1. Introduction
Cannabis is one of the most used psychoactive substances in the world. The recent rise in cannabis use in the USA, following its legalization across different states, will allow researchers to observe its effects in what will amount to be a huge field experiment. Cannabis use has been associated with increased prevalence of psychiatric disorders and other diseases including pulmonary diseases and cyclical hyperemesis syndrome [1]. However, it has also been linked to a reduction in obesity [2], hyperlipidemia and diabetes mellitus [3], which are risk factors for hepatic steatosis. Patients already affected by inflammatory diseases such as HIV and hepatitis C virus (HCV) infections are exposed to oxidative stress and inflammation, which lead to diabetes and diabetes-related complications. Previous studies and a recent review study [4] provided evidence that the endocannabinoid system – consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes [5] – significantly influences inflammation and associated tissue injury. In effect the endocannabinoid system participates in numerous biological processes, ranging from the regulation of energy homeostasis, inflammation, and gut permeability [4]. Activation of CB1 in the liver stimulates lipogenesis and contributes to diet-induced obesity [4]. CB2 is also implicated in obesity-associated inflammation, fatty liver disease, and insulin resistance [4]. It has been hypothesized that the mechanism through which cannabis reduces fatty deposits in obese tissues is related to the anti-inflammatory properties of its omega-3 (n-3) fatty acids [6,7], but also on its effect on gut permeability [4] through a CB1-dependent mechanism. Antagonists of CB1 decrease gut permeability and act as ‘gate keepers’. CB1 receptors participate in the pathogenesis of both alcoholic and nonalcoholic fatty liver disease, promote liver regeneration, and accelerate liver fibrogenesis. Accordingly, cannabidiol – being a CB1-antagonist – may offer some protection from developing nonalcoholic fatty liver disease.
We report the current scientific knowledge about the relationship between cannabis use and hepatic steatosis in people coinfected with HIV and HCV, a population at high risk of developing the disease.
2. Definition and clinical impact of hepatic steatosis
Hepatic steatosis (fatty liver), the accumulation of fat in hepatocytes, has multiple metabolic, behavioral, environmental, and virological risk factors, including obesity, diabetes, excessive alcohol consumption, exposure to certain treatments and chronic HCV infection [8]. It is a feature of nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, which is associated with central obesity, hypertension, dyslipidemia, and altered glucose tolerance [9]. NAFLD can be suspected when hepatic injury is not alcohol or virus related. NAFLD encompasses a wide spectrum of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma [10]. Typically, NASH is characterized by the joint presence of hepatocellular injury (ballooning of hepatocytes) and inflammation [10]. While simple steatosis does not affect the overall risk of mortality, NASH is associated with increased mortality risk and increased risk of progression to cirrhosis and hepatocellular carcinoma [11].
2.1. Hepatic steatosis in patients with chronic hepatitis C
There is clinical and experimental evidence that HCV interacts with glucido-lipidic metabolism [12]. In patients with chronic hepatitis C (CHC), the prevalence of hepatic steatosis ranges from 40% to 86% [8]. It is virus related in patients infected with genotype 3 virus, metabolic related in the other patients. Whatever its mechanism, hepatic steatosis may promote fibrosis progression and hepatocellular carcinoma in patients with CHC [13]. Hepatic lesions may still progress despite HCV eradication after successful treatment, due to the persistence of metabolic risks factors [14]. In a recent study which included 834 responders to HCV treatment, nearly 10% experienced ongoing elevation of aminotransferase levels, while another 25% experienced aminotransferase activity above the normal range, which is a sign of ongoing hepatic injury [15]. In that study, markers for liver steatosis were strong predictors of persistent ALT elevation. In a non-negligible proportion of patients therefore, steatosis lesions may persist after HCV eradication and influence the risk of fibrosis and hepatocellular carcinoma in this population [16]. Hepatic steatosis is present in 30–70% of HIV-HCV coinfected patients [17–19] and aggravates hepatic lesions [9].
2.2. Cannabis and risk factors for steatosis: an overall view
Previous results from a large sample of the general US adult population highlighted the association between cannabis use and lower fasting insulin and HOMA-IR levels, as well as a smaller waist circumference [20]. Globally, there is growing evidence that cannabis use and a reduced risk of insulin resistance and diabetes are associated, both in the general population and in HIV-HCV coinfected patients [3,21]. The inverse relationship between cannabis and diabetes [22] is age dependent, and is probably linked to reduced inflammation, as individuals exposed to cannabis tend to present lower levels of some inflammation markers.
In two cross-sectional studies conducted among 270 and 204 CHC patients with limited or no exposure to HCV treatment, daily cannabis use was a predictor of severe fibrosis [23,24]. Patients coinfected with HIV were excluded from one of these studies [23], while they represented 21% of patients included in the second study [24]. By contrast, two large longitudinal cohort studies conducted in 690 and 575 HIV-HCV coinfected patients showed no significant relationships between cannabis use and liver fibrosis [25,26]. Moreover, two recent population-based studies conducted in the USA with large study samples showed an inverse relationship between cannabis use and NALFD [27,28]. Although their cross-sectional design did not allow causation effects to be identified, they pave the way for future research on cannabinoids as a potential therapeutic option for the prevention or treatment of NAFLD.
2.3 Cannabis use and hepatic steatosis: current knowledge in the general population and HCV-infected patients
In a recent population-based case–control study including approximately 6 million adult individuals in the USA [28], the risk of NAFLD was 15% lower in non-dependent cannabis users (adjusted odds ratio(95% confidence interval): 0.85 (0.79–0.92); p < 0.0001) and 52% lower in dependent cannabis users (0.49 (0.36–0.65); p < 0.0001) than in non-users. These figures highlight a cannabis dose–response relationship in terms of the reduction of the risk of NAFLD. Another large recent study showed that cannabis use is associated with significantly lower incidence of steatosis in alcoholics [29].Studies conducted in Western countries show rates of cannabis users ranging from 48% to 53% among HIV-HCV coinfected patients [25,30]. There is very little literature concerning the association between cannabis use and hepatic steatosis in this population. A recent study including 838 coinfected patients showed a significant relationship between daily cannabis use and a reduced risk of steatosis (screened for by ultrasound examination), after adjustment for body mass index, alcohol consumption and exposure to certain antiretroviral agents [18]. Most patients had a history of injecting drug use and a quarter of them were HCV cleared. By contrast, in a different study including 315 patients with CHC, daily cannabis use was identified as a risk factor of steatosis severity (assessed using liver biopsy) [31]. However, the study was restricted to untreated HCV patients without concomitant hepatitis B or HIV infection, with no history of immunosuppression, and without ongoing use of illicit drugs other than cannabis. In a third study performed on 60 individuals with a case–control design (30 cannabis smokers and 30 controls), chronic cannabis smoking was not significantly associated with hepatic steatosis (assessed using magnetic resonance spectroscopy), despite its significant association with visceral adiposity and adipose tissue insulin resistance [32]. However, the study included neither patients with current or past hepatitis C nor HIV-infected patients.
3. Limitations of available studies
To our knowledge, to date only one study has analyzed the relationship between cannabis use and hepatic steatosis in HIV-HCV coinfected patients [18]. Available data on cannabis use and hepatic steatosis in other populations are based on cross-sectional studies and show contrasting results. More generally, there is a lack of longitudinal data on hepatic steatosis, as it is not assessed in routine clinical practice [10]. Cross-sectional studies conducted to date were not able to document the cumulated effect of cannabis use on hepatic steatosis. Another limitation of previously cited studies is that their data only concerned the smoking of cannabis, an ingestion mode with known adverse health effects. The heterogeneity of methods to assess hepatic steatosis also limits the possibility to draw definitive conclusions. Similarly, the absence of a validated ‘gold-standard’ noninvasive method complicates the diagnosis of NASH. With respect to hepatic steatosis, diagnosis is made using either a histological study of liver biopsy samples or imaging techniques. In many cases, non-invasive methods are preferred to liver biopsy because of its risks (including bleeding and infections), the associated discomfort for the patient, and its limitations due to sampling variability. In practice, magnetic resonance imaging – the gold-standard technique for hepatic steatosis – is frequently replaced with ultrasound as it is more widely available and cheaper [10]. In addition, ultrasound is easy to perform, and it is also more reliable than magnetic resonance imaging in patients with HCV genotype 3 chronic infection [33]. However, ultrasonography can only reliably detect moderate to severe steatosis (fat accumulation in >30% of hepatocytes) [34]. Recent studies showed the clinical value of using the controlled attenuation parameter (CAP) to diagnose hepatic steatosis. CAP is a new noninvasive measure based on the ultrasound signal acquired by elastography (Fibroscan®). In a study conducted on 726 individuals referred for abdominal ultrasound examinations in an Italian clinic, CAP performed better than ultrasound for assessing hepatic steatosis in patients with chronic viral hepatitis and advanced liver fibrosis. By contrast, in the same study, ultrasound performed better than CAP in patients without viral hepatitis and with non significant liver disease [35]. CAP was also found to be a reliable tool to monitor short-term changes in hepatic steatosis in HIV-infected patients [36], despite its limitations such as a high rate of elastometry failures in obese patients.
4. Conclusion
Whether or not cannabis itself or cannabinoids contained in it may help to reduce hepatic steatosis in HIV-HCV coinfected patients remains an open question. The existing body of knowledge on the interactions between cannabis and the liver suggest a protective effect of cannabinoids on insulin resistance, diabetes, and NAFLD in the general population. Clinical research with randomized study designs is needed to evaluate the efficacy and safety of cannabis-based pharmacotherapies in HIV-HCV coinfected patients. Targeting the endocannabinoid system seems essential to differently manage several pathological conditions such as intestinal inflammation, obesity, diabetes and fatty liver disease. However, to date, few drugs have been tested in clinical trials. CB1-antagonists and CB2 agonists appear to be viable therapeutic options that need to be explored for the management of liver diseases. As HCV cure rates are coming close to 100% in the era of direct-acting antivirals, it is especially important to be able to identify modifiable risk factors of complications and death in HIV-HCV coinfected patients, as well as possible levers for intervention. Given the persistence of metabolic risk factors after HCV eradication, cannabis-based therapies need to be evaluated both as preventive and therapeutic tools in patients living with or at risk of liver steatosis, possibly in combination with existing conventional approaches
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
