Category Archives: Liver Disease

Marijuana smoking does not accelerate progression of liver disease in HIV-hepatitis C coinfection: a longitudinal cohort analysis.

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“Marijuana smoking is common and believed to relieve many symptoms, but daily use has been associated with liver fibrosis in cross-sectional studies. We aimed to estimate the effect of marijuana smoking on liver disease progression in a Canadian prospective multicenter cohort of human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected persons.

In this prospective analysis we found no evidence for an association between marijuana smoking and significant liver fibrosis progression in HIV/HCV coinfection.”

https://www.ncbi.nlm.nih.gov/pubmed/23811492

“To conclude, in this first prospective evaluation of liver disease progression among HIV-HCV infected persons, we could not demonstrate any important effect of marijuana on liver disease outcomes. A causal association is unlikely: hazard ratios were weak and most importantly were attenuated when accounting for temporality in the exposure-disease relationship and there was no dose-response relationship. It is likely that previous studies have been biased by reverse causality as patients use more marijuana to relieve symptoms as liver disease progresses.”

https://academic.oup.com/cid/article/57/5/663/312934

History of marijuana use does not affect outcomes on the liver transplant waitlist.

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“Data are limited on marijuana use and its impact on liver transplant (LT) waitlist outcomes.

We aimed to assess the risk of waitlist mortality/delisting and likelihood of LT among prior marijuana users, and to determine the prevalence and factors associated with marijuana use.

Unlike illicit drug use, marijuana use was not associated with worse outcomes on the LT waitlist.”

https://www.ncbi.nlm.nih.gov/pubmed/29319619

https://insights.ovid.com/crossref?an=00007890-900000000-96711

https://journals.lww.com/transplantjournal/Abstract/onlinefirst/History_of_marijuana_use_does_not_affect_outcomes.96711.aspx

“Do Cannabinoids have a therapeutic role in transplantation? Transplantation is one critical area of medicine that requires the use of immunosuppressants. Cannabinoids have emerged as powerful drug candidates for the treatment of inflammatory and autoimmune diseases due to their immunosuppressive properties.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923447/
“The history of donor cannabis smoking does not appear to affect early and mid-term outcomes after lung transplantation (LTx) and potentially improve the donor pool. As it does not seem to negatively affect the outcomes after LTx, it should not be per se considered a contraindication for lung donation.” https://www.ncbi.nlm.nih.gov/pubmed/28077504
“THC In Marijuana Delays Organ Transplant Rejection In Mice. A new study suggests the active ingredient in marijuana delays the rejection of incompatible organs in mice.” http://www.iflscience.com/health-and-medicine/thc-marijuana-may-delay-organ-transplant-rejection/
“Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541500/
“Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation. CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation.” http://pubmedcentralcanada.ca/pmcc/articles/PMC5004721/
“Could CANNABIS help transplant patients? Drug ‘delays rejection of organs by slowing the immune system’s attack'” http://www.dailymail.co.uk/health/article-3279752/Could-CANNABIS-help-transplant-patients-Drug-delays-rejection-organs-slowing-immune-s-attack.html

Cannabis use is associated with reduced prevalence of progressive stages of alcoholic liver disease.

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Liver International

 

“Abusive alcohol use has well-established health risks including causing liver disease (ALD) characterized by alcoholic steatosis (AS), steatohepatitis (AH), fibrosis, cirrhosis (AC) and hepatocellular carcinoma (HCC). Strikingly, a significant number of individuals who abuse alcohol also use Cannabis, which has seen increased legalization globally. While cannabis has demonstrated anti-inflammatory properties, its combined use with alcohol and the development of liver disease remains unclear.

To determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol.

We analyzed the 2014 Healthcare Cost and Utilization Project – Nationwide Inpatient Sample (NIS) discharge records of patients 18years and older, who had a past or current history of abusive alcohol use(n=319,514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabisexposure groups: non-cannabis-users (90.39%), non-dependent-cannabis-users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4).

 

Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC (AOR: 0.55[0.48-0.64], 0.57[0.53-0.61], 0.45[0.43-0.48] & 0.62[0.51-0.76]). Further, dependent users had significantly lower odds than non-dependent users for developing liver disease.

CONCLUSIONS:

Our findings suggest that cannabis use is associated with reduced incidence of liver disease in alcoholics.”

https://www.ncbi.nlm.nih.gov/pubmed/29341392

http://onlinelibrary.wiley.com/doi/10.1111/liv.13696/abstract

Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States.

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“The impact of marijuana on nonalcoholic fatty liver disease (NAFLD) is largely unknown. We studied the association between marijuana and NAFLD utilizing cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from 2005-2014 and NHANES III (1988-1994).

RESULTS:

Of the 14,080 (NHANES 2005-2014) and 8,286 (NHANES III) participants, prevalence of suspected NAFLD and ultrasonographically-diagnosed NAFLD were inversely associated with marijuana use (p < 0.001). Compared to marijuana-naïve participants, marijuana users were less likely to have suspected NAFLD (odds ratio [OR]: 0.90, 95% confidence interval [CI]: 0.82-0.99 for past user; OR: 0.68, 95% CI: 0.58-0.80 for current user) and ultrasonographically-diagnosed NAFLD (OR: 0.75, 95% CI: 0.57-0.98 for current user) in the age, gender, ethnicity-adjusted model. On multivariate analysis, the ORs for suspected NAFLD comparing current light or heavy users to non-users were 0.76 (95% CI 0.58-0.98) and 0.70 (95% CI 0.56-0.89), respectively (P for trend = 0.001) with similar trends in ultrasonographically-diagnosed NAFLD (OR: 0.77, 95% CI: 0.59-1.00 for current user; OR: 0.71, 95% CI: 0.51-0.97 for current light user). In insulin resistance-adjusted model, marijuana use remained an independent predictor of lower risk of suspected NAFLD.

CONCLUSIONS:

In this nationally representative sample, active marijuana use provided a protective effect against NAFLD independent of known metabolic risk factors. The pathophysiology is unclear and warrants further investigation.”

https://www.ncbi.nlm.nih.gov/pubmed/29049354

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186702

Cannabinoid Receptor 1 Participates in Liver Inflammation by Promoting M1 Macrophage Polarization via RhoA/NF-κB p65 and ERK1/2 Pathways, Respectively, in Mouse Liver Fibrogenesis.

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“Macrophage M1/M2 polarization mediates tissue damage and inflammatory responses. Cannabinoid receptor (CB) 1 participated in liver fibrogenesis by affecting bone marrow (BM)-derived monocytes/macrophages (BMMs) activation. However, the knowledge of whether CB1 is involved in the polarization of BMMs remains limited.

Here, we found M1 gene signatures (including CD86, MIP-1β, tumor necrosis factor, IL-6, and inducible nitric oxide synthase) and the amount of M1 macrophages (CD86+ cells, gated by F4/80) were significantly elevated in carbon tetrachloride (CCl4)-induced mouse injured livers, while that of M2 type macrophages had little change by RT-qPCR and fluorescence-activated cell sorting (FACS).

Our preceding study confirmed CB1 was involved in CCl4-induced liver fibrogenesis. Our results noted CB1 expression showed positive correlation with CD86. Blockade of CB1 by its antagonist or siRNA in vivo downregulated the mRNA and protein levels of M1 markers using RT-qPCR, western blot, and Cytometric Bead Array (CBA) assays, and reduced the proportion of M1 macrophages. Moreover, chimera mouse models, which received BM transplants from EGFP-transgenic mice or clodronate liposome injection mouse models, in which Kupffer cells were depleted, were performed to clarify the role of CB1 on the polarization of Kupffer cells and BMMs.

We found that CB1 was especially involved in BMM polarization toward M1 phenotype but have no effect on that of Kupffer cells. The reason might due to the lower CB1 expression in Kupffer cells than that of BMMs. In vitro, we discovered CB1 was involved in the polarization of BMMs toward M1. Furthermore, CB1-induced M1 polarization was apparently impaired by PTX [G(α)i/o protein inhibitor], Y27632 (ROCK inhibitor), and PD98059 [extracellular signal-regulated kinase (ERK) inhibitor], while SB203580 (p38 inhibitor) and compound C (AMPK inhibitor) had no such effect. ACEA (CB1 agonist) activated G(α)i/o coupled CB1, then enlarged GTP-bound Rho and phosphor-ERK1/2, independently. NF-κB p65 nuclear translocation is also a marker of M1 phenotype macrophages. We found that CB1 switched on NF-κB p65 nuclear translocation only depending on G(α)i/o/RhoA signaling pathway.

CONCLUSION:

CB1 plays a crucial role in regulating M1 polarization of BMMs in liver injury, depending on two independent signaling pathways: G(α)i/o/RhoA/NF-κB p65 and G(α)i/o/ERK1/2 pathways.”

 https://www.ncbi.nlm.nih.gov/pubmed/29033935
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01214/full

Daily cannabis and reduced risk of steatosis in human immunodeficiency virus and hepatitis C virus co-infected patients (ANRS CO13-HEPAVIH).

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Journal of Viral Hepatitis

“Liver steatosis is common in Human Immunodeficiency Virus (HIV) – Hepatitis C Virus (HCV) co-infected patients. Some recent studies have found that cannabis use is negatively associated with insulin resistance in the general population and in HIV-HCV co-infected patients.

Given the causal link between insulin resistance and steatosis, we hypothesized that cannabis use has a positive impact on steatosis.

Therefore, we aimed to study whether cannabis use in this population was associated with a reduced risk of steatosis, measured by ultrasound examination.

The ANRS CO13-HEPAVIH cohort is a French nationwide multicenter of HIV-HCV co-infected patients. Medical and socio-behavioral data from clinical follow-up visits and annual self-administered questionnaires were prospectively collected. A cross-sectional analysis was conducted using data from the first visit where both ultrasound examination data for steatosis (positive or negative diagnosis) and data on cannabis use were available. A logistic regression model was used to evaluate the association between cannabis use and steatosis. Among study sample patients (n=838), 40.1% had steatosis. Fourteen percent reported daily cannabis use, 11.7% regular use, and 74.7% no use or occasional use (“never or sometimes”).

Daily cannabisuse was independently associated with a reduced prevalence of steatosis (adjusted odds ratio [95%]=0.64 [0.42;0.99]; p=0.046), after adjusting for body mass index, hazardous alcohol consumption and current or lifetime use of lamivudine/zidovudine. Daily cannabisuse may be a protective factor against steatosis in HIV-HCV co-infected patients. These findings confirm the need for a clinical evaluation of cannabis-based pharmacotherapies in this population.”

https://www.ncbi.nlm.nih.gov/pubmed/28984055

http://onlinelibrary.wiley.com/doi/10.1111/jvh.12797/abstract

Cannabidiol attenuates alcohol-induced liver steatosis, metabolic dysregulation, inflammation and neutrophil-mediated injury.

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“Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.”  https://www.ncbi.nlm.nih.gov/pubmed/28935932

“Cannabidiol (CBD) is the most abundant non-psychoactive constituent of marijuana plant (Cannabis Sativa) with excellent safety profile in humans even after chronic use. In conclusion, we demonstrate that CBD treatment significantly attenuates liver injury induced by chronic plus binge alcohol in a mouse model and oxidative burst in human neutrophils. CBD ameliorates alcohol-induced liver injury by attenuating inflammatory response involving E-selectin expression and neutrophil recruitment, and consequent oxidative/nitrative stress, in addition to attenuation of the alcohol-induced hepatic metabolic dysregulation and steatosis. These beneficial effects, coupled with the proven safety of CBD in human clinical trials and its current orphan drug approval by FDA for various indications suggest that it may have therapeutic potential in liver disease associated with inflammation, oxidative stress, metabolic dysregulation and steatosis.” https://www.nature.com/articles/s41598-017-10924-8

Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases.

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 Current Diabetes Reports

“The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism.

Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system.

Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities.

Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance).”

https://www.ncbi.nlm.nih.gov/pubmed/28913816

https://link.springer.com/article/10.1007%2Fs11892-017-0924-x

Cannabinoid receptor 2-63 RR variant is independently associated with severe necroinflammation in HIV/HCV coinfected patients.

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“This is the first study to analyze the impact of the rs35761398 variant of the CNR2 gene leading to the substitution of GLN (Q) of codon 63 of the cannabinoid receptor 2 (CB2) with ARG (R) on the clinical presentation of chronic hepatitis in HIV/HCV coinfected patients.

This study shows interesting interplay between the CB2-RR variant and liver necroinflammation in chronic hepatitis patients with HIV/HCV coinfection, an observation of clinical value that coincides with the interest in the use of the CB2 agonists and antagonists in clinical practice emerging from the literature.”

 https://www.ncbi.nlm.nih.gov/pubmed/28759568
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181890

Cannabis use is associated with reduced prevalence of non-alcoholic fatty liver disease: A cross-sectional study.

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“Cannabis use is associated with reduced prevalence of obesity and diabetes mellitus (DM) in humans and mouse disease models. Obesity and DM are a well-established independent risk factor for non-alcoholic fatty liver disease (NAFLD), the most prevalent liver disease globally. The effects of cannabis use on NAFLD prevalence in humans remains ill-defined. Our objective is to determine the relationship between cannabis use and the prevalence of NAFLD in humans.

We conducted a population-based case-control study of 5,950,391 patients using the 2014 Healthcare Cost and Utilization Project (HCUP), Nationwide Inpatient Survey (NIS) discharge records of patients 18 years and older. After identifying patients with NAFLD (1% of all patients), we next identified three exposure groups: non-cannabis users (98.04%), non-dependent cannabis users (1.74%), and dependent cannabis users (0.22%). We adjusted for potential demographics and patient related confounders and used multivariate logistic regression (SAS 9.4) to determine the odds of developing NAFLD with respects to cannabis use.

Our findings revealed that cannabis users (dependent and non-dependent) showed significantly lower NAFLD prevalence compared to non-users (AOR: 0.82[0.76-0.88]; p<0.0001). The prevalence of NAFLD was 15% lower in non-dependent users (AOR: 0.85[0.79-0.92]; p<0.0001) and 52% lower in dependent users (AOR: 0.49[0.36-0.65]; p<0.0001). Among cannabis users, dependent patients had 43% significantly lower prevalence of NAFLD compared to non-dependent patients (AOR: 0.57[0.42-0.77]; p<0.0001).

Our observations suggest that cannabis use is associated with lower prevalence of NAFLD in patients. These novel findings suggest additional molecular mechanistic studies to explore the potential role of cannabis use in NAFLD development.”  https://www.ncbi.nlm.nih.gov/pubmed/28441459

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176416