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Fibrosis
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http://www.natap.org Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C ....we show a significant relationship between daily cannabis use and fibrosis progression in patients with ongoing CHC. We believe that patients with ongoing CHC should be strongly advised to abstain from daily cannabis use..... Hepatology July 2005 Christophe Hézode 1 6, Françoise Roudot-Thoraval 2 6, Son Nguyen 1 5, Pascale Grenard 5, Boris Julien 5, Elie-Serge Zafrani 3 5, Jean-Michel Pawlostky 4 6, Daniel Dhumeaux 1, Sophie Lotersztajn 5, Ariane Mallat 1 5 * 1Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France 2Department of Public Health, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France 3Department of Pathology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France 4Department of Virology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France 5INSERM, U581, Université Paris XII, Hôpital Henri Mondor, Créteil, France; and 6INSERM, U635, Hôpital Henri Mondor, Créteil, France ABSTRACT Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis. We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC). Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied. Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system. Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed. On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort): --daily cannabis use (OR = 3.4 [1.5-7.4]), --Metavir activity grade A2 or higher (OR = 5.4 [2.9-10.3]), --age at contamination of more than 40 years (OR = 10.5 [3.0-37.1]), --genotype 3 (OR = 3.4 [1.5-7.7]), --excessive alcohol intake (OR = 2.2 [1.1-4.5]), and steatosis (OR = 2.0 [1.0-4.1]). Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5-7.5]). Finally, severe fibrosis (F3) was also predicted by daily cannabis use (OR = 2.5 [1.1-5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking. In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use. INTRODUCTION Cannabis (Cannabis sativa, marijuana), the most common recreational drug used in the Western world,[13] is the source of more than 60 cannabinoid compounds that bind two G protein-coupled receptors, CB1 and CB2.[14][15] CB1 receptors predominate in the brain and are responsible for the psychoactive effects of -9-tetrahydrocannabinol, the main active component of cannabis, whereas CB2 receptors are mainly expressed in cells of the immune system.[14][15] Expression of both receptors has also been demonstrated in a variety of peripheral tissues.[16] We recently found that CB1 and CB2 receptor expression undergo marked induction in the human liver with cirrhosis.[17-19] We also demonstrated that CB1 receptors strongly enhance experimental liver fibrogenesis, while CB2 receptors exert opposite antifibrogenic effects.[17-19] The present study was therefore undertaken to determine the clinical relevance of these experimental findings. To this aim, we investigated the impact of cannabis smoking on fibrosis progression in patients with CHC. AUTHOR DISCUSSION The present study investigates the impact of cannabis use on the natural history of CHC in a large series of patients with untreated CHC and known disease duration. Using multivariate analysis, we identify daily cannabis smoking as an independent predictor of FPR, in contrast to occasional cannabis use. In keeping with these results, severe fibrosis (F3) is also independently related to daily cannabis use. Major factors previously incriminated in fibrosis progression during CHC were identified as predictors of FPR and fibrosis stage, in addition to daily cannabis smoking, as expected. Older age at infection and chronic excessive alcohol intake are consistently considered primary determinants of fibrosis progression,[4][6][7][20][23][24] and the relationship between fibrosis stage and necroinflammatory grade has been documented in both longitudinal and cross-sectional studies.[3][12][25][26] Steatosis is also a recognized factor associated with severe fibrosis[11][27][28] and emerged as an independent predictor of FPR in our study, while being close to significance for the prediction of severe fibrosis. An impact of genotype 3 was found in analyses based on FPR, independently of steatosis, and was absent when considering fibrosis stage. This finding is rather unusual, because the majority of previous studies found no effect of viral genotype on fibrosis progression.[29] We considered the possibility of a confounding effect related to an interaction between daily cannabis use and genotype 3. However, in daily users of cannabis, the proportion of patients with a FPR greater than 0.074 or greater than 0.15 was not significantly different in patients with genotype 3 compared with patients who had other genotypes (data not shown; P = .411 and .583, respectively). In addition, there was no impact of genotype 3 on the prevalence of severe fibrosis in daily cannabis users (P = .411). Overall, discrepant results obtained with respect to viral genotype deserve additional investigation in further studies. Our study closely investigated possible confounders of cannabis impact. Arguably, the shorter duration of HCV infection in cannabis users compared with nonusers may result in overestimation of FPR in daily cannabis users. However, daily cannabis use was also independently related to fibrosis stage. Moreover, occasional cannabis smoking did not emerge as an independent predictor of FPR, although this group of patients had similar disease duration compared with daily users. As reported in several studies, prevalence of excessive alcohol intake was high in cannabis users.[13] Nevertheless, it should be noted that there was a significant relationship between fibrosis stage and daily cannabis use in the subgroup of patients with low disease-time alcohol intake. This finding therefore allows us to rule out a confounding effect of alcohol on cannabis impact. Ongoing use of illicit drugs other than cannabis is another potential confounding factor that was excluded at enrollment. An influence of maintenance treatment by methadone or buprenorphine in former IVDU was investigated and ruled out via univariate analysis. Finally, tobacco smoking was also taken into account, given the conflicting results of recent studies.[12][30] Several limitations of the study must be acknowledged. As in several previous reports,[6][9][24][31] fibrosis progression rate was calculated from a single liver biopsy and estimated disease duration. Potential inaccuracy in the presumed date of infection[32] was limited by exclusive enrollment of patients with a previous history of a single, well-identified route of exposure. The assumption of linearity of FPR has recently been disputed in a report suggesting late acceleration of fibrogenesis.[23] However, our findings are strongly supported by the fact that daily cannabis use was also identified as an independent predictor of fibrosis stage. Disease-time cannabis history recording is also subject to potential inaccuracy. Therefore, this possible bias was minimized by categorizing patients according to the pattern of cannabis use (none, occasional, or daily) rather than a quantitative estimation of usage. Uncertainties in quantification of disease-time alcohol intake were also controlled by grouping patients according to two types of behavior. Life prevalence of cannabis use has increased steadily over the past 30 years in the Western world.[33][34] A recent survey from the National Institutes of Health also shows that within a period of 10 years, there has been a significant increase in cannabis use among 45- to 64-year-old men and women.[35] In our study, cannabis use was recorded using a standardized questionnaire covering the span of HCV infection. Daily and occasional use of cannabis was reported in 32% and 17% of patients, respectively, and predominantly involved former IVDU, as expected. These findings are in keeping with the notion that prolonged cannabis use for up to 20 years predominantly occurs in near-daily and daily users.[36-38] There have been great advances in the understanding of mechanisms of action of plant-derived cannabinoids in recent years. Biological effects are elicited by two G protein-coupled cannabinoid receptors, CB1 and CB2, that also bind endogenous lipidic cannabinoid ligands with autocrine and paracrine effects.[14][15] Although the central properties of cannabinoids such as mood regulation, stimulation of appetite, and analgesia are best known, the peripheral effects of the compounds are becoming increasingly recognized.[16] In this respect, it has been shown that endogenous activation of the cannabinoid system plays a role in the pathogenesis of portal hypertension associated with cirrhosis via CB1-dependent splanchnic vasodilation.[39][40] We recently demonstrated that the cannabinoid system is involved in experimental liver fibrogenesis.[17-19] Along this line, results of the present study are in keeping with our experimental data demonstrating the profibrogenic role of CB1 receptors.[18][19] Indeed, we found a strong induction of CB1 receptor expression in samples of human livers with cirrhosis, predominating in liver fibrogenic cells. Moreover, we showed that mice genetically invalidated for the CB1 receptor display reduced fibrosis following chronic intoxication with carbon tetrachloride compared with wild-type littermates. These data suggest that CB1-receptor antagonism may open new therapeutic avenues in the treatment of liver fibrosis.[19] In conclusion, we show a significant relationship between daily cannabis use and fibrosis progression in patients with ongoing CHC. We believe that patients with ongoing CHC should be strongly advised to abstain from daily cannabis use. This recommendation might be particularly beneficial in difficult-to-treat patients.
Etanercept Treatment to Slow Fibrosis Progression Shows No Histological or Biochemical Improvement in Chronic HCV Genotype 1 Nonresponders to Peginterferon/Ribavirin There is no established treatment that prevents the progression of fibrosis in patients who fail interferon-based combination antiviral treatment. Tumor necrosis factor (TNF) alpha is an important mediator in the development of fibrosis, thereby implicating a possible role for the inhibition of TNF alpha (etanercept) in the treatment of chronic Hepatitis C (CHC). The aim of the current study was to asses the efficacy of etanercept treatment on the necroinflammatory and fibrotic change in patients with CHC infection, genotype 1, nonresponders to interferon-based combination antiviral treatment. Ten patients with CHC genotype 1, nonresponders to antiviral treatment with pegylated interferon and ribavirin, were enrolled. Active HCV infection was documented by a positive HCV RNA by PCR (Cobas Amplicor). Etanercept was administered for 24 weeks duration at a dose of 25 mg subcutaneously twice weekly. A liver biopsy prior and post etanercept treatment was obtained and reviewed by an independent pathologist using the METAVIR score. Patients were followed monthly for evaluation of side effects and liver related blood tests for a period of 32 weeks. Results · Of the ten patients enrolled, 50% (5/10) were women of mean age 50 years, and 50% (5/10) were men of mean age 40 years. · One patient was withdrawn due to abnormal elevation in serum alanine aminotransferase (ALT); one patient was lost to follow up. · Eight post treatment liver biopsies were evaluated; · 12% (1/8) had an improvement in the stage of fibrosis, 88% (7/8) had no change in fibrosis. · The mean baseline platelet count (PLT) and ALT level were (177,000 MCL/120 U/L) respectively. · None of the differences between platelet count and ALT levels at baseline and at follow up achieved statistical significance (p >0.05). · Even though one patient had an improvement in the stage of biopsy after treatment, these results did not reach statistical significance. Conclusion This is the first analysis of etanercept treatment for inhibition of hepatic fibrosis in patients with chronic HCV, genotype 1, nonresponders to combination antiviral therapy. There was no significant histological or biochemical improvement. 06/01-05
Reference http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hbc_060105_a.html
Long-term Fibrosis Progression in Nonresponders to Interferon-based Therapy Little is known on the long-term fibrosis progression in patients with chronic hepatitis C nonresponsders to IFN-based therapy. At the recent DDW 2005 meeting in Chicago, Spanish investigators presented a poster reporting the histologic outcome of 84 subjects failing anti-HCV therapy who underwent repeat liver biopsies (mean time between biopsies, 8.6 years). Median fibrosis progression rate, defined as the difference in fibrosis stage expressed in METAVIR units between the two liver biopsies divided by the time in years between the two biopsy specimens, was 0.112 METAVIR units/year. Results · In multivariate logistic regression analysis, low platelets [OR 3.1 (95%CI 1.2-8.2); p=0.02] and steatosis [OR 2.5 (95%CI 1.1-6.5); p= 0.05] were identified as independent factors predicting progression of fibrosis. · Overall, 27 / 84 (32.1 %) subjects developed cirrhosis during follow-up. · The diagnosis was made following a follow-up biopsy (10 individuals) or after the development of hepatic decompensation (10) or diagnosis of hepatocellular carcinoma (7). · The incidence of cirrhosis according to baseline fibrosis score is shown in table 1. Older age (p=0.002), low platelets (p=0.008) and steatosis in the first biopsy (p=0.001) were found to be predictor factors for the development of cirrhosis (p=0.002). · Stabilization or improvement of fibrosis progression rate after anti-HCV treatment was observed in 18/25 (72%), and worsening in 7/25 (28%) of subjects analyzed. · Mean fibrosis progression rate before treatment was 0.084, comparable to that after treatment (mean, 0.079). In conclusion, comparable fibrosis progression rates in patients with chronic hepatitis C prior and after failing anti-HCV treatment suggest that the histological benefit conferred by IFN-based therapy depends on virological success. Thrombocytopenia and steatosis in the initial biopsy were factors associated with fastened progression in this cohort. The authors stated that ‘re-treatment of this subgroup of patients with higher risk of progression is highly indicated’. Table 1. Incidence of cirrhosis according to baseline METAVIR fibrosis score
Baseline fibrosis n Cirrhosis, n (%) F0 19 1 (5.3%) F1 19 3 (15.8%) F2 10 1 (5.3%) F3 36 22 (61.1%) p=0.0001
05/25/05
Reference http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_052505_c.html
Baseline Fibrosis Score Does Not Predict SVR to Peginterferon Alfa-2a (Pegasys) Plus Ribavirin in HCV Patients with Persistently ¡°Normal¡± ALT Levels Patients (pts) with chronic hepatitis C and advanced fibrosis/ cirrhosis have lower sustained virological response (SVR) rates to interferon-based therapies. In this study, researchers aimed to determine whether there was a correlation between baseline fibrosis score and SVR rates in non-cirrhotic pts (Ishak stage 0-4) with persistently ¡®normal¡¯ ALT levels. Pts with persistently ¡®normal¡¯ ALT levels on ¡Ý3 occasions over 18 months were randomized to 24 or 48 weeks of treatment with peginterferon alfa-2a (Pegasys) 180 ¦Ìg/wk plus RBV 800 mg/d, or no treatment in a multinational trial. The study was initiated before the optimal RBV dose (1000/1200 mg/d) for genotype 1 was known. The primary endpoint was SVR (undetectable HCV RNA, <50IU/mL, after 24 wks untreated follow-up). Results were retrospectively analyzed according to baseline fibrosis score and genotype (1 or 2/3). Results ¡¤ 422 non-cirrhotic pts were randomized (402 were infected with genotype 1 or 2/3). ¡¤ No untreated control pts cleared HCV, thus they are not represented in our analysis. ¡¤ There was no significant correlation between baseline fibrosis score (table) or baseline necroinflammatory score (data not shown) and SVR. ¡¤ Baseline fibrosis and necroinflammation scores were not significant predictors of SVR according to multiple logistic regression analysis. Conclusions The authors conclude, ¡°In non-cirrhotic pts (stage 0-4) with persistently ¡®normal¡¯ ALT levels, baseline fibrosis scores (excluding 5-6) do not predict the outcome of treatment with peginterferon alfa-2a (40KD) plus RBV.¡± ¡°These data suggest that liver fibrosis should not be the sole determinant in the decision to treat such pts, rather the decision should include consideration of the probability of eradicating HCV and curing the disease.¡±
05/18/05 Reference R Reindollar and others. Baseline Fibrosis Score Does Not Predict Sustained Virological Response To Peginterferon Alfa-2a (40KD) Plus Ribavirin in Patients With Chronic Hepatitis C and Persistently ¡®norml¡¯ Alt Levels. Abstract S1566. Digestive Disease Week 2005. May 14-18, 2005. Chicago, IL. http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051805b.htm
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Role Of CYP2D6 Polymorphism in Predicting Liver Fibrosis Progression Rate in Caucasian Patients With Chronic Hepatitis C .S. Fishman, Y. Lurie, H. Peretz, T. Morad, E. Grinberg, L. Blendis, M. Leshno, E. Brazovsky, Z. Halpern, R. Oren Introduction Fifteen to twenty percent of chronic hepatitis C (HCV) patients progress during their life time to end stage liver disease. However, markers of fibrosis progression rate are yet to be defined. Recent studies have demonstrated that cytochrome P450-2D6 (CYP2D6) polymorphism is associated with liver cirrhosis. The aim of our study was to find out whether CYP2D6*4, the poor metabolizer allele can predict fibrosis progression rate. METHODS: Fifty caucasian patients with chronic HCV were recruited. They were divided to "fast fibrosers" and "slow fibrosers" according to Poynard's fibrosis progression curves, based on age of exposure and duration of infection. Thirty six underwent liver biopsy. Blood of 20 neonates served as a control. DNA was extracted from peripheral blood and CYP2D6*4 was tested by polymerase chain reaction (PCR) method, using fluorecent hybridization probes in a lightcycler instrument. RESULTS: Thirty three patients were classified as "fast fibrosers" and 17 patients as "slow fibrosers". The prevalence of CYP2D6*4 in the "fast fibrosers" (37.8%) was significantly higher than its prevalence in the "slow fibrosers" (P-value=0.0166). There was no significant difference between the prevalence of CYP2D6*4 in the "slow fibrosers" (14.7%) compared to the controls (11%). Carrier state of CYP2D6*4 was the only covariate that was significantly directed associated with fast progression to cirrhosis (OR=11.7 P= 0.022) CONCLUSIONS: This study indicates for the first time, that CYP2D6 genotype is a significant predictor of liver fibrosis progression rate in HCV patients. Prospective studies are needed to further validate the data that bear significant therapeutic importance . http://www.hcvadvocate.org/news/reports/DDW_2005/May%2016%20HCV.htm#May16_32
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Reviewed July 18 2005
