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Re: [GIWorld-Hepatitis] Fw: NATAP: Smoking May Worsen Fibrosis for HCV+

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  • avansi7465
    That figures...............Oh well, nobody s perfect!
    Message 1 of 2 , Jul 3, 2006
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      That figures...............Oh well, nobody's perfect!

      -----Original Message-----
      >From: Alley Pat <alleypat@...>
      >Sent: Jun 28, 2006 2:40 PM
      >To: GIWorld-Hepatitis Yahogroup <GIWorld-Hepatitis@yahoogroups.com>, Happy Heppers Yahoogroup <happyheppers@yahoogroups.com>
      >Subject: [GIWorld-Hepatitis] Fw: NATAP: Smoking May Worsen Fibrosis for HCV+
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      >NATAP http://natap.org/
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      >Smoking May Worsen Fibrosis for HCV+
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      >â?oRelationship of Smoking and Fibrosis in Patients With Chronic Hepatitis Câ?
      >
      >â?oâ?¦..This study confirms previous reports suggesting that hepatic fibrosis is more prevalent in CHC patients who smokeâ?¦ hepatoxicity likely results from exposure to the myriad of chemicals, including highly reactive free radicals, found in cigarettesâ?¦.. In this study we proposed a theoretic mechanism whereby cigarette intake could influence fibrosis progression: that is, smoking could induce VEGF cytokines and their receptors, which in turn would influence angiogenesis, an integral feature of hepatic fibrosisâ?¦.. If future studies confirm this association, particularly in relation to fibrosis progression, appropriate anti-angiogenic therapies theoretically could be developedâ?¦..â?
      >
      >Clinical Gastroenterology & Hepatology
      >June 2006, Volume 4, Issue 6, Pages 797-801
      >
      >Anouk DevâZ, Keyur PatelâZâ?¡, Andrew Conrad§, Lawrence M. Blattâ?-, John G. McHutchisonâZâ?¡
      >âZ Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
      >â?¡ Scripps Clinic, Division of Gastroenterology, La Jolla, California
      >§ National Genetics Institute, Los Angeles, California
      >â?- InterMune Pharmaceuticals, Brisbane, California
      >
      >published online 9 May 2006.
      >
      >ABSTRACT
      >Background & Aims: Preliminary studies have suggested that in patients with chronic hepatitis C (CHC), cigarette smoking increases the risk for developing liver fibrosis. Hypoxia caused by smoking may induce expression of the cytokines' vascular endothelial growth factor (VEGF) and VEGF-D and their corresponding soluble tyrosine kinase receptors fms-like tyrosine kinase receptor (s-Flt) and kinase insert domain receptor (s-KDR). These cytokine levels are increased in animals with cirrhosis and in human beings with CHC. We studied whether the concentrations of VEGF, VEGF-D, s-Flt, and s-KDR were increased in CHC smokers with and without hepatic fibrosis.
      >
      >Methods: A total of 170 CHC patients were identified retrospectively from a single center's database. In 59 patients, serum levels of VEGF, VEGF-D, s-Flt, and s-KDR were measured using an enzyme-linked immunosorbent assay.
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      >Results: All 170 patients were hepatitis C virus RNA positive, 117 (69%) were men, 43 (25%) were smokers, and their mean (±SD) age was 47 (±6) years. Overall, 21% of smokers had Metavir fibrosis scores of 3 and 4 compared with 14% of nonsmokers (P < .01). In an age-weighted multivariate model using step-wise logistic regression, smoking, infection with hepatitis C virus genotype 1, male sex, and increased VEGF-D concentration all were significant independent predictors of more severe liver fibrosis (P < .05 for all observations).
      >
      >Conclusions: These data suggest that CHC patients who smoke may have more hepatic fibrosis. The data also suggest that increased VEGF and VEGF-D concentrations are associated with smoking and may be involved in the molecular mechanisms of fibrogenesis.
      >
      >
      >Hepatic fibrosis is a well-recognized complication of chronic hepatitis C (CHC),1 yet the severity and rate of fibrosis progression varies among patients, suggesting that fibrosis results from a complex interplay of viral, host, and environmental factors. Host factors that affect fibrosis progression include age, age at infection, duration of infection, sex, presence of steatosis, and alcohol intake.2,3 In addition, recent data suggest that cigarette smoking is related independently to increased histologic activity and hepatic fibrosis.4-6 How smoking influences fibrosis progression is undefined, but it is likely a consequence of nicotine-induced oxidative damage.7,8 Another possible mechanism could include smoking-induced immunosuppression.9
      >
      >Fibrogenesis is a common wound-healing response and is characterized by the formation of collagen-laden extracellular matrix scar tissue and by angiogenesis,10,11 the formation of new vascular structures from pre-existing vessels. Traditionally, angiogenesis has been associated with the pathologic and physiologic processes of tumor growth, arthritis, and myocardial and cerebral ischemia,12,13 but recently it has emerged as a pivotal factor in the pathology of inflammatory, fibrotic, and ischemic conditions of the liver.14,15 The pathophysiologic significance of hepatitis C virus (HCV)-associated angiogenesis is unclear, but it probably contributes to tissue repair and liver regeneration. The most potent proangiogenic factor known is vascular endothelial growth factor (VEGF), a glycosylated multifunctional protein that binds with high affinity to 2 tyrosine kinase receptors: fms-like tyrosine kinase receptor (s-Flt) and kinase insert domain receptor (s-KDR).16,17 In response to liver hypoxia and, to a lesser degree, other forms of liver injury, the activation of hepatic parenchymal cells and stellate cells results in increased expression of VEGF and its soluble receptors.18 VEGF increases vascular permeability, facilitating the migration of plasma proteins and endothelial cells that are essential in forming fibrotic tissue. In addition, endothelial cells and hepatic stellate cells also can proliferate in response to VEGF.19,20 Increased VEGF expression has been observed in animals with cirrhosis15 and in human beings with CHC and hepatocellular carcinoma.21 VEGF-D, an additional member of the VEGF family, binds to the s-KDR receptor and is associated with regulation of lymphatic angiogenesis.22
      >
      >We hypothesized that in patients with CHC, smoking leads to the progression of chronic liver disease by inducing expression of VEGF.
      >
      >Discussion
      >This study confirms previous reports suggesting that hepatic fibrosis is more prevalent in CHC patients who smoke.4,5 In addition, this study also links changes in expression of VEGF family angiogenic cytokines to the fibrotic process associated with smoking.
      >
      >Unlike in previous studies, in our study smoking was not related strongly to risk factors such as sex, age, and alcohol intake. As mentioned previously, the vast majority of patients in this study were participating in antiviral therapy trials with strict inclusion and exclusion criteria regarding alcohol intake. Selection bias was limited in this retrospective study because patients were chosen before VEGF analysis from a database and medical charts based on eligibility criteria such as availability of appropriate pretreatment biopsy specimens, serum samples, and a recorded smoking history. The mean alcohol intake at the time of biopsy examination in both the smoking and nonsmoking groups was less than 10 g/day, the equivalent of 1 standard drink. Furthermore, the mean alcohol intake in years preceding the biopsy examination was 20-40 g/day. Therefore, in these patients it is unlikely that alcohol by itself or in combination with smoking played a significant role in fibrosis. The limitations in observational studies such as these include the potential for variability in patient self-reporting of alcohol and smoking. Few studies have evaluated the use of alternative and more objective measures of alcohol and smoking, such as carbohydrate-deficient transferrin and nicotine or carboxyhemoglobin levels, in CHC patients. However, these markers are not specific and may show considerable interindividual variability, limiting the interpretation of CHC disease associations related to these social habits.23,24
      >
      >In univariate analysis, increasing age was associated with fibrosis progression but not with a history of smoking. This may be because the patients who smoked were clustered around the age bracket of 40-48 years. We also constructed a more realistic age-weighted multivariate model that allowed evaluation of multiple interactions of the factors potentially affecting fibrosis. In this model, smokers had significantly higher liver fibrosis scores than nonsmokers (P < .0001). Not all studies examining the impact of smoking on the severity of the liver histology in hepatitis C patients have found a relationship between the severity of fibrosis and tobacco consumption.6 However, 2 previous studies examining the relationship between smoking and hepatitis C have shown a strong association between smoking and histologic activity.5,6 This suggests that in the setting of smoking, increased histologic activity may play an important role in fibrosis progression. Information regarding Metavir histologic activity scores was not available in this study but perhaps should be included in all future research examining fibrosis progression in smokers. In addition, we were not able to assess lifetime tobacco exposure. Stratifying tobacco exposure in relationship to fibrosis progression may in the future aid in identifying levels of cigarette consumption that either are unlikely to influence progression of hepatitis C or are associated with hepatotoxicity.
      >
      >Although the interaction between smoking and hepatitis C progression has not been defined clearly, hepatoxicity likely results from exposure to the myriad of chemicals, including highly reactive free radicals, found in cigarettes. In many cell lines, damage induced by oxygen free radicals is enhanced by age,25 which may explain why smokers had higher fibrosis scores in our model weighted for age.
      >
      >In this study we proposed a theoretic mechanism whereby cigarette intake could influence fibrosis progression: that is, smoking could induce VEGF cytokines and their receptors, which in turn would influence angiogenesis, an integral feature of hepatic fibrosis. Although not statistically significant in univariate analysis, smokers had higher VEGF and VEGF-D concentrations than nonsmokers. However, in a more stringent and appropriate age-weighted multivariate model, sex, HCV genotype, smoking, and increased levels of VEGF-D were associated significantly with the presence of fibrosis (P < .05 for all observations). S-Flt and s-KDR concentrations did not differ between smokers and nonsmokers. The small sample size of smokers with available serum levels could have influenced this result, as could the interactions between the numerous variables. In addition, VEGF receptors have differential expression, and the s-Flt receptor in particular can be difficult to detect.26 The majority of studies assessing VEGF concentrations have been performed using fresh, unfrozen serum. It is unknown whether freezing or storing serum for extended periods affects the accuracy of VEGF and receptor assays. VEGF can induce proliferation of activated hepatic stellate cells, and increased levels in our study simply may have reflected its independent association as a marker of fibrogenesis.27 Nevertheless, the finding of increased levels of VEGF and VEGF-D in smokers merits further investigation. If future studies confirm this association, particularly in relation to fibrosis progression, appropriate anti-angiogenic therapies theoretically could be developed. Combinations of angiogenesis inhibitors, including antibodies directed against VEGF, could play an important role in treating a disease process that is associated with significant morbidity and mortality.
      >
      >In conclusion, this study shows a significant relationship between smoking and hepatic fibrosis in CHC patients. In addition, our data suggest that smoking-associated increases in VEGF may be involved in the molecular mechanisms of fibrogenesis. Future studies examining the relationship between hepatotoxicity and smoking should assess prospectively the role of VEGF in fibrogenesis.
      >
      >Results
      >
      >Patient Characteristics
      >Of 170 patients, 25% were classified as smokers (Table 1). The majority of both smokers and nonsmokers were white men in their 40s with mild disease. In the smoking group, 60% smoked 15 or fewer cigarettes per day to a lower limit of at least 1 cigarette, cigar, or pipe per day. Because the majority of patients enrolled in the database participated in trials with criteria for strict alcohol abstinence, the mean alcohol intake in both groups was less than 10 g/day.
      >
      >The mean past use of alcohol also was similar in both groups. There was no significant association between smoking history and alcohol intake. Overall, smokers had higher Metavir fibrosis scores; specifically, 21% of smokers had Metavir fibrosis scores of 3 and 4, as did 14% of nonsmokers (P < .01).
      >
      >Cytokine Analysis
      >Thirty-one smokers and 28 nonsmokers had serum samples available for cytokine analysis. Although not statistically significant, serum VEGF concentrations were higher in smokers compared with nonsmokers (350 ± 38 ng/mL vs 287 ± 40 ng/mL, P = .26), as were VEGF-D concentrations (622 ± 53 ng/mL vs 556 ± 56 ng/mL, respectively, P = .40) (Figure 1). The S-Flt and s-KDR receptor levels did not differ between smokers and nonsmokers (Figures 2 and 3).
      >
      >Relationship Between Host Factors, Smoking, and Fibrosis
      >By univariate analysis, increased age, infection with HCV genotype 1, and male sex were associated with fibrosis (P < .01 for all observations). Univariate analysis also showed an association between fibrosis score and smoking (P < .001). Ethnicity, body mass index, percentage of steatosis, and HCV RNA concentrations were not associated with smoking or fibrosis scores. In addition, age and sex were not associated with smoking (P > .05 for all observations). In an age-weighted multivariate model using step-wise logistic regression, smoking, infection with HCV genotype 1, male sex, and increased VEGF-D concentrations all were significant independent predictors of increased liver fibrosis (P < .05 for all observations). Analysis of parameter estimates indicated that patients who smoked were at a marginally higher risk of fibrosis (odds ratio = 1.3, P = .04). Better predictors of fibrosis in our model included male sex (odds ratio = 6.7, P < .001), HCV genotype 1 infection (odds ratio = 1.6, P = .001), and higher VEGF-D serum concentration (odds ratio = 9.7, P < .001) (Table 2).
      >
      >Materials and Methods
      >Patient Selection
      >A total of 170 consecutive patients were identified retrospectively from a large hepatitis patient and clinical research database at Scripps Clinic in La Jolla, California, that includes demographic, virologic, serologic, and histologic data from more than 1600 individuals enrolled in treatment protocols at our tertiary referral center since 1992. Patient selection was based on the availability of pretreatment liver biopsy specimens for staging, serum samples for analysis, and a detailed smoking history in the medical chart. Patients enrolled in the database gave written informed consent for the studies in which they participated and for the use of their data and stored serum for future studies, which also had been approved separately by the institutional review board.
      >
      >Demographic Data
      >Demographic data including age, sex, ethnicity, duration of infection, current alcohol intake, remote history of alcohol use, and smoking history were obtained through physician-patient interviews and patient questionnaires at the initial visit. Current alcohol intake was defined as consumption at the time of the liver biopsy examination, and past intake as the average consumption during periods of heaviest use 6 months or more before the biopsy examination. The number of beverages was converted to average grams of alcohol per day. The average alcohol intake was categorized as 0, less than 10, 10-20, 20-40, 40-60, 60-80, or more than 80 g/day. The estimated duration of infection was calculated as the time from first exposure to an established hepatitis C risk factor to the time of pretreatment liver biopsy examination. Height and weight were recorded at the time of the biopsy examinations and was used to calculate body mass index. For this study, smoking history was obtained retrospectively from the database and medical records. Patients were classified as smokers if they reported any smoking activity at time of presentation or in the past. The quantity of cigarettes smoked per day was noted at the time of initial presentation. Neither quantity of cigarettes smoked in the past nor duration of smoking history was available.
      >
      >Histologic Evaluation
      >Three pathologists with a high degree of concordance for Metavir fibrosis staging (κ coefficient = .83) assessed fibrosis in these pretreatment liver biopsy specimens by using the Metavir scoring system. All 3 pathologists were blinded to the clinical information. The rate of fibrosis progression was calculated as Metavir units/years infection. The percentage of steatosis was calculated as the average proportion of hepatocytes affected by macrovesicular steatosis in 5 fields at 10Ã- magnification.
      >
      >Laboratory Data
      >Pretreatment serum specimens (stored at -70°C within 2 hours of collection) were available for cytokine analysis in 59 of the 170 patients. Commercially available kits (R&D Systems, Minneapolis, MN) were used to measure serum VEGF, VEGF-D, s-Flt, and s-KDR levels by quantitative sandwich enzyme-linked immunosorbent assay. All samples were analyzed in a blinded fashion
      >
      >Statistical Analyses
      >Statistical significance was assessed at the .05 level. Means, SDs, medians, and ranges were computed for all continuous data. To identify factors associated with the histologic fibrosis score, univariate analysis was performed using analysis of variance for parametric data and Ï?2 analysis for nonparametric data. Post hoc paired t tests were applied to determine pair-wise statistical difference after analyses of variance. Thereafter, multivariate stepwise logistic regression was used to determine the association between the presence of fibrosis and independent risk.
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