Understanding the factors influencing HCV disease severity, especially those that are potentially modifiable, is of great importance in patient management. The strong recommendation for HCV-infected persons to limit or abstain from alcohol use (18
) reflects the consistent association between heavy alcohol use and more severe fibrosis and greater risk of cirrhosis (2
). Similarly, steatosis has recently been identified as an important factor associated with fibrosis severity (23
). Metabolic, virologic and alcohol-related contributions to fatty liver are recognized, and at least some of these factors can be modifiable. Based on our results, we recommend that cannabis be added to the list of modifiable risk factors for HCV disease severity. We have shown that daily cannabis use is an independent risk factor for moderate to severe fibrosis and one of substantial magnitude, with daily cannabis users having a nearly sevenfold higher odds of moderate to severe fibrosis compared to non-daily users. HCV-HIV coinfected subjects were significantly more likely to use cannabis daily and to have a prescription for medical cannabis than HCV monoinfected subjects. The recommendation to avoid cannabis use may be especially important for HCV/HIV coinfected persons given that fibrosis progression is already enhanced in this group (24
Our results support the findings of a French study of liver clinic patients with chronic HCV infection, which found that daily cannabis smoking was an independent risk factor for severe fibrosis (≥F3 on the METAVIR scale) and rapid fibrosis progression (>0.15 METAVIR units/year) (11
). This study assumed a linear model of progression and did not examine predictors of mild fibrosis and moderate to severe fibrosis, as was done in our study. It is of interest that we found a strong association between daily cannabis use and having moderate to severe fibrosis compared to mild fibrosis, but little association was apparent between cannabis use and the presence of mild fibrosis compared to no fibrosis. This suggests that there may be a different or minimal effect of cannabis in early versus later stage disease. Cannabis may have little or no influence on the initiation of fibrosis, but once fibrosis is present, it may be an important cofactor in fibrosis progression. Further studies are needed to confirm this apparent difference in association by stage of fibrosis. Pending such studies, the safest recommendation to patients would be to reduce or avoid daily cannabis use, regardless of the stage of disease.
Fibrosis results from an imbalance in the profibrogenic and antifibrogenic factors expressed in the setting of chronic liver injury (25
). Studies in human livers and mouse models of fibrosis demonstrate upregulated expression of the cannabinoid receptors, CB1 and CB2, in chronic liver injury compared to normal controls (8
). Immunohistochemical staining of human specimen with cirrhosis shows localization of the CB receptors to hepatic myofibroblasts (8
). In experimental models of fibrosis, CB1 receptor activation is associated with profibrogenic effects whereas CB2 receptor activation is associated with antifibrogenic effects (8
). In, studies of liver injury in mice, blockade of the CB1 receptor by a CB1 antagonist or use of CB1 knockout is associated with lesser fibrosis than control animals (9
). Antagonism of the CB1 receptor has been associated with reduced expression of the TGFβ1, a cytokine central to fibrosis production, and decreased stellate cell proliferation and increased apoptosis, all of which would be predicted to reduce fibrosis (9
). Additionally, CB1 receptor antagonism has been associated with increased levels of adiponectin (26
), an adipokine with antifibrotic properties in animal models (27
). Thus, there are several potential mechanisms by which enhanced CB1 receptor expression or activity may lead to increased fibrosis. In terms of the CB2 receptor, activation is associated with antiproliferative and apoptotic effects in myofibroblasts and activated stellate cells, and in a mouse model of chronic liver injury, CB2 receptor blockade is associated with enhanced liver fibrosis compared to control mice (8
). While studies suggest tetrahydrocannabinol binds equally to CB1 and CB2 receptors, whether this is true in the setting of chronic liver injury due to HCV is unknown. Dysregulation of ligand binding to the CB1 and/or CB2 receptors or post-binding alterations may result in a situation favoring fibrogenesis.
Similar to other studies evaluating the factors associated with severe fibrosis, we found that duration of moderate to heavy alcohol use was an independent predictor of moderate to severe fibrosis (2
). Definitions of “heavy” alcohol use vary across different studies and not all studies use gender-specific cut-offs. We used the Lifetime Drinking History to carefully evaluate lifetime alcohol use and defined moderate to heavy use as 2 or more drink equivalents per day on average in women and 4 or more drink equivalents per day on average in men. For every 10 years of alcohol use at these levels, the odds of having moderate to severe fibrosis compared to mild fibrosis increased by nearly 2-fold. Alcohol use at levels below these cutoffs did not appear to be associated with a substantially increased risk of fibrosis in our models. Our results are consistent with a recent metaanalysis of 20 studies including 15,000 HCV-infected persons, in which heavy alcohol intake, defined by a range of at least 210–560 g of alcohol per week, had a pooled relative risk of cirrhosis of 2.33 (95% CI, 1.67–3.26) (4
). There remains a paucity of data on the effects of infrequent and light alcohol intake on HCV disease progression (30
), particularly in persons with minimal fibrosis.
This is the first study to evaluate the relationship between alcohol and cannabis use. This relationship is critical to understand for two reasons. First, concurrent use or abuse of alcohol and marijuana is not an uncommon behavior. Second, those who are moderate and heavy users of alcohol may substitute cannabis for alcohol in efforts to reduce alcohol intake, particularly once they learn of their HCV diagnosis. The risks from daily cannabis use and moderate and heavy lifetime alcohol use, which we defined as an average daily intake of 2 or more drink equivalents for women and 4 or more drink equivalents in men, had a suggestion of synergy but with very wide uncertainty in our model of moderate to severe fibrosis.
HCV viral load has not been shown consistently to have an effect on fibrosis severity (3
). Whether the relationship between HCV viral load and disease severity is dependent upon the stage of fibrosis is unknown. In our study, HCV viral load was the only factor with a statistically significant association with mild fibrosis compared to no fibrosis. Two recent paired biopsy studies of individuals with chronic HCV infection and predominantly mild fibrosis identified HCV viral load as an independent predictor of fibrosis progression (29
). These results suggest that the relationship between HCV viral load and risk of fibrosis progression warrants reevaluation, with a focus on those persons with minimal or mild HCV disease. If the association between HCV viral load and disease severity is confirmed in this subgroup of HCV-infected persons, this may become an additional factor influencing decisions related to the urgency of undertaking antiviral therapy.
Having a greater number of portal tracts was associated with greater odds of detecting mild and moderate to severe fibrosis. This finding is in keeping with the increasing body of literature that stresses the importance of biopsy adequacy (as measured by length and the number of portal tracts) in the assessment of fibrosis (16
Limitations of this study must be acknowledged. First, the cross-sectional design limits our ability to establish a temporal relationship between cannabis use and fibrosis stage. It is possible that having moderate to severe fibrosis may lead to increased usage of cannabis. However, the majority of subjects were non-cirrhotic and HCV infection is largely asymptomatic until cirrhosis and decompensation occur, making this a less likely explanation for the association. Secondly, we lack detailed information on the quantity, duration and method of cannabis use. Such information may have allowed us to better characterize the dose-effect relationship between cannabis and fibrosis severity. However, one of the challenges in studying cannabis is the lack of a standardized “product” and future studies may benefit from the inclusion of biologic markers of cannabis dose. The finding of a higher rate of cannabis use in the included versus excluded subjects raises the issue of whether there was a selection bias. This is not likely as the study cohort was initially assembled to study the effects of alcohol use on HCV disease progression without any regard to cannabis intake. The strengths of our study include the use of a community-based cohort rather than a tertiary referral cohort, prospective collection of alcohol and other substance use, and a detailed assessment of liver biopsy adequacy. Additionally, our approach of evaluating predictors of severity in mild compared to more severe disease offers potential insights into the factors influencing disease progression at different stages of disease.
In summary, we found that daily cannabis use was significantly associated with the presence of moderate to severe fibrosis compared to mild fibrosis in persons with chronic HCV infection. Furthermore, daily cannabis use and moderate to heavy alcohol use appeared to have at least multiplicative effects on the odds of severe fibrosis. Based on our results, we would advise that individuals with chronic HCV infection be counseled to reduce or abstain from cannabis use.