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Cigarette smoking (CS) is a world-wide major cause of preventable morbidity and mortality.1, 2 Exposure to cigarette smoke predisposes to cardiovascular and lung diseases as well as to several types of cancer.3 The risk of death in these patients increases with increasing exposure to cigarette smoke, measured by the number of cigarettes smoked daily, the duration of smoking, the degree of inhalation, and the age of initiation. In addition, exposure to environmental tobacco smoke in nonsmokers is associated with an increased risk of cardiovascular events and asthma.4 There is convincing evidence that smoking cessation has beneficial effects, even after a cardiovascular event.5 In the last decade, a considerable effort promoting smoking cessation by U.S. health authorities and other countries has been somewhat successful. Although the smoking prevalence has declined over the last few decades, it is rapidly increasing in developing countries, with an emerging epidemic of tobacco related diseases.6

In addition to these well-known consequences of tobacco consumption, recent clinical studies suggests that CS may accelerate the progression of “fibrogenic” conditions such as chronic renal, cardiac or pancreatic diseases.7, 8 For example, heavy cigarette smokers are predisposed to develop chronic renal failure and CS accelerates the rate of fibrosis progression in patients with nephrosclerosis.9 The mechanisms by which CS promotes the progression of chronic diseases are largely unknown. Cigarette smoke induces an array of pathogenic effects potentially involved in tissue fibrogenesis including systemic inflammation, thrombogenesis and oxidative stress.10 Moreover, CS exerts powerful immunoregulatory actions that can result in impaired wound healing response to injury. These effects may be more pronounced in susceptible individuals, as suggested by genetic epidemiological studies.11 The strongest evidence supporting a fibrogenic effect of CS is the fact that smoking cessation has beneficial effects on the progression of chronic renal diseases.12, 13 In these patients, smoking cessation should be encouraged and, if necessary, assisted. Current therapeutic methods to improve smoking reduction and cessation include nicotine replacement, behavioral interventions, and medications (e.g. bupropion, clonidine, rimonabant).14

Hepatologists have traditionally paid scant attention to the deleterious effects of CS. Honestly, we are not particularly sensitized to encourage smoking cessation among our patients. This reflects the fact that smoking per se does not appear to cause liver injury and therefore is not considered a causative agent for chronic liver diseases.15 However, there is increasing evidence that CS may negatively impact the incidence, severity, and clinical course of many types of chronic liver diseases.16 Epidemiological studies indicate CS as a risk factor for primary biliary cirrhosis (PBC) in susceptible individuals.17 Smoking may aggravate the pathogenic effects of alcohol on the liver, while its effect on the occurrence of nonalcoholic steatohepatitis in patients with metabolic syndrome is still unknown.18 Importantly, CS may influence the clinical course of chronic liver diseases by promoting fibrogenesis. Cigarette smoking accelerates the progression of liver fibrosis in patients with chronic hepatitis C and may decrease the efficacy of antiviral therapy.19–22 Smoking could also favor the occurrence of clinical decompensations in patients with established cirrhosis and is associated with an increased incidence of hepatocellular carcinoma.21, 23 Finally, patients submitted to liver transplantation are particularly sensitive to the cardiovascular and renal effects of CS. Transplanted patients who smoke have an increased risk for vascular complications including hepatic artery thrombosis.24 Although further studies should investigate the effects of CS on the liver, the available evidence suggests it may be an avoidable co-factor in the progression and clinical course of chronic liver diseases.

The mechanisms underlying the fibrogenic effect of CS on the liver are largely unknown. Potential mechanisms are depicted in Fig. 1. Cigarette smoke contains a large number of chemical substances with hepatotoxic potential including nicotine.25 Smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6, and IL-13 and TNF-α), angiogenic factors (VEGF-A) and fibrogenic mediators (leptin, TGFβ1, and angiotensin II).26 Cigarette smoke also induces oxidative stress by stimulating NADPH oxidase and decreasing antioxidant defenses, leading to lipid peroxidation.10 These effects could lead to increased hepatocellular damage and subsequent activation of resident hepatic stellate cells, a major fibrogenic cell-type. In fact, other fibrogenic cell-types such as mesangial cells are stimulated by products from cigarette smoke, such as nicotine to proliferate and produce increased amounts of extracellular matrix proteins.27 Future studies should explore whether cigarette smoke also exerts fibrogenic and inflammatory actions in hepatic stellate cells. Another potential mechanism by which CS leads to liver fibrogenesis may be iron deposition. Heavy smokers with chronic hepatitis C are characterized by polyglobulia and commonly show parameters indicative of iron accumulation.28 Smoking also induces profound changes in the microvasculature such as endothelial dysfunction, smooth muscle cell proliferation and vasoconstriction, leading to impaired delivery of nitric oxide and tissue hypoxia.29 All these events are potentially implicated in the wound healing response of the liver to chronic injury. Finally, heavy smokers commonly exhibit several features of the insulin resistance syndrome and are at an increased risk for type 2 diabetes.30 Because insulin resistance promotes liver fibrogenesis, it could participate in the fibrogenic effects of CS in the liver. Future epidemiological, clinical and experimental studies are needed to clarify the role of CS on liver fibrosis and the mechanisms involved.

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Figure 1. Potential mechanisms by which cigarette smoke may stimulate hepatic fibrogenesis. Abbreviations: IL, interleukin; ROS, reactive oxygen species.

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In this issue of HEPATOLOGY, Zein et al. provide a new evidence suggesting the association of CS with increased severity of hepatic fibrosis in patients with PBC. In this study, 97 patients were recruited from 3 major academic hospitals. Smoking history was more common and the number of pack-years was higher in patients with advanced histological disease, as assessed by fibrosis stage, than in those with early disease. The association between lifetime smoking of >10 pack-years and advanced histological disease at presentation remained significant after adjusting for age and alcohol consumption. The authors confirmed these results in an independent cohort of 172 patients with PBC by cross-validation. The results of this study shed a new light on the negative impact of CS in the progression of chronic liver diseases and suggest a positive role for smoking cessation in the outcome of patients with PBC. Nonetheless, the study by Zein et al. has some limitations. For both the retrospective and confirmatory validation cohorts, data on alcohol and tobacco consumption were obtained from medical records. These results should be confirmed in studies using carefully validated questionnaires assessing both alcohol and tobacco consumption. Still, it is unlikely that measurement error was substantial between subjects with more versus less advanced fibrosis in a way that would falsely inflate associations. Second, patients were recruited in academic tertiary hospitals. In these institutions, patients usually suffer from more advanced disease compared to primary care centers. To rule out the possibility of effects due to selection bias, it is necessary to carry out a prospective study that includes subjects diagnosed in primary as well as tertiary care centers. Finally, data on metabolic consequences of CS such as insulin resistance, which may play a role in the increased liver fibrogenesis, were only obtained in a subset of patients.

The results of the study by Zein et al. raise some important questions for clinical hepatologists. Are all types of chronic liver diseases equally sensitive to the fibrogenic effects of cigarette smoke? Does CS increase the incidence of other types of chronic liver diseases such as alcohol-induced liver diseases or chronic viral hepatitis? Are there patients genetically predisposed to fibrogenic effects of CS on the liver? We cannot answer these questions yet, but the preliminary data provided by Zerin et al. should certainly stimulate research in this interesting field. A more sensitive question is whether smoking cessation should be required as an eligibility criterion for liver transplantation, as is the case for alcohol consumption in most centers. Further investigation on the benefits of smoking cessation and outcome after liver transplantation should be undertaken. It is time to seriously take up the cause of banning cigarette smoking in the field of hepatology. Patients with chronic liver diseases should be strongly encouraged (and helped) to quit smoking.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. References

I thank Michele Mendez, Andrés Cardenas and Nicki Van Berkel for revising the manuscript.

References

  1. Top of page
  2. Acknowledgements
  3. References
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