Secondary Logo

Journal Logo

Systematic Review

Smoking & risk of advanced liver fibrosis among patients with primary biliary cholangitis

A systematic review & meta-analysis

Wijarnpreecha, Karn1,*; Werlang, Monia1; Panjawatanan, Panadeekarn2; Pungpapong, Surakit1; Lukens, Frank J.1; Harnois, Denise M.1; Ungprasert, Patompong3,#,

Author Information
Indian Journal of Medical Research: December 2021 - Volume 154 - Issue 6 - p 806-812
doi: 10.4103/ijmr.IJMR_639_19
  • Open


Primary biliary cholangitis (PBC) is a chronic autoimmune disease of the liver characterized by inflammation and intrahepatic bile duct destruction, resulting in intrahepatic cholestasis1. PBC is a relatively uncommon disease with the reported prevalence of only 20-400 cases per million persons in Northern Europe and North America23. The precise aetiology of PBC is unknown but is believed to be an interplay between genetic and environmental factors45. Patients with PBC may present with abnormal liver chemistry tests without any symptoms, symptoms of cholestasis (pruritus, yellow eyes and fatigue) or signs and symptoms of cirrhosis67.

Cigarette smoking is a known cause of several preventable non-communicable diseases such as coronary artery disease (CAD), cerebrovascular disease, chronic obstructive pulmonary disease (COPD) and malignancy89. The impact of smoking cessation on the prevention of those diseases is substantial. For instance, a study of postmenopausal women found that smoking cessation can decrease the risk of stroke by almost 40 per cent10. Recent studies found that smoking may also have deleterious effects on the liver because of the increased oxidative stress burden and lipid peroxidation, which may lead to hepatic injury and fibrosis11. The effect may be more pronounced among patients who already have chronic inflammation in the liver, including patients with PBC, although clinical data from epidemiologic studies are still limited121314. The current systematic review and meta-analysis was conducted with the aim to comprehensively analyze the association between risk of liver fibrosis and history of smoking among patients with PBC.

Material & Methods

Information sources and search strategy: A systematic literature search was carried out using the MEDLINE and Embase databases from inception to February 2019 to identify original studies reporting the relationship between history of smoking and risk of advanced liver fibrosis in patients with PBC. The systematic literature review was independently conducted by three investigators using the search strategy that included the terms such as, ‘primary biliary cholangitis’, ‘primary biliary cirrhosis’, ‘smoking’, and ‘cigarettes’ (Supplementary Table I). A manual search for additional potentially relevant studies was also carried out using the references of the included studies as well as some selected review articles. This study was conducted in accordance with the Preferred reporting items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (checklist available as Supplementary Table II). EndNote X7 (Clarivate Analytics, Pennsylvania, United States) was used for study retrieval.

Supplementary Table I:
Search Strategy
Supplementary Table II:
PRISMA checklist

Selection criteria: Only cross-sectional studies that recruited patients with PBC with data on (i) smoking status, and (ii) presence or absence of advanced liver fibrosis for each participant were selected. Odds ratios (OR) with 95 per cent confidence intervals (CI) or sufficient raw data to calculate the same for this association should have been reported. Inclusion was not restricted by study size. When more than one study using the same database/cohort was available, only the study with the most comprehensive data/analyses was included. Retrieved articles were independently reviewed to determine their eligibility by the same three investigators. Any discrepancy was resolved by discussion. The modified Newcastle-Ottawa scale was used for quality assessment of the included studies as described previously15.

Data abstraction: A structured data asbtraction form was used to extract details such as title of the study, publication year, name of the first author, calendar year(s) when and in which country the study was conducted, number and demographic data of participants, definiton of advanced liver fibrosis, method(s) used to evalaute liver fibrosis, definition of positive history of smoking (i.e., definition of ever-smokers), method(s) used to determine smoking status, adjusted effect estimates with 95 per cent CI as well as covariates that were adjusted for in the multivariable analysis.

To ensure the accuracy, this data extraction process was independently performed by two investigators. The data abstraction forms were cross-checked by the senior investigator. Any data discrepancy was resolved by referring back to the original articles.

Statistical analysis: Data analysis was performed using the RevMan 5.3 software (Cochrane, London, UK). Adjusted point estimates for the association between ever-smoker status and advanced liver fibrosis were extracted from each study and combined together using the generic inverse variance method as described earlier16, to assign the weight of each study in the pooled analysis inversely.

Random-effects, rather than fixed-effects model, was utitlized for the meta-anlayses as the assumption of the latter that all studies, regardless of study design and participants, should produce the same result is almost always not true for clinical research. Cochran’s Q test and I2 statistic were used to determine the between-study heterogeneity. This I2 statistic quantified the proportion of total variation across studies due to true heterogeneity rather than chance. A value of I2 of 0-25 per cent represents insignificant, 26-50 per cent represents low, 51-75 per cent represents moderate heterogeneity and more than 75 per cent represents high heterogeneity, respectively17. If enough number of eligible studies were identified, visualization of funnel plot was used to assess for the presence of publication bias.


Two-hundred and ninety-six potentially eligible articles were identified as per the described search strategy (107 from MEDLINE and 189 from Embase). After the exclusion of 105 duplicated articles, 191 articles underwent title and abstract review. A total of 170 articles were excluded at this stage since these did not fulfill the eligibility criteria based on type of article, study design, population or measured outcomes, leaving 21 articles for full-text review. Eighteen of these were excluded after the full-length review as these did not report the outcome of interest. Finally, three cross-sectional studies121314 with 544 participants were included in the meta-analysis. It should be noted that the study by Zein et al14 consisted of two cohorts that were recruited from different centers. The effect estimates for each cohort were reported separately and, therefore, were both included in the meta-analysis. The literature review and selection process are depicted in Fig. 1. The characteristics and quality assessment of these studies are detailed in the Table. In brief, all included studies diagnosed PBC based on clinical presentation, serology, and histopathology. The definition of ever-smokers was consistent across the studies (defined as current or history of smoking of ≥5 packs at any time during the patient’s lifetime up to the time of PBC diagnosis)121314.

Fig. 1:
Literature review process.
Main characteristics of the studies included in this meta-analysis

Risk of advanced liver fibrosis among patients with primary biliary cholangitis (PBC) who were ever-smokers versus patients who were non-smokers: The pooled analysis found a significantly increased risk of advanced liver fibrosis among patients with PBC who were ever-smokers compared to patients who were non-smokers with the pooled OR of 3.00 (95% CI, 1.18-7.65) as shown in Fig. 2. Statistical heterogeneity was high with I2 of 89 per cent.

Fig. 2:
Forest plot of the meta-analysis.


As per our acknowledge, this study is the first systematic review and meta-analysis that summarizes all available data on the association between smoking status and risk of advanced liver fibrosis among patients with PBC. The pooled analysis found a three-fold increased risk of advanced liver fibrosis among patients with PBC who were ever-smokers compared to patients without history of tobacco exposure. The mechanism behind the increased risk is not known with certainty. Possible explanations are discussed below.

First, smoking has been shown to alter the balance of T helper cells, Th1 and Th2, and several cytokine levels, including IL-5 and IL-131819. IL-13 has been implicated in progression of fibrosis in animal studies and smoking can increase the production of IL-1311202122. It has been demonstrated that IL-5 can augment the progression of liver fibrosis by up-regulating activity of IL-1323. Th1 cells that are inducible by smoking24 have been shown to accelerate the progression of fibrosis by activating hepatic stellate cells to secrete more profibrogenic markers through the IFN-γ/STAT pathway25.

The second possible explanation involves pro-angiogenic factors. A study in patients with chronic hepatitis C virus infection found that the level of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF) and VEGF-D, are higher among smokers compared to non-smokers and the higher level was independently associated with advanced fibrosis26. Tissue hypoxia induced by smoking is the likely cause of the higher level of these factors.

Third, smoking can lead to insulin resistance as demonstrated by Houston et al27 in the CARDIA study. Furthermore, studies have also demonstrated that insulin resistance is associated with higher prevalence of severe hepatic fibrosis in patients with NAFLD2728. Some other studies have suggested that hyperinsulinemia can stimulate influx of fatty acid to the liver, leading to hepatic triglyceride accumulation293031. This excessive fatty deposition will cause cellular injury through oxidative stress and hepatocyte apoptosis, which will eventually lead to hepatic fibrosis32.

The present study has some limitations that may affect the validity of the results. First, statistical heterogeneity was high in this meta-analysis. We believe that the difference in background populations and methods used to evaluate liver fibrosis were the main source of the between-study variation. In addition, there was variation in adjustment of the effect estimates as two studies1213 adjusted their effect estimates for sex and alcohol consumption while one study14 did not. Second, a formal assessment for the presence of publication bias could not be performed due to the limited number of included studies. Therefore, it is possible that publication bias in favour of studies that showed positive association may have been present and may have skewed the pooled result. Third, all of the studies were conducted in Western countries and the results may not be generalizable to other populations. Fourth, subgroup analysis comparing heavy, regular, occasional, and ex-smokers could not be performed compared to non-smokers as the included studies did no provide such data. Similarly, there was no subgroup data to perform subgroup analysis based on sex and age. Lastly, this was a systematic review and meta-analysis of observational studies. Thus, it is still possible that the observed association was not causal but was a function of a confounding effect. Other factors related to the smoking habit, but not smoking itself, could still be the actual etiology of the increased risk. This limitation is true for all observation studies but is of particular concern for the current study because only minimal to none adjustment for potential confounders was performed by the primary studies.

In summary, the current study demonstrated that smoking is associated with a significantly higher risk of advanced liver fibrosis among patients with PBC. Further prospective studies are required to determine whether this association is indeed causal.

Financial support & sponsorship: None.

Conflicts of Interest: None.


1. European Association for the Study of the Liver. EASL clinical practice guidelines: The diagnosis and management of patients with primary biliary cholangitis J Hepatol 2017 67 145–72
2. Kim WR, Lindor KD, Locke GR 3rd, Therneau TM, Homburger HA, Batts KP, et al Epidemiology and natural history of primary biliary cirrhosis in a US community Gastroenterology 2000 119 1631–6
3. Sood S, Gow PJ, Christie JM, Angus PW Epidemiology of primary biliary cirrhosis in Victoria, Australia: High prevalence in migrant populations Gastroenterology 2004 127 470–5
4. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al Risk factors and comorbidities in primary biliary cirrhosis: A controlled interview-based study of 1032 patients Hepatology 2005 42 1194–202
5. Jones DE Pathogenesis of primary biliary cirrhosis J Hepatol 2003 39 639–48
6. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M Primary biliary cholangitis: 2018 practice guidance from the American Association for the study of liver diseases Hepatology 2019 69 394–419
7. Mahl TC, Shockcor W, Boyer JL Primary biliary cirrhosis: Survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years J Hepatol 1994 20 707–13
8. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity losses –United States, 2000-2004 MMWR Morb Mortal Wkly Rep 2008 57 1226–8
9. Centers for Disease Control and Prevention. Cigarette smoking among adults and trends in smoking cessation –United States, 2008 MMWR Morb Mortal Wkly Rep 2009 58 1227–32
10. Dinh PC, Schrader LA, Svensson CJ, Margolis KL, Silver B, Luo J Smoking cessation, weight gain, and risk of stroke among postmenopausal women Prev Med 2019 118 184–90
11. El-Zayadi AR Heavy smoking and liver World J Gastroenterol 2006 12 6098–101
12. Corpechot C, Chrétien Y, Chazouillères O, Poupon R Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis J Hepatol 2010 53 162–9
13. 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 Eur J Gastroenterol Hepatol 2018 30 1461–9
14. Zein CO, Beatty K, Post AB, Logan L, Debanne S, McCullough AJ Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment Hepatology 2006 44 1564–71
15. Herzog R, Álvarez-Pasquin MJ, Díaz C, Del Barrio JL, Estrada JM, Gil Á Are healthcare workers’ intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review BMC Public Health 2013 13 154
16. DerSimonian R, Laird N Meta-analysis in clinical trials Control Clin Trials 1986 7 177–88
17. Higgins JP, Thompson SG, Deeks JJ, Altman DG Measuring inconsistency in meta-analyses BMJ 2003 327 557–60
18. Cozen W, Diaz-Sanchez D, James Gauderman W, Zadnick J, Cockburn MG, Gill PS, et al Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption J Clin Immunol 2004 24 617–22
19. Whetzel CA, Corwin EJ, Klein LC Disruption in Th1/Th2 immune response in young adult smokers Addict Behav 2007 32 1–8
20. Cooper PR, Poll CT, Barnes PJ, Sturton RG Involvement of IL-13 in tobacco smoke-induced changes in the structure and function of rat intrapulmonary airways Am J Respir Cell Mol Biol 2010 43 220–6
21. Kaviratne M, Hesse M, Leusink M, Cheever AW, Davies SJ, McKerrow JH, et al IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent J Immunol 2004 173 4020–9
22. Sadeghnejad A, Karmaus W, Arshad SH, Kurukulaaratchy R, Huebner M, Ewart S IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study Respir Res 2008 9 2
23. Reiman RM, Thompson RW, Feng CG, Hari D, Knight R, Cheever AW, et al Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity Infect Immun 2006 74 1471–9
24. Tollerud DJ, Clark JW, Brown LM, Neuland CY, Mann DL, Pankiw-Trost LK, et al The effects of cigarette smoking on T cell subsets. A population-based survey of healthy caucasians Am Rev Respir Dis 1989 139 1446–51
25. Wen J, Zhou Y, Wang J, Chen J, Yan W, Wu J, et al Interactions between Th1 cells and Tregs affect regulation of hepatic fibrosis in biliary atresia through the IFN-γ/STAT1 pathway Cell Death Differ 2017 24 997–1006
26. Dev A, Patel K, Conrad A, Blatt LM, McHutchison JG Relationship of smoking and fibrosis in patients with chronic hepatitis C Clin Gastroenterol Hepatol 2006 4 797–801
27. Houston TK, Person SD, Pletcher MJ, Liu K, Iribarren C, Kiefe CI Active and passive smoking and development of glucose intolerance among young adults in a prospective cohort: CARDIA study BMJ 2006 332 1064–9
28. Angulo P, Keach JC, Batts KP, Lindor KD Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis Hepatology 1999 30 1356–62
29. Bugianesi E, McCullough AJ, Marchesini G Insulin resistance: A metabolic pathway to chronic liver disease Hepatology 2005 42 987–1000
30. Cavallo-Perin P, Cassader M, Bozzo C, Bruno A, Nuccio P, Dall’Omo AM, et al Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect J Clin Invest 1985 75 1659–65
31. Saltiel AR, Kahn CR Insulin signalling and the regulation of glucose and lipid metabolism Nature 2001 414 799–806
32. Kim MY The progression of liver fibrosis in non-alcoholic fatty liver disease Korean J Gastroenterol 2017 69 341–7

Cigarettes; liver fibrosis; meta-analysis; primary biliary cholangitis; smoking

© 2021 Indian Journal of Medical Research | Published by Wolters Kluwer – Medknow