Smoking May Worsen Liver Fibrosis in Patients
with Hepatitis C

A complex interplay of viral, host, and environmental factors – not all of which are recognized -- influences the progression of liver fibrosis.  

Some past research has suggested that tobacco smoking increases the risk of fibrosis in patients with chronic hepatitis C. A study reported in the June 2006 issue of Clinical Gastroenterology & Hepatology confirmed these earlier results.

 The mechanism(s) by which smoking promotes fibrosis progression are not well understood, but may involve oxidative damage, increased necroinflammatory activity, and/or immune suppression.  

The researchers hypothesized that hypoxia (low oxygen levels) caused by smoking may induce expression of cytokines known as vascular endothelial growth factor (VEGF) and VEGF-D, and their corresponding soluble fms-like tyrosine kinase receptors (s-Flt) and kinase insert domain receptors (s-KDR). VEGF and VEGF-D stimulate angiogenesis (blood vessel proliferation), an integral feature of liver fibrosis, wound healing, tumor formation, and other processes that involve growth of new tissue. Past studies have shown that levels of these cytokines are increased in animals with cirrhosis and in humans with chronic hepatitis C or hepatocellular carcinoma.

 In this study, the researchers analyzed whether serum concentrations of VEGF, VEGF-D, s-Flt, and s-KDR were increased in HCV positive smokers with and without liver fibrosis. A total of 170 chronic hepatitis C patients were selected retrospectively from a database of patients at the Scripps Clinic in La Jolla, California; 69% were men, most were Caucasian, the mean age was 47 years, and 25% were smokers. A majority (60%) smoked 15 or fewer cigarettes per day. Most were participating in antiviral therapy trials with strict criteria regarding alcohol use (a potential confounding factor because people who smoke are more likely to drink alcohol, which damages the liver). Serum levels of VEGF, VEGF-D, s-Flt, and s-KDR were measured in 59 patients (31 smokers and 28 nonsmokers) using an enzyme-linked immunosorbent assay. 

Results 

Overall, 21% of smokers had Metavir fibrosis scores of 3 or 4, compared with 14% of nonsmokers (P < 0.01). Smokers had significantly higher liver fibrosis scores than nonsmokers (P < 0.0001).  

Concentrations of s-Flt and s-KDR did not differ significantly between smokers and nonsmokers, nor did levels of VEGF or VEGF-D in a univariate analysis (though they trended higher in smokers). 

In an age-weighted multivariate model using step-wise logistic regression, however, the following factors were all significant independent predictors of more severe liver fibrosis (all P < 0.05):

Smoking
Genotype 1 HCV
Male sex
Increased VEGF-D concentration.

In contrast with some other studies, race/ethnicity, body mass index, and presence of steatosis were not associated with worse fibrosis. 

Conclusion

The authors concluded that chronic hepatitis C patients who smoke may be more likely to develop liver fibrosis. Their data also suggest that increased VEGF and VEGF-D concentrations, which are associated with smoking, may be involved in the molecular mechanisms of fibrogenesis. 

07/7/06 

Reference 
A Dev, K Patel, A Conrad, and others. Relationship of smoking and fibrosis in patients with chronic hepatitis C. Clinical Gastroenterology & Hepatology 4(6): 797-801. June 2006.