The socioeconomic burden and high mortality rates associated with cirrhosis emphasize the need for therapeutic interventions. Because most treatment recommendations for cirrhosis aim to address complications of decompensated cirrhosis, there is a need for further investigation of antifibrogenic therapies that can slow the progression of fibrosis and thereby prevent cirrhosis and its complications. The endocannabinoid system has demonstrated powerful antifibrogenic as well as profibrogenic properties, as summarized in Table 1 and Table 2 , that can be pharmacologically manipulated to potentially treat cirrhosis at the histologic level. Further research is warranted to develop pharmacotherapies that utilize this endogenous system as a means of treating a debilitating, costly disease. Additionally, further studies investigating exocannabinoid use in cirrhosis may be warranted as marijuana is the most widely used illicit drug in the United States to recommend for or against its use in this context .
Cytokines and microRNAs also play major roles in mediating cirrhosis [7,9]. Cytokines are predominantly produced by CD4 T-helper lymphocytes . Platelet-derived growth factor activates HSCs and reduces extracellular matrix degradation, resulting in mitogenic and fibrogenic effects . TGF-β is pro-fibrogenic as it inhibits degradation of extracellular matrix, and causes deposition of collagen . It also induces apoptosis of hepatocytes by inhibiting DNA synthesis . Tumor necrosis factor-α activates HSCs and increases synthesis of extracellular matrix . Interleukins, some of which are anti-fibrogenic, can also be pro-fibrogenic . Interleukin-1 activates HSCs and promotes their production of matrix metalloproteinases, which causes fibrosis . Interleukins 17, 22, and 6 have also been named pro-inflammatory and pro-fibrogenic . Micro RNAs control fibrosis progression and are expressed by HSCs . Specific pathogenic mechanisms can also be associated with type of injury, such as alcohol-induced injury and viral hepatitis .
Specific findings regarding the role and impact of the endocannabinoid system have been studied for etiologies of chronic liver disease that can progress to cirrhosis. In those with hepatitis C, daily cannabis use was associated with more severe fibrosis and steatosis . Dai et al. demonstrated that CB1 and CB2 were expressed in patients with chronic hepatitis B and the degree of fibrosis was increased with increased expression of both . In alcoholic liver disease, animal studies demonstrated that blockade of CB2 results in more pronounced liver damage after ethanol intake, suggesting a protective mechanism for CB2 in the setting of chronic alcohol use . In the same study, fibrogenesis was increased in CB1 blockade in the setting of chronic alcohol use . In hepatic ischemic-reperfusion injury, the data regarding endocannabinoids are conflicting .
Cirrhosis results from chronic insults to the liver, causing persistent wound healing and fibrosis that result in the disruption of normal liver architecture . The socioeconomic burden is vast  and mortality rates, although underestimated globally, are high [3,4]. Multiple etiologies can cause liver injury, all of which risk progression to cirrhosis . The transition of liver parenchyma from initial injury to cirrhosis is scored by the MATEVIR scoring system based on histologic progression . Treatment recommendations are focused on specific interventions for manifestations of decompensated cirrhosis such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and variceal hemorrhage. However, antifibrogenic treatment modalities are still being studied. The endocannabinoid system and its pharmacomodulation have shown promising therapeutic benefits in cirrhosis. Because of the socioeconomic burden of cirrhosis, partially attributed to the lack of antifibrogenic therapies, and the concurrent increased use of recreational and therapeutic marijuana, the investigation of endocannabinoid system in cirrhosis may be beneficial based on its pro- and anti-fibrogenic properties.
Cirrhosis is defined as a condition that disrupts the normal architecture of the liver. It is caused by chronic insults which lead to persistent wound healing and hepatic parenchymal fibrosis resulting in progressive, diffuse, fibrosing architecture . Common causes include alcohol, biliary obstruction, biliary cirrhosis, chronic hepatitis B or C, hemochromatosis, and NAFLD . Less common causes include autoimmune hepatitis, drugs/toxins, genetic metabolic diseases, infection, vascular abnormalities, veno-occlusive disease, and idiopathic etiologies. In early and compensated disease, patients can present with anorexia, weight loss, fatigue, weakness, and osteoporosis . In decompensated disease, patients may present with ascites, variceal bleeding from portal hypertension, hepatic encephalopathy, spontaneous bacterial peritonitis, jaundice, icterus, pruritus, or coagulopathy .
For those patients with spontaneous bacterial peritonitis (SBP), treatment includes the use of antibiotics as recommended by EASL and AASLD with chemoprevention thereafter to prevent recurrence [15,16]. Recommendations regarding management of hyponatremia include fluid restriction and use of vaptans in certain scenarios [15,16]. If a patient develops hepatorenal syndrome, EASL suggests specific monitoring parameters and potentially, drug therapy and renal replacement therapy; ultimately, EASL recommends liver transplantation . AASLD also recommends evaluation for liver transplantation for those with hepatorenal syndrome . For those who develop hepatic encephalopathy, lactulose is the recommended first-line agent as suggested by AASLD and EASL . Rifaximin is suggested to be added on to lactulose to prevent recurrence . Guidelines also exist in the management of portal hypertensive bleeding secondary to cirrhosis based on very specific classifications and parameters .
The roles of exocannabinoids are as aforementioned. As THC, functions on multiple receptors in addition to CB1 and CB2 , THCV was found as dose-dependent, functioning as a CB1 antagonist in low doses or a CB1 agonist in high doses [21,37]. In a study by Bolognini, et al., THCV was investigated for its anti-inflammatory properties particularly for its function as a CB1 antagonist in vivo and a CB2 agonist in vitro in humans and in vivo and vitro in mice . CBD functions primarily on CB1 . Therefore, based on the associations made with CB1 and CB2 agonism and antagonism in the literature, hypotheses can be developed as to the effect of THC, cannabidiol, THCV, and cannabis in cirrhosis although prospective studies are warranted.
3. Definition, Etiologies and Clinical Presentation
Approximately 3.9 million adults in the United States were diagnosed with liver disease in 2015 . A study conducted the same year estimated the prevalence of cirrhosis as 0.27%, with a higher prevalence in non-Hispanic blacks and Mexican Americans, those living below the poverty level, and those with an education level less than high school . Death rates for chronic liver disease and cirrhosis within the United States increased 31% between 2000 and 2015 in both men and women between ages 45 and 64 . In 2004, the direct costs of chronic liver disease and cirrhosis in the United States (excluding patients with hepatitis C) were estimated at $2.5 billion, and indirect costs were estimated at $10.6 billion . The societal impact of cirrhosis includes total costs and reduced employment, especially in those who have received liver transplants . Although the global health burden of cirrhosis is undeniable, the global mortality data is vague due to a paucity of information in 58 out of 187 countries, primarily in Africa .
The treatment of cirrhosis largely involves specific management of complications of cirrhosis, treatment of etiologies to prevent development of cirrhosis, and liver transplantation based on etiology of cirrhosis . For those with ascites, first-line treatment as recommended by the AASLD includes cessation of alcohol use if present, sodium restriction, diuretic therapy, discontinuation of non-steroidal anti-inflammatories, and evaluation for liver transplant . Second-line therapy as recommended by the AASLD includes discontinuation of beta blockers, angiotensin converting enzymes, and angiotensin receptor blockers, consideration of midodrine, therapeutic paracenteses, evaluation for liver transplantation, and/or transjugular intrahepatic portosystemic shunt (TIPS) . Third-line treatment as recommended by the AASLD includes a peritoneovenous shunt . The European Association for the Study of Liver (EASL) recommends no intervention for mild ascites, restriction of sodium intake and diuretics for moderate ascites evident by symmetrical distention of the abdomen, and large volume paracentesis followed by sodium restriction and diuretics in those with large or gross ascites . Therapies proposed by EASL for refractory ascites include repeated large volume paracenteses, TIPS under certain criteria, and peritovenous shunt .
Glial fibrillary acidic protein (GFAP) immunohistochemistry indicating the astrocytic reaction throughout the parahippocampal area in naïve controls (A, B) and thioacetamide (TAA)-treated animals (C,D) following treatment with vehicle (A,C) or cannabidiol (CBD) (B,D). CBD treatment had no effect on the astrocytic activation of naïve animals. However, in the case of animals with hepatic encephalopathy, CBD treatment induced significant reduction in the total number of activated astrocytes, although the level of individual cell activation was not impaired. E. Quantification of GFAP-positive cells·mm −2 ; the number was reduced in TAA mice treated with 5 mg·kg −1 CBD compared to TAA mice treated with vehicle. ***P < 0.001 versus control, #P < 0.01 versus TAA. F. Quantification of GFAP-positive surface in µm 2 ; 5 mg·kg −1 CBD had no effect on the GFAP-positive surface in the brains of TAA-treated mice. ***P < 0.001 versus control. Scale bars: 100 µm.
Cognitive function, tested 8 days after induction of hepatic failure, was impaired following thioacetamide (TAA) and was improved by cannabidiol (CBD). *P < 0.05 versus control, #P < 0.01 versus TAA. AUC, area under the curve.
Results are presented as the mean number of crossings·min −1 .
Kerfoot et al. (2006) showed the infiltration of peripheral monocytes into the brain of bile duct-ligated mice 10 days after the ligation and suggested that this infiltration may cause the activation of inflammatory cells in the brain. Therefore, it is conceivable that such a mechanism was responsible for the astrogliosis observed in our study, since we found evidence of liver inflammation (data not shown). As evident from the histopathology results, CBD did not appear to affect the development of TAA-induced necrotic lesions in the liver of mice. However, the levels of liver transaminases in the serum of CBD-treated mice were significantly reduced compared to their untreated counterparts, indicating that this substance contributed to a partial restoration of liver function. Recent evidence elucidating the complicated mechanisms involved in the release of hepatocyte cytosolic enzymes such as ALT and AST in the blood may explain the discrepancy between histopathology and serum biochemistry data observed in the present study. Indeed, it is now generally accepted that the release of cytosolic enzymes during both the reversible and irreversible phases of hepatocyte injury and therefore their appearance in blood does not necessarily indicate cell death and also that enzyme release during reversible cell damage occurs with an apparent lack of histological evidence of necrosis (Solter, 2005). Following this reasoning, it could be hypothesized that although CBD did not reduce the levels of histologically detectable necrosis, it may have ameliorated the minute reversible hepatocyte damage that causes the so-called ‘leakage’ of cytoplasmic ALT and AST in blood. The interaction between hyperammonaemia and inflammation as a precipitating factor for HE has been discussed in two recent reviews (Shawcross and Jalan, 2005; Wright and Jalan, 2007). Further work is required to reveal the exact mechanism/s of the manner by which liver damage is related to dysfunction/damage in the brain, and studies using antagonists of the A2A adenosine receptors, which are potential targets of CBD that may mediate its anti-inflammatory effect (Carrier et al., 2006), need to be carried out in order to elucidate the receptors involved in this effect.
Neurological function, evaluated 2 days after induction of hepatic failure, was impaired in thioacetamide (TAA) mice and was restored by cannabidiol (CBD). **P < 0.01 versus control, #P < 0.01 versus TAA.
On day 12, mice killed by decapitation and their brains were dissected out for determination of 5-HT levels. The assays for 5-HT were performed by standard alumina extraction, and HPLC with electrochemical detection using dehydroxybenzylamine (DHBA) as an internal standard (Avraham et al., 2006).
The activity test was performed 2 days after the induction of hepatic failure. Activity of two mice was measured simultaneously for a 5 min period. Two mice were tested together to lower stress to the minimum, as it has been shown that separation of mice induces stress (van Leeuwen et al., 1997; Hao et al., 2001). Activity was assessed in the open field (20 × 30 cm field divided into 12 squares of equal size) as described previously (Fride and Mechoulam, 1993). Locomotor activity was recorded by counting the number of crossings by the mice at 1 min intervals.
Hepatic encephalopathy (HE) is a syndrome observed in patients with end-stage liver disease. It is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of other known brain diseases, and is characterized by personality changes, intellectual impairments and a depressed level of consciousness associated with multiple neurotransmitter systems, astrocyte dysfunction and cerebral perfusion (Riggio et al., 2005; Magen et al., 2008; Avraham et al., 2006; 2008a; 2009; Butterworth, 2010). Subtle signs of HE are observed in nearly 70% of patients with cirrhosis and approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy (Ferenci, 1995). HE, accompanying the acute onset of severe hepatic dysfunction, is the hallmark of fulminant hepatic failure (FHF), and patients with HE have been reported to have elevated levels of ammonia in their blood (Stahl, 1963). In addition, the infiltration of tumour necrosis factor-α-secreting monocytes into the brain of bile duct-ligated mice, a model of chronic liver disease, has been found 10 days after the ligation, indicating that neuroinflammation is involved in the pathogenesis of HE. This infiltration was shown to be associated with activation of the cerebral endothelium and an increase in the expression of adhesion molecules (Kerfoot et al., 2006).