Endocannabinoids and liver disease--review.

AIMS: Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease. METHODS: The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered. RESULTS: Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function. CONCLUSIONS: Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.     

大麻素系统抗动脉粥样硬化作用的研究进展

大麻素系统包括内源性大麻素;大麻素受体;降解大麻素的酶。研究显示大麻素与动脉粥样硬化关系密切。主要体现为：大麻素受体1与摄食,肥胖,胰岛素抵抗有密切关系,大麻素受体2与调节免疫,抑制炎症关系密切;大麻素降解酶可抑制体内的炎症物质产生,改善与年龄相关的心脏功能降低。以上这些都具有潜在的抗动脉粥样硬化作用。因此,深入探讨大麻素系统在动脉粥样硬化过程的作用对阐明动脉粥样硬化发生机制,开发抗动脉粥样硬化药物有重要意义。     

Endocannabinoids in endocrine and related tumours

The 'endocannabinoid system', comprising the cannabinoid CB1 and CB2 receptors, their endogenous ligands, endocannabinoids and the enzymes that regulate their biosynthesis and degradation, has drawn a great deal of scientist attention during the last two decades. The endocannabinoid system is involved in a broad range of functions and in a growing number of physiopathological conditions. Indeed, recent evidence indicates that endocannabinoids influence the intracellular events controlling the proliferation of numerous types of endocrine and related cancer cells, thereby leading to both in vitro and in vivo antitumour effects. In particular, they are able to inhibit cell growth, invasion and metastasis of thyroid, breast and prostate tumours. The chief events of endocannabinoids in cancer cell proliferation are reported highlighting the correspondent signalling involved in tumour processes: regulation of adenylyl cyclase, cyclic AMP-protein kinase-A pathway and MEK-extracellular signal-regulated kinase signalling cascade.     

Endocannabinoids selectively enhance sweet taste

Endocannabinoids such as anandamide [N-arachidonoylethanolamine (AEA)] and 2-arachidonoyl glycerol (2-AG) are known orexigenic mediators that act via CB₁ receptors in hypothalamus and limbic forebrain to induce appetite and stimulate food intake. Circulating endocannabinoid levels inversely correlate with plasma levels of leptin, an anorexigenic mediator that reduces food intake by acting on hypothalamic receptors. Recently, taste has been found to be a peripheral target of leptin. Leptin selectively suppresses sweet taste responses in wild-type mice but not in leptin receptor-deficient db/db mice. Here, we show that endocannabinoids oppose the action of leptin to act as enhancers of sweet taste. We found that administration of AEA or 2-AG increases gustatory nerve responses to sweeteners in a concentration-dependent manner without affecting responses to salty, sour, bitter, and umami compounds. The cannabinoids increase behavioral responses to sweet-bitter mixtures and electrophysiological responses of taste receptor cells to sweet compounds. Mice genetically lacking CB₁ receptors show no enhancement by endocannnabinoids of sweet taste responses at cellular, nerve, or behavioral levels. In addition, the effects of endocannabinoids on sweet taste responses of taste cells are diminished by AM251, a CB₁ receptor antagonist, but not by AM630, a CB₂ receptor antagonist. Immunohistochemistry shows that CB₁ receptors are expressed in type II taste cells that also express the T1r3 sweet taste receptor component. Taken together, these observations suggest that the taste organ is a peripheral target of endocannabinoids. Reciprocal regulation of peripheral sweet taste reception by endocannabinoids and leptin may contribute to their opposing actions on food intake and play an important role in regulating energy homeostasis.     

Endocannabinoids in arthritis: current views and perspective

Preclinical and clinical studies using cannabis‐based therapy have been shown to provide both analgesia and anti‐inflammatory effects, with an overall alleviation of clinical symptoms in animal models of arthritis, highlighting its promising therapeutic application for humans. Despite this, the development of cannabis‐based therapeutics remains in its infancy, with further investigation into its efficacy and safety profile in patients still required. This synopsis reviews the various components of the endocannabinoid system in health and disease and their potential as therapeutic targets.     

Ascites in liver disease

Summary The formation of ascites in any patient having liver disease is due to multiple factors. These factors vary in individual importance from case to case and thereby determine in part the wise choice of therapeutic measures to be employed for controlling a given ascitic collection.The various mechanisms causing ascites and the various principles of therapeutic attack have been discussed briefly.     

Screening in liver disease

SCREENING STRATEGIESScreening is def ined as the application of a diagnostic test to an asymptomatic population in order to detect a disease at a stage when intervention may improve its outcome and natural history[1]. For many years screening has attracted physicians and policy makers as a way of reducing the mortality of chronic illness with a cost effective model of medical care. It was perceived that generalized screening for the most common diseases, could reach the poorest populati…     

Prevention in liver disease

Prevention has become an important component of medical therapy for a variety of diseases. Preventive strategies in liver disease are relatively underdeveloped and have focused mainly on specific complications of chronic liver disease and vaccination for viral hepatitis. Although public health initiatives designed to prevent certain forms of liver disease are in place, they seem to be underutilized and their utility has not been evaluated. The development of a comprehensive approach using public health initiatives in conjunction with strategies by health care providers is important because of the potential for decreasing the human and health care costs associated with hepatic dysfunction. This article reviews the available literature regarding prevention for health care providers, includes a summary of ongoing public health initiatives, and suggests an approach to prevention in liver disease. It is intended to raise awareness and encourage implementation of preventive strategies in hepatology.     

Auto-antibodies in liver disease

Autoantibodies are a nonpathogenic manifestation of immune reactivity that may occur in acute and chronic liver diseases. Autoantibodies are the consequence rather than the cause of liver injury, and they can be used as diagnostic tools rather than etiologic markers. Conventional autoantibodies used in the categorization of liver disease are antinuclear antibodies, smooth muscle antibodies, antibodies to liver/kidney microsome type 1, antimitochondrial antibodies, and perinuclear antineutrophil cytoplasmic antibodies. However, the final diagnosis and the treatment strategies do not depend solely on the serological markers. Autoantibodies titles vary overtime and their behavior does not correlate with disease activity. Over-interpretation is the major pitfall in the clinical application of the serological results. Recognition and characterization of new autoantibodies is expected to improve the diagnostic precision, provide diagnostic parameters, and elucidate target autoantigens for the management of liver diseases.     

Coagulopathy in liver disease

Opinion statement The liver plays a central role in hemostasis, as it is the site of synthesis of clotting factors, coagulation inhibitors, and fibrinolytic proteins. The most common coagulation disturbances occurring in liver disease include thrombocytopenia and impaired humoral coagulation. Therapy’s overall goal is not to achieve complete correction of laboratory value abnormalities but to gain hemostasis. Therapy with vitamin K may be a useful option in patients with increased prothrombin time due to vitamin K deficiency; in patients with malnutrition; in patients using antibiotics; and in patients with cholestatic liver disease, particularly prior to invasive procedures. Infusion of fresh frozen plasma is more often effective and is recommended in patients with liver disease before invasive procedures or surgery, as such patients require transient correction in their prothrombin time. Therapy with plasma exchange may be considered in patients who cannot be treated with fresh frozen plasma due to volume overload risk. In patients with severe coagulopathy and hypofibrinogenemia, cryoprecipitate therapy is ideal. Therapy with prothrombin-complex concentrate is seldom pursued in patients with liver disease due to high risk of thrombotic complications. Transfusions of platelets are appropriate for patients with thrombocytopenia (< 50,000/mm³) associated with active bleeding or before invasive procedures in which a short-term platelet count increase is noted. Trial with desmopressin may be considered before invasive procedures in patients with liver disease and with refractory and prolonged bleeding time. Recombinant activated factor VIIa administration is suggested for patients with significantly prolonged prothrombin time and contraindications to fresh frozen plasma therapy; however, this is expensive. Thrombopoietin and interleukin-11 are currently investigational for patients with thrombocytopenia of chronic liver disease. Liver transplantation completely restores impaired coagulation abnormalities and is the ultimate intervention that corrects coagulopathy of advanced liver disease and liver failure.