of alcohol misuse.
      • Crabb D.W.
      • Bataller R.
      • Chalasani N.P.
      • Kamath P.S.
      • Lucey M.
      • Mathurin P.
      • et al.
      Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA Alcoholic Hepatitis Consortia.
      ,
      • Klatsky A.L.
      • Armstrong M.A.
      Alcohol, smoking, coffee, and cirrhosis.
      Population-based studies show that smoking prevalence is high, with important differences depending on the target population and geographic region (e.g., 30% in young UK adults vs. 60% in middle-aged Danish adults from the general population).
      • Abeysekera K.W.M.
      • Fernandes G.S.
      • Hammerton G.
      • Portal A.J.
      • Gordon F.H.
      • Heron J.
      • et al.
      Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.
      ,
      • Dam M.K.
      • Flensborg-Madsen T.
      • Eliasen M.
      • Becker U.
      • Tolstrup J.S.
      Smoking and risk of liver cirrhosis: a population-based cohort study.
      Consequently, studies in patients with liver disease are difficult to compare, given the differences in population selection (age, underlying disease), fibrosis assessment (liver stiffness measurements [LSMs], ICD codes), smoking definition (dichotomised, categorised by dose) and covariables selected for adjustment. The prevalence of smoking history in patients with liver disease is high (around 40%) in most studies, suggesting that this is a clinically relevant issue. Smoking history is not associated with a higher LSM in “healthy individuals”, but it is associated with an increase in cirrhosis prevalence in female heavy smokers (>10 cigarettes/day) and fibrosis degree in patients with underlying liver disease.
      • Abeysekera K.W.M.
      • Fernandes G.S.
      • Hammerton G.
      • Portal A.J.
      • Gordon F.H.
      • Heron J.
      • et al.
      Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.
      • Dam M.K.
      • Flensborg-Madsen T.
      • Eliasen M.
      • Becker U.
      • Tolstrup J.S.
      Smoking and risk of liver cirrhosis: a population-based cohort study.
      • Bazerbachi F.
      • Haffar S.
      • Wang Z.
      • Cabezas J.
      • Arias-Loste M.T.
      • Crespo J.
      • et al.
      Range of normal liver stiffness and factors associated with increased stiffness measurements in apparently healthy individuals.
      • Hodge A.
      • Lim S.
      • Goh E.
      • Wong O.
      • Marsh P.
      • Knight V.
      • et al.
      Coffee intake is associated with a lower liver stiffness in patients with non-alcoholic fatty liver disease, hepatitis C, and hepatitis B.
      Epidemiological studies specifically aimed at evaluating the impact of cigarette smoking on liver fibrosis are summarised in Table 2. Earlier studies in this field focused on viral hepatitis with a retrospective and cross-sectional approach, while more recent studies targeting NAFLD have used prospective longitudinal assessments.
      Cigarette smoking is strongly associated with CVD events, the main cause of death in patients with NAFLD.
      Table 2Main clinical studies focused on the impact of cigarette smoking on liver fibrosis.
      StudyPatients, n (country)DesignSmoking assessmentSmoking prevalenceGold standardResults
      Kleiner DE, 2019
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • Behling C.
      • Guy C.
      • Contos M.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      446 with NAFLD (USA)Prospective, NASH CRN longitudinalInterview, grouping by status9% active, 37% ever smokerHistologyCurrent smoker ↓ fibrosis regression (p = 0.03)
      Ou H, 2019
      • Ou H.
      • Fu Y.
      • Liao W.
      • Zheng C.
      • Wu X.
      Association between smoking and liver fibrosis among patients with nonalcoholic fatty liver disease.
      225 with NAFLD (China)Retrospective cross-sectional case-controln.a., smoking index (nº cig/day ∗ duration of smoking)44% smokersLiver stiffnessSmoking index ↑ liver fibrosis (OR 1.3; 1.1–2.1)
      Xiong M, 2019
      • Xiong M.
      • Li J.
      • Yang S.
      • Zeng F.
      • Ji Y.
      • Liu J.
      • et al.
      Impacts of cigarette smoking on liver fibrosis and its regression under therapy in male patients with chronic hepatitis B.
      2,144 males with CHB (China)Prospective, longitudinal cohort, propensity score matchedInterview, grouping by pack-years47% smokersLiver stiffnessSmokers ↑ advanced fibrosis (OR 1.5; 1.1–1.9), dose-response (≥10 pack-years ↓ fibrosis regression p = 0.02)
      Mantaka A, 2018
      • Mantaka A.
      • Koulentaki M.
      • Samonakis D.
      • Sifaki-Pistolla D.
      • Voumvouraki A.
      • Tzardi M.
      • et al.
      Association of smoking with liver fibrosis and mortality in primary biliary cholangitis.
      117 with PBC (Greece)Retrospective cross-sectional case-controlInterview, grouping by status and pack-years26% active, 30% ex-smokerHistologySmoking history ↑ advanced fibrosis (p = 0.04), dose-response (OR 3.2; 2.0–6.3)
      Musterman ID, 2017
      • Munsterman I.D.
      • Smits M.M.
      • Andriessen R.
      • van Nieuwkerk C.M.J.
      • Bloemena E.
      • Mulder C.J.J.
      • et al.
      Smoking is associated with severity of liver fibrosis but not with histological severity in nonalcoholic fatty liver disease. Results from a cross-sectional study.
      56 with NAFLD (Netherlands)Retrospective cross-sectional case-controlChart review and interview39% history of smokingHistologySmoking history ↑ fibrosis score (p = 0.04), dose-response (nº of pack-years ↑ advanced fibrosis)
      Dam MK, 2013
      • Dam M.K.
      • Flensborg-Madsen T.
      • Eliasen M.
      • Becker U.
      • Tolstrup J.S.
      Smoking and risk of liver cirrhosis: a population-based cohort study.
      18,479 from the general population (Denmark)Population-based cohortInterview, groups: ex, never, ≤ and >10 cig/day56% ♀

      67% ♂
      Hospital register: cirrhosis ICD codeAdjusted HR for >10 cig/day: ♀ 2.2; 1.4–3.4 ♂1.4; 0.9–2.2
      Corpechot C, 2012
      • Corpechot C.
      • Gaouar F.
      • Chrétien Y.
      • Johanet C.
      • Chazouillères O.
      • Poupon R.
      Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis.
      164 with PBC (France)Prospective, cohortInterview, grouping by pack-years11% active smokers, 26% smoking historyHistologySmoking history ↑ advanced fibrosis (OR 3.6; 1.5–8.5), dose-response (OR 1.2; 1.0–1.3)
      Zein CO, 2011
      • Zein C.O.
      • Unalp A.
      • Colvin R.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease.
      1,091 with NAFLD (USA)Prospective, NASH CRN cross-sectional studiesInterview, significant smoking: ≥10 pack-years24% with significant smoking historyHistologySignificant smoking ↑ advanced fibrosis (OR 1.6; 1.2–2.2)
      TsochatzisE, 2009
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Tiniakos D.G.
      • Manesis E.K.
      • Archimandritis A.J.
      Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B.
      271 with CHB and CHC (Greece)Prospective, cross-sectional case-controlInterview, groups: never, smoker, ≥20 pack-years42% CHB

      61% CHC smokers
      HistologyNo association with CH fibrosis. ≥20 pack-years ↑ CHC advanced fibrosis (OR 3.9; 1.4–11.3)
      Dev A, 2006
      • Dev A.
      • Patel K.
      • Conrad A.
      • Blatt L.M.
      • McHutchison J.G.
      Relationship of smoking and fibrosis in patients with chronic hepatitis C.
      244 with CHC (USA)Retrospective, cross-sectional case-controlMedical records, grouping by nº of cig/day25% smokersHistologySmoking ↑ risk of fibrosis (OR 1.3; 1.0–1.8)
      Zein CO, 2006
      • Zein C.O.
      • Beatty K.
      • Post A.B.
      • Logan L.
      • Debanne S.
      • McCullough A.J.
      Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment.
      97 with PBC (USA)Retrospective, cross-validated case-controlInterview, significant smoking: ≥10 pack-years44% with significant smoking historyHistologySmoking history ↑ advanced fibrosis (p <0.001), dose-response (≥10 pack-years: OR 13.3; 4.3–49.3)
      Hézode C, 2003
      • Hézode C.
      • Lonjon I.
      • Roudot-Thoraval F.
      • Mavier J.P.
      • Pawlotsky J.M.
      • Zafrani E.S.
      • et al.
      Impact of smoking on histological liver lesions in chronic hepatitis C.
      244 with CHC (France)Prospective, cross-sectional case-controlInterview, grouping by nº of cig/day44% smokers, 25% >15 cig/dayHistologyNo association with fibrosis (p = 0.5), >15 cig/day ↑ activity grade

      (OR 3.6; 1.5-8.8)
      Pessione F, 2001
      • Pessione F.
      • Ramond M.J.
      • Njapoum C.
      • Duchatelle V.
      • Degott C.
      • Erlinger S.
      • et al.
      Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.
      310 with CHC (France)Retrospective, cross-sectional case-controln.a., grouping by pack-years57% smokersHistologySmoking ↑ fibrosis score (p = 0.03), dose-response (≥15 pack-years: OR 1.9; 1.1-3.6)
      Yu MW, 1997
      • Yu M.W.
      • Hsu F.C.
      • Sheen I.S.
      • Chu C.M.
      • Lin D.Y.
      • Chen C.J.
      • et al.
      Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers.
      1,506 with CHB (Taiwan)Prospective, longitudinalInterview, groups: 0,

      <20 and ≥20 cig/day
      43% smokersUltrasound image of cirrhosis≥20 cig/day

      ↑ risk of cirrhosis (OR 2.1; 1.2-3.7)
      Included studies used logistic regression models to explore the association between smoking and fibrosis. OR with 95% confidence intervals determine the strength of statistical associations. p value <0.05 was considered to be statistically significance. CHB, chronic hepatitis B; CH, chronic hepatitis; CHC, chronic hepatitis C; HR, hazard ratio; NAFLD, non-alcoholic fatty liver disease, n.a., not available; NASH CRN: Non-Alcoholic Steatohepatitis Clinical Research Network; OR, odds ratio; PBC, primary biliary cholangitis.
      Prospective studies performed in Asian patients with chronic hepatitis B (CHB) showed a deleterious effect of smoking on the progression to cirrhosis in heavy smokers (≥20 cigarettes/day), with a magnitude of effect that was even higher than alcohol consumption. The effect was particularly pronounced in regular alcohol consumers, suggesting a possible additive effect of cigarettes and alcohol. Recently, the impact of cigarette smoking on responses to antiviral therapy in patients with CHB has been explored in a longitudinal study from China. Smoking was associated with both an aggravation of liver fibrosis and a delay in fibrosis regression in patients under HBV antiviral therapy.
      • Xiong M.
      • Li J.
      • Yang S.
      • Zeng F.
      • Ji Y.
      • Liu J.
      • et al.
      Impacts of cigarette smoking on liver fibrosis and its regression under therapy in male patients with chronic hepatitis B.
      Also, smoking may contribute to sustained high viral loads and have a greater effect on liver inflammation (alanine aminotransferase increase).
      • Wang Y.H.
      • Chuang Y.H.
      • Wu C.F.
      • Jan M.C.
      • Wu W.J.
      • Lin C.L.
      • et al.
      Smoking and hepatitis B virus-related hepatocellular carcinoma risk: the mediating roles of viral load and alanine aminotransferase.
      These studies strongly suggest that cigarette consumption influences the progression of liver injury in CHB. Regarding chronic hepatitis C (CHC), conflicting results have been observed. Retrospective studies showed that tobacco use was an independent predictor of fibrosis stage.
      • Dev A.
      • Patel K.
      • Conrad A.
      • Blatt L.M.
      • McHutchison J.G.
      Relationship of smoking and fibrosis in patients with chronic hepatitis C.
      ,
      • Zein C.O.
      • Beatty K.
      • Post A.B.
      • Logan L.
      • Debanne S.
      • McCullough A.J.
      Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment.
      However, a weak relationship was seen on multivariate analysis, particularly when histologic inflammatory activity was taken into consideration.
      • Pessione F.
      • Ramond M.J.
      • Njapoum C.
      • Duchatelle V.
      • Degott C.
      • Erlinger S.
      • et al.
      Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.
      Hezode et al. performed a prospective study and found no significant relationship between fibrosis stage and smoking history.
      • Hézode C.
      • Lonjon I.
      • Roudot-Thoraval F.
      • Mavier J.P.
      • Pawlotsky J.M.
      • Zafrani E.S.
      • et al.
      Impact of smoking on histological liver lesions in chronic hepatitis C.
      In contrast, smoking was independently and strongly associated with higher inflammatory activity (OR 3.6; 95% CI 1.5-8.8). Finally, Tsochatzis et al., also in a prospective study, linked heavy smoking with steatosis and fibrosis severity in CHC but not in CHB.
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Tiniakos D.G.
      • Manesis E.K.
      • Archimandritis A.J.
      Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B.
      Collectively, this data suggests that cigarette smoking may enhance fibrosis severity in viral hepatitis by increasing necroinflammatory grade and fat deposition.
      History of smoking has traditionally been considered as a predisposing factor for primary biliary cholangitis (PBC).
      • Gershwin M.E.
      • Selmi C.
      • Worman H.J.
      • Gold E.B.
      • Watnik M.
      • Utts J.
      • et al.
      Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients.
      Epidemiological and clinical studies have consistently demonstrated this association, which is likely to be due to the proinflammatory effects of smoking and a possible deleterious effect in biliary epithelial cells.
      • Hézode C.
      • Lonjon I.
      • Roudot-Thoraval F.
      • Mavier J.P.
      • Pawlotsky J.M.
      • Zafrani E.S.
      • et al.
      Impact of smoking on histological liver lesions in chronic hepatitis C.
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Tiniakos D.G.
      • Manesis E.K.
      • Archimandritis A.J.
      Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B.
      • Gershwin M.E.
      • Selmi C.
      • Worman H.J.
      • Gold E.B.
      • Watnik M.
      • Utts J.
      • et al.
      Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients.
      • Corpechot C.
      • Chrétien Y.
      • Chazouillères O.
      • Poupon R.
      Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis.
      • Lammert C.
      • Nguyen D.L.
      • Juran B.D.
      • Schlicht E.
      • Larson J.J.
      • Atkinson E.J.
      • et al.
      Questionnaire based assessment of risk factors for primary biliary cirrhosis.
      Smoking impacts both innate and adaptive immunity and plays dual roles in regulating immunity by either exacerbating pathogenic immune responses or attenuating defensive immunity.
      • Qiu F.
      • Liang C.L.
      • Liu H.
      • Zeng Y.Q.
      • Hou S.
      • Huang S.
      • et al.
      Impacts of cigarette smoking on immune responsiveness: up and down or upside down?.
      This dual effect is central to the pathogenesis of autoimmune diseases and mechanisms linking cigarette smoking to autoimmune disorders are starting to be revealed. For instance, it has been shown that tobacco components may promote an adaptive T helper 1 (TH1) immune cell response to autoantigens and disrupt regulatory T-cell function.
      • Arnson Y.
      • Shoenfeld Y.
      • Amital H.
      Effects of tobacco smoke on immunity, inflammation and autoimmunity.
      In patients with PBC, the predominant T cells infiltrating portal tracts are TH1 cells.
      • Harada K.
      • Van de Water J.
      • Leung P.S.
      • Coppel R.L.
      • Nakanuma Y.
      • Gershwin M.E.
      In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset.
      This feature, together with autoantigen overload in individuals with impaired capacity for apoptotic cell removal, supports the potential role of smoking in inducing an immune-mediated bile duct injury.
      • Corpechot C.
      • Gaouar F.
      • Chrétien Y.
      • Johanet C.
      • Chazouillères O.
      • Poupon R.
      Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis.
      In addition to an effect on PBC risk, 2 independent studies have shown that smoking history and level of tobacco consumption also impact on the degree of fibrosis.
      • Zein C.O.
      • Beatty K.
      • Post A.B.
      • Logan L.
      • Debanne S.
      • McCullough A.J.
      Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment.
      ,
      • Corpechot C.
      • Gaouar F.
      • Chrétien Y.
      • Johanet C.
      • Chazouillères O.
      • Poupon R.
      Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis.
      Like the association of smoking with NAFLD-fibrosis but not NASH,
      • Zein C.O.
      • Unalp A.
      • Colvin R.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease.
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • Behling C.
      • Guy C.
      • Contos M.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      • Munsterman I.D.
      • Smits M.M.
      • Andriessen R.
      • van Nieuwkerk C.M.J.
      • Bloemena E.
      • Mulder C.J.J.
      • et al.
      Smoking is associated with severity of liver fibrosis but not with histological severity in nonalcoholic fatty liver disease. Results from a cross-sectional study.
      these PBC studies showed that necroinflammatory activity was not higher in smokers, cautiously suggesting that tobacco may exert profibrogenic effects through mechanisms that do not interfere with inflammation.
      • Zein C.O.
      • Beatty K.
      • Post A.B.
      • Logan L.
      • Debanne S.
      • McCullough A.J.
      Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment.
      ,
      • Corpechot C.
      • Gaouar F.
      • Chrétien Y.
      • Johanet C.
      • Chazouillères O.
      • Poupon R.
      Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis.
      Possible mechanisms promoting fibrosis progression will be further discussed. The strong association between tobacco and PBC has not been seen in other autoimmune liver diseases, such as autoimmune hepatitis.
      • Webb G.J.
      • Ryan R.P.
      • Marshall T.P.
      • Hirschfield G.M.
      The epidemiology of UK autoimmune liver disease varies with geographic latitude.
      In patients with increased genetic susceptibility to autoimmune hepatitis, environmental factors such as pathogens, xenobiotics, or pollutants may trigger humoral and cellular autoimmune responses to liver autoantigens by molecular mimicry.
      • Mieli-Vergani G.
      • Vergani D.
      • Czaja A.J.
      • Manns M.P.
      • Krawitt E.L.
      • Vierling J.M.
      • et al.
      Autoimmune hepatitis.
      Whether toxic components of tobacco may precipitate autoimmune-mediated liver injury via this mechanism deserves further investigation. Table 3 summarises the prevalence of smoking in particular disease groups and stages, compared to the prevalence in the corresponding reference population.
      There is an increased risk of fibrosis progression to more advanced stages in smokers across the different liver disease aetiologies, with a higher impact on heavy smokers.
      Table 3Prevalence of smoking in particular liver disease groups and stages, compared to the prevalence in the corresponding reference population.
      Disease, stagePrevalenceReferencePrevalence
      NAFLD
      • Kim N.H.
      • Jung Y.S.
      • Hong H.P.
      • Park J.H.
      • Kim H.J.
      • Park D.I.
      • et al.
      Association between cotinine-verified smoking status and risk of nonalcoholic fatty liver disease.
      ,
      • Zein C.O.
      • Unalp A.
      • Colvin R.
      • Liu Y.C.
      • McCullough A.J.
      Nonalcoholic Steatohepatitis Clinical Research Network
      Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease.
      ,
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • Behling C.
      • Guy C.
      • Contos M.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      ,
      • Abeysekera K.W.M.
      • Fernandes G.S.
      • Hammerton G.
      • Portal A.J.
      • Gordon F.H.
      • Heron J.
      • et al.
      Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.
      Steatosis (S1-3)Current S1: 29%No steatosis (S0)Current: 14-29%
      Current S2: 32%
      Current S3: 28%
      NASHFormer: 38%Simple steatosisFormer: 33%
      Current: 9%Current: 11%
      F3-4Former: 34%F0-2Former: 9%
      Current: 10%Current: 9%
      >10 pack-years: 43%>10 pack-years: 28%
      ALD
      • Grucza R.A.
      • Bierut L.J.
      Co-occurring risk factors for alcohol dependence and habitual smoking: update on findings from the Collaborative Study on the Genetics of Alcoholism.
      ,
      • Dam M.K.
      • Flensborg-Madsen T.
      • Eliasen M.
      • Becker U.
      • Tolstrup J.S.
      Smoking and risk of liver cirrhosis: a population-based cohort study.
      ,
      • Pessione F.
      • Ramond M.J.
      • Peters L.
      • Pham B.N.
      • Batel P.
      • Rueff B.
      • et al.
      Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence.
      ,
      • Corrao G.
      • Lepore A.R.
      • Torchio P.
      • Valenti M.
      • Galatola G.
      • D'Amicis A.
      • et al.
      The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. A case-control study. Provincial Group for the Study of Chronic Liver Disease.
      Alcohol-related cirrhosisCurrent: 60-78%General populationCurrent: 12%
      Other CLD cirrhosisCurrent: 71%
      CHB
      • Xiong M.
      • Li J.
      • Yang S.
      • Zeng F.
      • Ji Y.
      • Liu J.
      • et al.
      Impacts of cigarette smoking on liver fibrosis and its regression under therapy in male patients with chronic hepatitis B.
      ,
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Tiniakos D.G.
      • Manesis E.K.
      • Archimandritis A.J.
      Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B.
      ,
      • Yu M.W.
      • Hsu F.C.
      • Sheen I.S.
      • Chu C.M.
      • Lin D.Y.
      • Chen C.J.
      • et al.
      Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers.
      F3-4Current: 40-56%F0-2Current: 42-44%
      >20 pack-years: 28%>20 pack-years: 17%
      CirrhosisCurrent: 59%No cirrhosisCurrent: 42%
      >20 pack-years: 27%>20 pack-years: 18%
      CHC
      • Pessione F.
      • Ramond M.J.
      • Njapoum C.
      • Duchatelle V.
      • Degott C.
      • Erlinger S.
      • et al.
      Cigarette smoking and hepatic lesions in patients with chronic hepatitis C.
      • Hézode C.
      • Lonjon I.
      • Roudot-Thoraval F.
      • Mavier J.P.
      • Pawlotsky J.M.
      • Zafrani E.S.
      • et al.
      Impact of smoking on histological liver lesions in chronic hepatitis C.
      • Tsochatzis E.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Tiniakos D.G.
      • Manesis E.K.
      • Archimandritis A.J.
      Smoking is associated with steatosis and severe fibrosis in chronic hepatitis C but not B.
      F3-4Former: 19%F0-2Former: 18%
      Current: 54-63%Current: 57-61%
      >20 pack-years: 43%>20 pack-years: 22%
      A2-3Current: 48%A0-1Current: 34%
      S1-3>20 pack-years: 32%S0>20 pack-years: 12%
      PBC
      • Zein C.O.
      • Beatty K.
      • Post A.B.
      • Logan L.
      • Debanne S.
      • McCullough A.J.
      Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: a cross validated retrospective assessment.
      ,
      • Corpechot C.
      • Gaouar F.
      • Chrétien Y.
      • Johanet C.
      • Chazouillères O.
      • Poupon R.
      Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis.
      ,
      • Mantaka A.
      • Koulentaki M.
      • Samonakis D.
      • Sifaki-Pistolla D.
      • Voumvouraki A.
      • Tzardi M.
      • et al.
      Association of smoking with liver fibrosis and mortality in primary biliary cholangitis.
      F3-4Current: 21-71%F0-2Current: 19-33%
      >10 pack-years: 71%>10 pack-years: 19%
      A2-3Former: 20-25%A0-1Former: 18%
      Current: 10-23%Current: 16%
      A, necroinflammatory activity grade; ALD, alcohol-related liver disease; CHB, chronic hepatitis B; CHC, chronic hepatitis C; F, fibrosis stage; CLD, chronic liver disease; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PBC, primary biliary cholangitis; S, steatosis grade.
      The mechanisms underlying the profibrogenic effect of cigarette smoking have been mostly explored at the experimental level. In vivo and in vitro studies showed that nicotine modulates fibroblast activation and enhances pro-fibrogenic mechanisms.
      • Jensen K.
      • Nizamutdinov D.
      • Guerrier M.
      • Afroze S.
      • Dostal D.
      • Glaser S.
      General mechanisms of nicotine-induced fibrogenesis.
      These effects have also been observed in other organs.
      • Rockey D.C.
      • Bell P.D.
      • Hill J.A.
      Fibrosis--a common pathway to organ injury and failure.
      In the liver, mice models have shown that nicotine has a deleterious influence by aggravating the hepatotoxic effects of carbon tetrachloride.
      • Yuen S.T.
      • Gogo A.R.
      • Luk I.S.C.
      • Cho C.H.
      • Ho J.C.
      • Loh T.T.
      The effect of nicotine and its interaction with carbon tetrachloride in the rat liver.
      It should be noted that experimental data on the direct hepatotoxic effects of tobacco components are more limited than data reported for other organs.
      • Yuen S.T.
      • Gogo A.R.
      • Luk I.S.C.
      • Cho C.H.
      • Ho J.C.
      • Loh T.T.
      The effect of nicotine and its interaction with carbon tetrachloride in the rat liver.
      ,
      • Soeda J.
      • Morgan M.
      • McKee C.
      • Mouralidarane A.
      • Lin C.
      • Roskams T.
      • et al.
      Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells.
      Overall, potential mechanisms of cigarette smoking-induced fibrogenesis include (Fig. 2):
      • Release of transforming growth factor-β1 with activation and proliferation of resident fibrogenic cells. In response to injury, transforming growth factor-β1 stimulates the production of extracellular matrix proteins, mainly collagen synthesis by hepatic stellate cells (HSCs), and plays a key role in the regulation of fibrosis.
        • Soeda J.
        • Morgan M.
        • McKee C.
        • Mouralidarane A.
        • Lin C.
        • Roskams T.
        • et al.
        Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells.
      • Increased production of proinflammatory cytokines (interleukin [IL]-1, IL-6 and tumour necrosis factor-α) and recruitment of inflammatory cells such as neutrophils and monocyte-macrophages.
        • Yang S.R.
        • Chida A.S.
        • Bauter M.R.
        • Shafiq N.
        • Seweryniak K.
        • Maggirwar S.B.
        • et al.
        Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages.
        ,
        • Bataller R.
        • Brenner D.A.
        Liver fibrosis.
      • Toll-like receptor 4 activation, a key pathway promoting fibrosis in steatohepatitis.
        • Seki E.
        • De Minicis S.
        • Osterreicher C.H.
        • Kluwe J.
        • Osawa Y.
        • Brenner D.A.
        • et al.
        TLR4 enhances TGF-beta signaling and hepatic fibrosis.
        Cigarette smoking is associated with impaired intestinal barrier, increased permeability and bacterial translocation.
        • Zuo L.
        • Li Y.
        • Wang H.
        • Wu R.
        • Zhu W.
        • Zhang W.
        • et al.
        Cigarette smoking is associated with intestinal barrier dysfunction in the small intestine but not in the large intestine of mice.
        Toll-like receptor 4 is activated on the surface of HSCs by intestinal bacterial lipopolysaccharides derived from the gut, triggering cell activation and fibrogenesis.
        • Fouts D.E.
        • Torralba M.
        • Nelson K.E.
        • Brenner D.A.
        • Schnabl B.
        Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease.
        This mechanism links fibrosis to the microbiome.
      • Activation of reactive oxygen species (ROS) production by NADPH oxidase. Subsequent oxidative stress can lead to lipid peroxidation and hepatocellular damage.
        • Muriel P.
        Role of free radicals in liver diseases.
      • Increase of carboxyhaemoglobin and decreased oxygen-carrying capacity of red blood cells which leads to tissue hypoxia. Induced erythropoietin production and secondary polycythaemia contribute to the accumulation of iron in macrophages and hepatocytes, enhancing liver injury and fibrosis.
        • El-Zayadi A.R.
        • Selim O.
        • Hamdy H.
        • El-Tawil A.
        • Moustafa H.
        Heavy cigarette smoking induces hypoxic polycythemia (erythrocytosis) and hyperuricemia in chronic hepatitis C patients with reversal of clinical symptoms and laboratory parameters with therapeutic phlebotomy.
        In this line, an interaction between current smoking and haemoglobin levels and the risk of NAFLD-advanced fibrosis have been shown.
        • Enc F.Y.
        • Ulasoglu C.
        • Bakir A.
        • Yilmaz Y.
        The interaction between current smoking and hemoglobin on the risk of advanced fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease.
      • Changes in the microvasculature such as endothelial dysfunction, smooth muscle cell proliferation and vasoconstriction, leading to an impairment in nitric oxide delivery and tissue hypoxia.
        • Zhang W.Z.
        • Venardos K.
        • Chin-Dusting J.
        • Kaye D.M.
        Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress.
        In response to liver hypoxia, expression of vascular endothelial growth factor and type I collagen are increased in activated HSCs, enhancing fibrogenesis.
        • Dev A.
        • Patel K.
        • Conrad A.
        • Blatt L.M.
        • McHutchison J.G.
        Relationship of smoking and fibrosis in patients with chronic hepatitis C.
        ,
        • Corpechot C.
        • Barbu V.
        • Wendum D.
        • Kinnman N.
        • Rey C.
        • Poupon R.
        • et al.
        Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.
      In conclusion, there is mounting evidence from cross-sectional and retrospective studies that suggest that cigarette smoking has a deleterious effect on the progression of chronic viral hepatitis, PBC and NAFLD (Fig. 1). The mechanisms implicated are complex and involve different pathophysiological pathways. However, smoking status is not consistently reported in studies investigating fibrosis progression. A recent meta-analysis evaluating the association between fibrosis stage and outcomes of patients with NAFLD showed that only 3 out of 13 included studies accounted for this baseline prognostic characteristic (Fig. 4).
      • Taylor R.S.
      • Taylor R.J.
      • Bayliss S.
      • Hagström H.
      • Nasr P.
      • Schattenberg J.M.
      • et al.
      Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.
      Given that reducing the number of pack-years or complete cessation of smoking can impact on relevant treatment outcomes like fibrosis regression after HCV clearance or NAFLD-fibrosis progression, special attention should be paid to identify and treat this deleterious lifestyle component in patients with liver disease.
      • Kleiner D.E.
      • Brunt E.M.
      • Wilson L.A.
      • Behling C.
      • Guy C.
      • Contos M.
      • et al.
      Association of histologic disease activity with progression of nonalcoholic fatty liver disease.
      ,
      • Balmaceda J.B.
      • Aepfelbacher J.
      • Belliveau O.
      • Chaudhury C.S.
      • Chairez C.
      • McLaughlin M.
      • et al.
      Long-term changes in hepatic fibrosis following hepatitis C viral clearance in patients with and without HIV.

      Smoking and hepatocellular carcinoma

      Liver cancer is a major contributor to the worldwide cancer burden with an estimated global incidence rate of 9.3 per 100,000 person-years and a nearly equivalent mortality rate of 8.5.
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      It is responsible for 22% of cancer-related deaths worldwide.
      • Forouzanfar M.H.
      • Afshin A.
      • Alexander L.T.
      • Anderson H.R.
      • Bhutta Z.A.
      • Biryukov S.
      • et al.
      Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.
      In line with the carcinogenic properties of tobacco in several organs, a large number of studies indicate that cigarette smoking is associated with an increased incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis.
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      Several case-control and cohort studies have demonstrated that cigarette smoking is associated with an increased incidence of HCC. Relative risk variation can be explained by differences in the study design, the severity of smoking and the underlying disease.
      • Altamirano J.
      • Bataller R.
      Cigarette smoking and chronic liver diseases.
      This association has been confirmed by several well deigned meta-analyses.
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      • Lee Y.C.
      • Cohet C.
      • Yang Y.C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      • Abdel-Rahman O.
      • Helbling D.
      • Schöb O.
      • Eltobgy M.
      • Mohamed H.
      • Schmidt J.
      • et al.
      Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies.
      Fig. 5 summarises the pooled risk ratios for HCC development from 3 large meta-analyses differentiating between former, current and heavy smokers, compared to never smokers.
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      • Lee Y.C.
      • Cohet C.
      • Yang Y.C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      • Abdel-Rahman O.
      • Helbling D.
      • Schöb O.
      • Eltobgy M.
      • Mohamed H.
      • Schmidt J.
      • et al.
      Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies.
      The earliest meta-analysis published in 2009, included 38 cohort studies and 58 case-control studies. The observed adjusted relative risk for HCC was 1.12 (95% CI 0.78–1.60) for former smokers and 1.51 (95% CI 1.37–1.67) for current smokers.
      • Lee Y.C.
      • Cohet C.
      • Yang Y.C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      In 2017, a meta-analysis including 81 epidemiological studies, showed an OR for HCC development of 1.39 (95% CI 1.26–1.52) for former smokers and 1.55 (95% CI 1.46–1.65) for current smokers.
      • Abdel-Rahman O.
      • Helbling D.
      • Schöb O.
      • Eltobgy M.
      • Mohamed H.
      • Schmidt J.
      • et al.
      Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies.
      Finally, the Liver Cancer Pooling Project consortium of 14 prospective cohort studies from the USA reported a HR for incident HCC of 1.24 (95% CI 1.08–1.43) for former smokers and 1.86 (95% CI 1.57–2.20) for current smokers.
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      Considering the high prevalence of smoking, the population attributable risk fraction for HCC seems to be relatively large despite the modest risk estimates. Tobacco accounts for 13% of HCC worldwide and its interaction with chronic viral hepatitis increases the risk of liver cancer.
      • Baecker A.
      • Liu X.
      • La Vecchia C.
      • Zhang Z.F.
      Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors.
      ,
      • Chuang S.C.
      • Lee Y.C.
      • Hashibe M.
      • Dai M.
      • Zheng T.
      • Boffetta P.
      Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis.
      There are no studies that have specifically examined the association between smoking and NAFLD-related HCC. However, tobacco and obesity may have a synergistic effect on HCC development (synergistic index: 2.9; 95% CI 1.8–3.5).
      • Marrero J.A.
      • Fontana R.J.
      • Fu S.
      • Conjeevaram H.S.
      • Su G.L.
      • Lok A.S.
      Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.
      Alcohol and smoking also synergise as risk factors of HCC, but no interaction is seen in terms of HCC-related mortality.
      • Marrero J.A.
      • Fontana R.J.
      • Fu S.
      • Conjeevaram H.S.
      • Su G.L.
      • Lok A.S.
      Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.
      • Kuper H.
      • Tzonou A.
      • Kaklamani E.
      • Hsieh C.C.
      • Lagiou P.
      • Adami H.O.
      • et al.
      Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma.
      • Jee S.H.
      • Ohrr H.
      • Sull J.W.
      • Samet J.M.
      Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea.
      Finally, even if there is relevant heterogeneity among different studies, a positive dose-response relationship between the number of cigarettes smoked has also been reported.
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      ,
      • Lee Y.C.
      • Cohet C.
      • Yang Y.C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      ,
      • Marrero J.A.
      • Fontana R.J.
      • Fu S.
      • Conjeevaram H.S.
      • Su G.L.
      • Lok A.S.
      Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma.
      ,
      • Tanaka K.
      • Tsuji I.
      • Wakai K.
      • Nagata C.
      • Mizoue T.
      • Inoue M.
      • et al.
      Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan
      Cigarette smoking and liver cancer risk: an evaluation based on a systematic review of epidemiologic evidence among Japanese.
      In patients particularly predisposed to HCC, such as those with chronic viral hepatitis, the association between smoking and liver cancers remained for current smokers but significantly reduced for former smokers.
      • Lee Y.C.
      • Cohet C.
      • Yang Y.C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      In contrast, no interaction among smoking and HBsAg status has been seen in terms of HCC mortality.
      • Jee S.H.
      • Ohrr H.
      • Sull J.W.
      • Samet J.M.
      Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in Korea.
      Cigarette smoking has been clearly identified as a risk factor for HCC in chronic liver disease.
      Figure thumbnail gr5
      Fig. 5Relative risk for HCC development stratified by smoking status.
      Small dark blue dots represent the reported HCC risk for individual case-control and cohort studies. Each circle represents the reported HCC risk in 3 large meta-analysis: Petrick et al. study
      • Petrick J.L.
      • Campbell P.T.
      • Koshiol J.
      • Thistle J.E.
      • Andreotti G.
      • Beane-Freeman L.E.
      • et al.
      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the Liver Cancer Pooling Project.
      (orange circle, 14 studies); Abdel-Rahman et al. study
      • Abdel-Rahman O.
      • Helbling D.
      • Schöb O.
      • Eltobgy M.
      • Mohamed H.
      • Schmidt J.
      • et al.
      Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: an updated systematic review of 81 epidemiological studies.
      (green circle, 81 studies), Lee et al. study
      • Lee Y.C.
      • Cohet C.
      • Yang Y.C.
      • Stayner L.
      • Hashibe M.
      • Straif K.
      Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer.
      (purple circle, 66 studies). Light blue boxes represent the median value for the risk ratio (dashed line) and 95% confidence intervals. HCC, hepatocellular carcinoma.
      Regarding the underlying mechanisms, it is biologically plausible that smoking plays an important role in HCC. Several chemicals present in tobacco smoke, including 4-aminobiphenyl and polycyclic aromatic hydrocarbons, can be metabolised into reactive carcinogenic agents in the liver.
      • Sugamori K.S.
      • Brenneman D.
      • Sanchez O.
      • Doll M.A.
      • Hein D.W.
      • Pierce Jr., W.M.
      • et al.
      Reduced 4-aminobiphenyl-induced liver tumorigenicity but not DNA damage in arylamine N-acetyltransferase null mice.
      ,
      • Chen S.Y.
      • Wang L.Y.
      • Lunn R.M.
      • Tsai W.Y.
      • Lee P.H.
      • Lee C.S.
      • et al.
      Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls.
      These molecules induce histopathological changes such as liver parenchyma degeneration in animal models.
      • Balansky R.
      • Ganchev G.
      • Iltcheva M.
      • Nikolov M.
      • Steele V.E.
      • De Flora S.
      Differential carcinogenicity of cigarette smoke in mice exposed either transplacentally, early in life or in adulthood.
      Different tobacco components such as nitrosamines and benzenes can be activated into procarcinogens by CYP2E1.
      • Lieber C.S.
      Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998) --a review.
      This enzyme is the most important in the microsomal ethanol oxidising system, an alternate pathway of ethanol metabolism. Chronic ethanol consumption induces the activity of this system, which biotransforms ethanol into acetaldehyde, a highly toxic and carcinogenic metabolite.
      • Lieber C.S.
      Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968-1998) --a review.
      In patients with advanced ALD, carcinogenesis can be triggered by acetaldehyde and ROS, which promote mutagenesis and interfere with DNA methylation, synthesis, and repair.
      • Teschke R.
      Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects.
      It is likely that the simultaneous consumption of alcohol and tobacco contributes to the development of HCC via common metabolic pathways.
      • Yalcin E.B.
      • Tong M.
      • de la Monte S.M.
      Enzymatic responses to alcohol and tobacco nicotine-derived nitrosamine ketone exposures in long evans rat livers.
      Experimental data revealed that inflammation plays a critic role in generating a tumourigenic microenvironment (Fig. 2). Tobacco smoke exposure leads to the release of proinflammatory cytokines, such as IL-33, IL-1β and TNFα.
      • Kearley J.
      • Silver J.S.
      • Sanden C.
      • Liu Z.
      • Berlin A.A.
      • White N.
      • et al.
      Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.
      ,
      • Sakamoto T.
      • Higaki Y.
      • Hara M.
      • Ichiba M.
      • Horita M.
      • Mizuta T.
      • et al.
      Interaction between interleukin-1beta -31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese.
      IL-33 regulates liver inflammation through the activation of p38 MAPK. Increased expression of hepatic cancer stem cells and epithelial to mesenchymal transition, both major determinants of HCC development, were shown to be induced by smoke exposure.
      • Xie C.
      • Zhu J.
      • Wang X.
      • Chen J.
      • Geng S.
      • Wu J.
      • et al.
      Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway.
      Moreover, peripheral blood studies have associated smoking with immunosuppression and telomere dysfunction, both of which are early events in cancer development.
      • Geng Y.
      • Savage S.M.
      • Razani-Boroujerdi S.
      • Sopori M.L.
      Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy.
      ,
      • Hoare M.
      • Das T.
      • Alexander G.
      Ageing, telomeres, senescence, and liver injury.
      In line with these findings, hepatocarcinogenesis is promoted by reduced immune surveillance and telomere attrition in mouse models and liver tissue.
      • Ma C.
      • Kesarwala A.H.
      • Eggert T.
      • Medina-Echeverz J.
      • Kleiner D.E.
      • Jin P.
      • et al.
      NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
      ,
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      These key features were related to NASH, aging, fibrosis and alcohol, all of which are closely related to smoking.
      Fig. 3 depicts the cause-effect relationship between cigarette smoking and HCC and the potential underlying mechanisms. Importantly, smoking cessation is inversely associated with HCC risk. There is data suggesting that individuals who quit smoking more than 20 years ago have a near equivalent risk to never smokers.
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      Impact of smoking on clinical outcomes in patients with liver disease

      In 2015, 6.4 million deaths were attributable to smoking worldwide, representing a 4.7% increase in smoking-attributable deaths since 2005 and ranking cigarette smoking as the second-leading risk factor for attributable mortality just behind high-systolic blood pressure .
      GBD 2015 Tobacco Collaborators
      Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015.
      With this scenario and the bio-pathological background that smoking is associated with chronic liver disease and advanced fibrosis, it seems pertinent to review the evidence for its impact on liver-related clinical outcomes (Fig. 3).
      Smoking has a negative impact on the outcomes of patients with cirrhosis and HCC and may have deleterious effects in patients after liver transplantation.
      Modern personalised medicine entails detecting individuals that are at high risk of developing advanced/decompensated liver disease, in order to target a more intense diagnostic liver work-up, possible specific treatment and closer follow-up. A systemic review on predictors of mortality in cirrhosis, beyond the Child-Pugh and MELD (model for end-stage liver disease) score, was performed by Gennaro D’Amico.
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      Smoking was only assessed in 2 of the 118 included studies (46% ALD, 46% chronic viral hepatitis) and it was shown to be an independent predictive factor for survival (Fig. 4). Smoking was highly prevalent in alcohol-related cirrhosis (60-78%) and increased mortality independently of abstinence, with 5-year survival rates in smokers and non-smokers of 42% and 73% in patients <55 years, and 17% and 43% in patients >55 years, respectively.
      • Dam M.K.
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      Smoking and risk of liver cirrhosis: a population-based cohort study.
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      The impact of smoking on the natural history of NAFLD has been investigated in prospective population-based studies. Analysis from the USA and Thai National Health Examination Surveys revealed that smoking consistently leads to a 2-fold increase in mortality among patients with NAFLD (HR 2.33; 95% CI 1.66-3.27).
      • Wijarnpreecha K.
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      The interaction of nonalcoholic fatty liver disease and smoking on mortality among adults in the United States.
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      Differences were stronger among heavy smoking women (HR for ≥10 pack-years: 5.40; 95% CI 2.19–13.4).
      • Charatcharoenwitthaya P.
      • Karaketklang K.
      • Aekplakorn W.
      Cigarette smoking increased risk of overall mortality in patients with non-alcoholic fatty liver disease: a nationwide population-based cohort study.
      Adjusted by sex, the magnitude of increase in mortality differed from the non-NAFLD population if fatty liver was diagnosed with biochemical tests (hepatic steatosis index) but not if it was based on ultrasound.
      • Wijarnpreecha K.
      • Scribani M.
      • Kim D.
      • Kim W.R.
      The interaction of nonalcoholic fatty liver disease and smoking on mortality among adults in the United States.
      ,
      • Hajifathalian K.
      • Torabi Sagvand B.
      • McCullough A.J.
      Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study.
      The most common cause of death among patients with NAFLD was CVD, but smoking also had an impact on non-cardiovascular mortality (HR 2.79).
      • Hajifathalian K.
      • Torabi Sagvand B.
      • McCullough A.J.
      Effect of alcohol consumption on survival in nonalcoholic fatty liver disease: a national prospective cohort study.
      In patients with biopsy-proven NAFLD, current smoking has been associated with mortality or need for liver transplantation (HR 2.62; 95% CI 1.67–4.10).
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      In the presence of other well-known stronger risk factors, any possible impact of tobacco may be easily masked. Considering the changing trends in liver disease aetiology in the current metabolic-era, new studies on larger patient series should be performed. Regarding PBC aetiology, mortality is increased in smokers with advanced disease (bridging fibrosis and cirrhosis) at presentation .
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      Collectively, this data strongly suggest that smoking negatively impacts the outcome of patients with advanced chronic liver disease, including cirrhosis and HCC, further reinforcing the need to identify and treat this significant lifestyle factor.
      Besides mortality, smoking is an identifiable risk factor for other liver-related outcomes. In severe metabolic-associated liver disease, cigarette smoking increases the risk of liver-related events (e.g. hospital admission, cirrhosis, liver cancer or decompensation) in addition to other metabolic syndrome components.
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      In patients with NAFLD, smoking not only has an impact on CVD events or cancer development, but also on patient-reported outcomes.
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      ,
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      Factors independently associated with poorer patient-reported outcomes included cirrhosis, female sex, history of smoking, and metabolic comorbidities.
      • Younossi Z.M.
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      Reduced patient-reported outcome scores associate with level of fibrosis in patients with nonalcoholic steatohepatitis.
      In a cross-sectional nationwide study from India evaluating patients with cirrhosis (mainly alcohol and viral aetiology), smoking was significantly associated with the presence of minimal hepatic encephalopathy, a well-known factor that impacts the quality of life and leads to increased hospitalisations.
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      The prevalence of e-cigarette use has rapidly increased worldwide, especially among adolescents who are not fully aware of its potential harmful effects, including liver injury.
      Finally, liver transplantation significantly improves the survival and quality of life of patients with end-stage liver disease. Tobacco smoking has been shown to negatively impact liver transplantation outcomes (Fig. 1). Among complications related to cigarette smoking, there are 3 main factors to be highlighted: i) increased risk of vascular complications such as hepatic artery thrombosis, a potential cause of graft loss
      • Pungpapong S.
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      Cigarette smoking is associated with an increase incidence of vascular complications after liver transplantation.
      ; ii) development of de novo tumours
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      ; iii) increased rate of non-graft-related mortality, mostly due to CVD events.
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      ,
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      Cardiovascular events and cancer are mainly seen among liver transplant recipients for ALD, the second most frequent indication for liver transplantation.
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      The International Liver Transplant Society guidelines on Liver Transplantation for Alcoholic Liver Disease strongly recommend promoting smoking cessation in alcoholic liver transplant recipients in order to improve overall health and patient outcomes.
      • Addolorato G.
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      Liver transplantation for alcoholic liver disease.
      Many liver transplant programmes and health insurance plans do not offer/cover liver transplantation in patients who are current smokers. A cessation period of at least 2 months prior to liver transplantation may lead to a significant reduction in the risk of vascular complications.
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      Cigarette smoking is associated with an increase incidence of vascular complications after liver transplantation.
      The benefits of smoking cessation should be discussed at every office visit, and accordingly, medical assistance should be offered to promote smoking cessation prior to listing a patient for liver transplant.

      Electronic cigarette exposure and liver disease

      Electronic nicotine delivery systems, also known as e-cigarettes, are battery powered inhalation devices resembling a cigarette that deliver nicotine to users without burning tobacco. E-cigarette and other vaping devices such as waterpipe smoking are rapidly gaining popularity, especially among younger populations .
      • Dutra L.M.
      • Glantz S.A.
      Electronic cigarettes and conventional cigarette use among U.S. adolescents: a cross-sectional study.
      The misconception of representing a healthier alternative to cigarette smoking may be a key factor.
      • Eissenberg T.
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      • Chapman S.
      • Jordt S.E.
      • Shihadeh A.
      • Soule E.K.
      Invalidity of an oft-cited estimate of the relative harms of electronic cigarettes.
      Like the cigarette smoking debate in the era of Ronald A. Fisher, e-cigarettes and other vaping devices have become the subject of public health disputes driven by the scarce data on this issue.
      • Fairchild A.L.
      • Bayer R.
      • Colgrove J.
      The renormalization of smoking? E-cigarettes and the tobacco “endgame”.
      As e-cigarettes are a relatively new product, studies are needed to determine their long-term detrimental effects, some of which may be similar to nicotine exposure.
      Like conventional cigarettes, e-cigarettes and other vaping devices contain multiple substances with potentially harmful effects on human health. Components such as nicotine, nitrosamines, polycyclic aromatic hydrocarbons, metals, and carbon monoxide, among others, have been shown to have toxic effects and potentially induce inflammation, mental disorders, acute lung and subclinical CVD, metabolic disease, and certain cancers (oral and lung).
      • Waziry R.
      • Jawad M.
      • Ballout R.A.
      • Al Akel M.
      • Akl E.A.
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      • Snoderly H.T.
      • Nurkiewicz T.R.
      • Bowdridge E.C.
      • Bennewitz M.F.
      E-cigarette use: device market, study design, and emerging evidence of biological consequences.
      • Münzel T.
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      • Kuntic M.
      • Keaney J.F.
      • Deanfield J.E.
      • Daiber A.
      Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes.
      The impact of e-cigarettes on health has recently been studied in other disciplines, mainly in lung and cardiovascular diseases.
      • Snoderly H.T.
      • Nurkiewicz T.R.
      • Bowdridge E.C.
      • Bennewitz M.F.
      E-cigarette use: device market, study design, and emerging evidence of biological consequences.
      ,
      • Münzel T.
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      • Kuntic M.
      • Keaney J.F.
      • Deanfield J.E.
      • Daiber A.
      Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes.
      However, only a few studies have explored the impact of vaping devices on liver function. Some in vitro and in vivo studies suggest that exposure to the smoke and components of e-cigarettes may induce liver injury through different mechanisms. Mice on a western diet (NASH model) exposed to e-cigarettes exhibited a marked increase in hepatic lipid accumulation and hepatocyte apoptosis compared with control mice.
      • Hasan K.M.
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      Contrary to cigarette smoking, the detrimental effects of e-cigarettes on hepatic steatosis were associated with oxidative stress independent of AMPK signalling. In this mouse model of NASH, hepatic RNA sequencing analysis also showed a significant differential expression in more than 400 genes compared to controls not exposed to e-cigarettes, especially those associated with lipid metabolism and cholesterol biosynthesis.
      • Hasan K.M.
      • Friedman T.C.
      • Shao X.
      • Parveen M.
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      • Lee D.L.
      • et al.
      E-cigarettes and western diet: important metabolic risk factors for hepatic diseases.
      These results suggest that e-cigarettes may contribute to liver injury and lipogenesis disturbances in the context of NAFLD. Other mechanisms such as direct DNA damage and mitochondrial dysfunction have been proposed to play a role in this setting.
      • Espinoza-Derout J.
      • Shao X.M.
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      • Mtume N.
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      Hepatic DNA damage induced by electronic cigarette exposure is associated with the modulation of NAD+/PARP1/SIRT1 axis.
      Finally, the flavouring chemicals used for e-cigarettes may induce hepatocyte injury independently of smoke and nicotine. The exposure of HepG2 cells to flavouring chemicals significantly reduces cell viability in a dose-dependent way.
      • Rickard B.P.
      • Ho H.
      • Tiley J.B.
      • Jaspers I.
      • Brouwer K.L.R.
      E-cigarette flavoring chemicals induce cytotoxicity in HepG2 cells.
      These data provide the basis for expanding our knowledge on e-cigarette-induced liver injury. The mechanisms behind the development of liver disease associated with these devices are probably multiple and complex. There are studies supporting the idea that the use of e-cigarettes plays an important role in inducing endothelial dysfunction and subsequent CVD.
      • Snoderly H.T.
      • Nurkiewicz T.R.
      • Bowdridge E.C.
      • Bennewitz M.F.
      E-cigarette use: device market, study design, and emerging evidence of biological consequences.
      ,
      • Münzel T.
      • Hahad O.
      • Kuntic M.
      • Keaney J.F.
      • Deanfield J.E.
      • Daiber A.
      Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes.
      It is well-known that endothelial dysfunction is a critical event involved in the interplay between liver injury, fibrosis progression and haemodynamic derangement.
      • Iwakiri Y.
      • Shah V.
      • Rockey D.C.
      Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions.
      Therefore, as in CVD, it could be speculated that liver endothelial damage triggered by toxic compounds in e-cigarettes could significantly contribute to the development of liver injury. More translational and clinical studies are warranted to unravel the mechanisms involved and set the basis for evidence-based recommendations in clinical practice.

      Conclusions

      Increasing evidence indicates that smoking is associated with the development and progression of liver disease, HCC development and poorer clinical outcomes. The magnitude of the associations should increase the awareness of hepatologists about its deleterious effects and prompt strategies to encourage and assist patients to stop smoking. Although most providers are aware of this situation, referral to smoking cessation programmes is not routinely performed in clinical practice. Active smoking should be considered as a potential confounding factor in NAFLD, fibrosis, and HCC clinical trials.
      • Iruzubieta P.
      • Arias-Loste M.T.
      • Fortea J.I.
      • Cuadrado A.
      • Rivas-Rivas C.
      • Rodríguez-Duque J.C.
      • et al.
      National digestive disease specialists survey on cardiovascular risk management in non-alcoholic fatty liver disease in Spanish hospitals.
      ,
      • Ampuero J.
      • Romero-Gomez M.
      Stratification of patients in NASH clinical trials: a pitfall for trial success.
      ,
      • Loomba R.
      • Lim J.K.
      • Patton H.
      • El-Serag H.B.
      AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: expert review.
      Finally, due to the deleterious effects of smoking in patients undergoing liver transplantation, an increased number of centres should make smoking cessation an explicit requirement to be listed. Future studies should evaluate the association between objective smoking measurements, including urinary nicotine levels, and liver-related outcomes.

      Abbreviations

      ALD, alcohol-related liver disease; AMPK, AMP-activated protein kinase; CHB, chronic hepatitis B; CHC, chronic hepatitis C; CVD, cardiovascular disease; FLD, fatty liver disease; HCC, hepatocellular carcinoma; HR, hazard ratio; HSCs, hepatic stellate cells; IL, interleukin; LSM, liver stiffness measurement; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NASH CRN, Non-Alcoholic Steatohepatitis Clinical Research Network; PBC, primary biliary cholangitis; ROS, reactive oxygen species; TH1, T helper 1.

      Financial support

      This research received no specific grant from any funding agency in the public, commercial or non-for-profit sectors. David Marti-Aguado is recipient of a Río Hortega award (CM19/00212), Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). Ana Clemente-Sanchez is recipient of a scholarship grant for study extension abroad, sponsored by the Spanish Association for the Study of the Liver (AEEH). Ramón Bataller is a recipient of NIH / NIAAA grants: RO1AA018873 , 1U01AA026978-01 , 1U01AA026972-01 , 1U01AA026264-01 and NIDDK grant: 1R01DK117881-01 .

      Authors’ contributions

      All of the authors performed the research, writing, and review of all of the drafts of this paper and approved the final version.

      Conflict of interest

      The authors declare no conflicts of interests.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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