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Hepatology. 2010 May ; 51(5): 14871490. doi:10.1002/hep.23694.

Clearing the Smoke in Chronic Liver Diseases

Claudia O. Zein1
Cleveland Clinic, Cleveland, OH, USA

Keywords
Smoking; liver fibrosis; nonalcoholic fatty liver disease

In the 1930s, serious concerns about the health risks of cigarette smoking (CS) began to
surface. During subsequent decades, scientific reports linking CS and specific ailments
rapidly accumulated [1,2], but it was not until 1964 that the Surgeon Generals Advisory
Committee on Smoking and Health finally acknowledged that CS was linked to specific
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diseases and to increased mortality. Today, the evidence is robust: The adverse effects of CS
on several cancer outcomes as well as on cardiovascular and respiratory disease are
established [3, 4]. Although in the US the prevalence of CS has been decreasing [5], the
overall worldwide prevalence is steadily rising. Independent of prevalence rates, the
absolute number of smokers everywhere keeps increasing due to population growth.

The case against CS in patients with chronic liver diseases (CLD) has been highlighted
recently as data reporting hepatic injury due to smoking have emerged [6,7]. A role for CS
in CLD was first suggested by two studies in the mid 1990s [8,9]. By now, CS has been
clearly identified as a risk factor for hepatocellular carcinoma in CLD [1011], but its effect
on histological activity or fibrosis progression in CLD still needs further characterization.
Published studies have been limited predominantly by cross-sectional and retrospective
study designs, and lack of supportive experimental data. Nonetheless, the evidence from
clinical studies consistently indicates that CS may accelerate liver disease progression in
patients with chronic hepatitis C and B and those with primary biliary cirrhosis [Table 1] [8,
1217]. CS also appears to exacerbate the liver injury in alcoholic liver disease [8,9].
Regarding nonalcoholic fatty liver disease (NAFLD), data supporting a potential role of CS
are just recently surfacing.
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Delineating the effect of CS in NAFLD is essential because of the vast number of subjects
that may benefit from risk factor modification. Over 30 million adults in the United States
have NAFLD [18] and approximately 8 million may have nonalcoholic steatohepatitis
(NASH) and hence a significant risk of developing cirrhosis, its complications and liver
related mortality [1920]. Unfortunately, no beneficial therapy can be recommended yet for
patients with NASH. Therefore, the identification of modifiable risk factors that may impact
disease progression, by itself important, is even more critical.

Corresponding Author: Claudia O. Zein, MD, MSc, Department of Gastroenterology and Hepatology, Digestive Disease Institute,
Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44915.
1Dr. Zein is supported by Grant Number KL2 RR024990 from the National Center for Research Resources (NCRR), a component of
the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the
responsibility of the author and do not necessarily represent the official view of the NCRR or NIH. Information on NCRR is available
at http:www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://
nihroadmap.nih.gov/clinicalresearch/overview-traslational.asp.
 Zein Page 2

Although the exact mechanisms by which CS worsens CLD are unknown, knowledge on the
effects of CS in other organs together with available liver related clinical and experimental
data provide insight into the pathophysiology of CS induced injury in NAFLD. These
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include enhanced insulin resistance (IR), altered lipid metabolism, chronic hypoxia,
increased oxidative stress, and enhancement of inflammatory cytokines. Because insulin
resistance influences histological severity in NAFLD [21, 22], CS may worsen NAFLD
through its effect on IR, glucose intolerance and diabetes development [23,24]. Changes in
lipid metabolism induced by CS may also aggravate NAFLD. Experimental studies have
shown that CS aggravates the hepatic steatosis elicited by high fat diet in mice [25,26] via
enhanced fatty acid synthesis through inhibition of AMP-activated protein kinase
phosphorilation in liver tissue [25]. Chronic hypoxia, a hallmark side effect of CS, induces
steatosis, liver inflammation and fibrosis in mice [2729]. CS also causes oxidative stress
[30], a recognized mechanism of injury in NAFLD [31]. Mice on an ethanol diet develop
increased hepatocellular injury when exposed to CS and have increased CYP2E1, known to
play a role in oxidative injury in NAFLD [28]. Finally, CS may worsen NAFLD through
enhancing pro-inflammatory cytokines, such as tumor necrosis factor alpha, that are known
to play a key role in NAFLD [32].

In this issue of Hepatology, Azzalini et al. provide novel evidence suggesting that CS
exacerbates liver injury in NAFLD. In their study, control and obese Zucker rats were
divided into smoker and nonsmoker groups based on controlled exposure to CS. Exposure to
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CS increased ALT levels, and increased hepatocellular ballooning and lobular inflammation
in the liver of obese rats, whereas significantly smaller changes were noted in control rats.
The authors showed that CS increased oxidative stress, and hepatocyte apoptosis in obese
rats. In addition, CS exposure induced TIMP-1 and pro-collagen alpha2 synthesis at the
transcription level. The effects of CS on ALT level, histological hepatic injury, and
expression of fibrogenic genes occurred only with long-term exposure (4 weeks) to CS and
did not occur with a shorter exposure (5 days). This indicates that the aggravating effects of
CS on NAFLD are the result of prolonged exposure to CS. The results of Azzalini et al
provide some elucidation of the underlying mechanisms involved in CS related liver injury
not only in NAFLD but potentially also in other types of CLD. The value of the findings of
experimental studies such as this study by Azzalini et al. is further underscored by the fact
that it would be impossible to conduct a prospective randomized controlled study of the
effects of CS in humans with chronic liver disease. Even case-control or cohort studies
attempting to isolate the effect of CS on CLD prove to be challenging in the clinical setting
and are limited by multiple confounders.

Nonetheless, the study by Azzalini et al has some limitations. As the authors acknowledge,
the 4 week study design may not have allowed the occurrence of some effects of long-term
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CS that may have been observed with longer exposure. In this regard, although this study
did not show changes in IR or lipid profiles of rats exposed to CS, it is possible that longer
exposures to CS may adversely affect these metabolic factors [2326]. Interestingly, the
observation of increased hepatic injury induced by CS in the absence of worsening IR,
together with the knowledge that CS also worsens IR [23,24] and IR in turn worsens
NAFLD [21,22] suggests that that the deleterious effect of CS in human NAFLD, and in
CLD in general, may engage several pathways. The 4 week study design may also have
resulted in an inability to demonstrate increased hepatic fibrosis. A second study limitation
also relates to the assessment of hepatic fibrosis. Although CS up-regulated the expression
of genes involved in fibrogenesis in obese rats, this was not associated with evident
development of increased liver fibrosis. However, the absence of leptin receptor in the
Zucker rat model may have influenced these results. Evidence for this possibility is that
whereas a methionine-choline-deficient diet induces steatohepatitis and increased oxidative
stress in Zucker rats, the occurrence of increased neovascularization, hepatic expression of

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vascular endothelial growth factor, and liver fibrosis development are restricted in this
model [33]. Therefore, although conclusions cannot be made regarding the lack of increased
angiogenesis and liver fibrosis development reported in the study by Azzalini et al, the CS
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induced worsening of histological injury and apoptosis support the concept that CS may
cause fibrosis progression in NASH [34]. Additional studies in different animal models are
needed to clarify and substantiate the profibrogenic effects of CS in NALFD suggested by
gene up-regulation. Finally, this study demonstrated that CS increases hepatic apoptosis in
the liver of obese rats. This is of great importance given the crucial role of apoptosis in
NAFLD progression. However, the exact apoptotic pathways involved were not identified.
A key observation was that CS decreased caspase-3-driven-apoptosis in both obese and
control rats, suggesting that CS induces a caspase-3 independent pathway in NAFLD.
Further studies are warranted to elucidate the exact mechanism behind CS induced apoptosis
in NAFLD.

To sum up, the study by Azzalini et al. demonstrates that CS worsens liver injury in a rat
model of obesity-related NAFLD. These results, together with other experimental data [25
29], provide compelling evidence that CS exacerbates NAFLD. Similarly, clinical studies in
CLD have consistently indicated that CS aggravates liver injury in humans [8,9,1117].
There are very few published studies on the effects of CS in human NAFLD. Although two
studies did not find an association between CS and the presence of NAFLD in the general
population [35, 36], only one published clinical study has looked at the possible effect of CS
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in patients already identified as having NAFLD [37]. In that study, CS exposure was
associated with increased ALT.

Future studies are needed to better elucidate the mechanistic aspects of the effects of CS in
NAFLD, and to better characterize the role of CS in human NAFLD. Nonetheless, this study
provides one more reminder that there is already ample experimental and clinical evidence
consistently pointing in the same direction: That CS aggravates liver injury in CLD. It is
time to take the harmful effects of CS in CLD more seriously. As hepatologists, we need to
incorporate the intake of a more thorough smoking history during our evaluations, educate
our patients on the effects of this modifiable risk factor on liver injury, and strongly
recommend smoking cessation in all patients with CLD.

Abbreviations

CS Cigarette Smoking
CLD Chronic Liver Diseases
NALFD Nonalcoholic fatty liver disease
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NASH Nonalcoholic steatohepatitis

References
1. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in brochogenic carcinoma.
A study of 684 proved cases. J Am Med Assoc. 1950 May 27; 143(4):32936. [PubMed: 15415260]
2. Dolgoff S, Shcrek S, Ballard GP, et al. Tobacco smoking as an etiologic factor in disease. 2.
Coronary disease and hypertension. Angiology. 1952 Aug; 3(4):32334. [PubMed: 14952880]
3. Freund KM, Belanger AJ, DAgostino RB, Kannel WB. The health risks of smoking. The
Framingham study: 34 years of follow up. Ann Epidemiol. 1993 Jul; 3(4):41724. [PubMed:
8275219]
4. The Health Consequences of Smoking: A report of the Surgeon General. May. 2004 http://
www.surgeongeneral.gov/library/smokingconsequences/index.html

Hepatology. Author manuscript; available in PMC 2013 March 04.

 Zein Page 4

5. National Health Interview Survey. National Center for Chronic Disease Prevention and Health
Promotion. Centers for Disease Control and Prevention; 2008. Office on Smoking and Health.
http://www.cdc.gov
NIH-PA Author Manuscript

6. Bataller R. Time to ban smoking in patients with chronic liver diseases. Hepatology. 2006;
44:13941396. [PubMed: 17133465]
7. El-Zayadi AR. Heavy smoking and the liver. World J Gastroenterol. 2006; 12:60986101.
[PubMed: 17036378]
8. Corrao E, Lepore AR, Torchio P, 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. Eur J Epidemiol. 1994; 10:65764. [PubMed: 7672043]
9. Klatsky AL, Armstrong MA. Alcohol, smoking, coffee and cirrhosis. Am J Epidemiol. 1992;
136:12481257. [PubMed: 1476147]
10. Marrero JA, Fontana RJ, Fu S. Alcohol, tobacco and obesity are synergistic risk factors for
hepatocellular carcinoma. J Hepatol. 2005; 42:21824. [PubMed: 15664247]
11. Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk
factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009; 136:13848.
[PubMed: 18848939]
12. Tsochatzis E, Papatheodoridis GV, Manolakopoulos S, et al. Smoking is associated with steatosis
and severe fibrosis in chronic hepatitis C but not B. Scand J Gastroenterol. 2009; 44:7529.
[PubMed: 19296398]
13. Dev A, Patel K, Conrad A, Blatt A, et al. Relationship between smoking and fibrosis in patients
NIH-PA Author Manuscript

with chronic hepatitis C. Clinical Gastroenterology and Hepatology. 2006; 4:797801. [PubMed:
16682255]
14. Hezode C, Lonjon I, Roudot-Thoraval F, et al. Impact of Smoking of histological liver lesions in
chronic hepatitis C. Gut. 2003; 52:126129. [PubMed: 12477773]
15. Pessione F, Ramond MJ, Njapoum C, et al. Cigarette smoking and hepatic lesions in patients with
chronic hepatitis C. Hepatology. 2001; 34:121125. [PubMed: 11431742]
16. Yu MW, Hsu FC, Sheen IS, et al. Prospective study of hepatocellular carcinoma and liver cirrhosis
in asymptomatic chronic hepatitis B virus carriers. Am J Epidemiol. 1997; 145:103947.
[PubMed: 9169913]
17. Zein CO, Beatty K, Post AB, et al. Cigarette smoking is associated with increased severity of
hepatic fibrosis in primary biliary cirrhosis. Hepatology. 2006; 44:15641571. [PubMed:
17133468]
18. Browning JD, et al. Prevalence of hepatic steatosis in an urban population in the United States:
impact of ethnicity. Hepatology. 2004; 40:138795. [PubMed: 15565570]
19. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: A spectrum of
clinical and pathological severity. Gastroenterology. 1999; 116:14131419. [PubMed: 10348825]
20. Adams LA, et al. The natural history of NAFLD: a population-based cohort study.
Gastroenterology. 2005; 129:113121. [PubMed: 16012941]
NIH-PA Author Manuscript

21. Silverman JF, OBrien KF, Long S, et al. Liver pathology in morbidly obese patients with and
without diabetes. Am J Gastroenterol. 1990; 85:134955. [PubMed: 2220728]
22. Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with
nonalcoholic steatohepatitis. Hepatology. 1999; 30:13561362. [PubMed: 10573511]
23. Attvall S, Fowelin J, Lager I, et al. Smoking induces insulin resistance a potential link with the
insulin resistance syndrome. J Intern Med. 1993; 233:32732. [PubMed: 8463765]
24. Will JC, Galuska DA, Ford ES, et al. Cigarette smoking and diabetes mellitus: evidence of a
positive association from a large prospective cohort study. In J Epidemiol. 2001; 30:5406.
25. Yuan H, Shyy JYJ, Martin-Green M. Second hand smoke stimulates lipid accumulation in the liver
by modulating AMPK and SREBP-1. J Hepatol. 2009; 51:535547. [PubMed: 19556020]
26. Chen H, Hansen MJ, Jones JE, et al. Detrimental metabolic effects of combining long term
cigarette smoke exposure and high fat diet in mice. Am J Physiol Endocrinol Metab. 2007;
293:E1564E1571. [PubMed: 17940214]

Hepatology. Author manuscript; available in PMC 2013 March 04.

 Zein Page 5

27. Savransky V, Bevans S, Nanayakkara A, et al. Chronic intermittent hypoxia causes hepatitis in a
mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol. 2007;
293:G871G877. [PubMed: 17690174]
NIH-PA Author Manuscript

28. Bailey SM, Mantena SK, Millender-Swain T, et al. Ethanol and tobacco smoke increase hepatic
steatosis and hypoxia in the hypercholesterolemic apoE(/) mouse: implications for a multihit
hypothesis of fatty liver disease. Free Radic Biol Med. 2009; 46:92838. [PubMed: 19280709]
29. Moon JOK, Welch TP, Gonzalez FJ, et al. Reduced liver fibrosis in hypoxia inducible factor-1
alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2009; 296:G582G592. [PubMed:
19136383]
30. Agarwal R. Smoking, oxidative stress and inflammation: impact on resting energy expenditure in
diabetic nephropathy. BMC Nephrol. 2005; 22:613.
31. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Non-alcoholic steatohepatitis: association of
insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001; 120:11831192.
[PubMed: 11266382]
32. Zeidel A, Beitlin B, Yakerni I, et al. Immune response in asymptomatic smokers. Acta
Anesthesiologica Scandinavica. 2002; 46:959964.
33. Kitade M, Yoshiji H, Kojima H, et al. Leptin-mediated neovascularization is a pre-requisite for
progression of nonalcoholic steatohepatitis in rats. Hepatology. 2006; 44:98391. [PubMed:
17006938]
34. Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and Fas Expression are prominent
features of human nonalcoholic steatohepatitis. Gastroenterology. 2003; 125:437443. [PubMed:
NIH-PA Author Manuscript

12891546]
35. Haenle MM, Brockmann SO, Kron M, et al. Overweight, physical activity, tobacco and alcohol
consumption in a cross-sectional random sample of German adults. BMC Public Health. 2006;
6:233244. [PubMed: 16981990]
36. Chavez-Tapia NC, Lizardi-Cervera J, Perez-Bautista O, et al. Smoking is not associated with
nonalcoholic fatty liver disease. Wold J Gastroenterol. 2006; 12:51965200.
37. Suzuki A, Lindor K, St Saver J, et al. Effect of changes on body weight and lifestyle in
nonalcoholic fatty liver disease. J Hepatol. 2005; 43:10601066. [PubMed: 16140415]
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Table 1
Studies in patients with CLD investigating the association between smoking and histological severity of
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disease.

Association with Smoking

Author REF Condition n Histological Disease Activity Severity of Liver Fibrosis

Dev et al. 13 HCV 170 - Yes

Pessione et al. 15 HCV 310 Yes Yes

Hezode et al. 14 HCV 244 Yes No

Tsochatzis et al. 12 HCV 176 - Yes

Tsochatzis et al. 12 HBV 85 - No

Yu et al. 16 HBV 1506 - Yes

Corrao et al. 8 Cirrhosis 115 - Yes

Zein et al. 17 PBC 269 - Yes

- indicates not reported or not applicable

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