Abstract

1. The Benefits of Milk Thistle (Silymarin) in Prevention and Treatment of Alcoholic Liver DiseasePerry Eliassen, Allison Krippene, Stephanie ThompsonDepartment of Food Science & Human Nutrition, Colorado State University, Fort Collins, CO Spring 2011 • Background • Analysis Alcoholic Liver Disease: While the liver is one of the largest organs in the human body, it is responsible for the metabolism of various substances, including harmful toxins such as alcohol. Alcoholic liver disease can result from heavy drinking over time and includes three conditions: fatty liver, alcoholic hepatitis, and cirrhosis (1). The earliest stage of alcoholic liver disease involves a fatty liver, or steatosis, which refers to the accumulation of excessive amounts of fat inside liver cells. In some patients, this may be accompanied by liver inflammation (hepatitis), resulting in a more severe condition called steatohepatitis. Fatty liver and steatohepatitis may be reversible with abstinence from alcohol; however, if drinking continues this may lead to end-stage alcoholic liver disease, or cirrhosis, in which scar tissue replaces healthy liver tissue (fibrosis), thus impairing the liver’s ability to repair cell damage (1). Symptoms of alcoholic liver disease include jaundice (caused by elevated bilirubin), fever, abdominal pain, nausea, vomiting, edema (caused by low serum albumin), and possible esophageal varices. Milk Thistle: Milk thistle (silybummarianum) is a thorny pink flowering plant that belongs to the Asteraceaeplant family and is native to southern Europe, southern Russia, northern Africa, and the Middle East (8). The seeds of this plant contain a flavonoid called silymarin, which is a mixture of flavonolignans (polyphenols that are part flavonoid and part lignan) of which include silybin (2). Silybin, also known as silibinin, is the main component of silymarin and functions as an antihepatotoxic agent due its antioxidant properties. Because of these antioxidant properties, silybin, and therefore silymarin, may be helpful in treating liver disease and preventing the liver from toxins such as alcohol. • Silymarin has metabolic and cell-regulating effects, namely carrier mediated regulation of cell membrane permeability, inhibition of the 5-lipogenase pathways, scavenging of reactive oxygen species (free-radical scavenging), and action on DNA expression. • 1. Regulation of cell membrane permeability: • - Silybin increases the stability of hepatocytes against xenobiotic (ie. alcohol-induced) injury. • - The phallodin-transporting system is the membranous site of the action of silymarin. This may be part of the hepatic system that clears portal blood of bile acids, lipophillic hormones or xenobiotics. A similar transport mechanism inhibited by silybin has been described for A. phalloides (xenotoxin). Therefore silymarin is able to reduce the cellular absorption of xenobiotics thereby exerting cellular protection (3). • - Alcohol and xenobiotics share the same oxidative microsomal pathway. This pathway is mainly located in the endoplasmic reticulum of hepatocytes. • 2. Leukotriene Inhibition: • - Concentrations of silybin on Kupffercelles at 15 umol/L can cause inhibition of Leukotriene B4 (LTB4) at the 5-lipoxygenase pathway. LTB4, which is a potent chemo-attractant, is able to induce the formation of reactive oxygen species (ROS), which are highly reactive free-radicals (3). • - Ethyl alcohol increases the production of LTB4, which leads to ROS formation (4). • - Inhibition of the 5-lipogenase pathway is achieved at silybin concentrations that are able to be reached in vivo. This selective inhibition can partly account for hepatoprotective properties of silybin. • 3. Reactive Oxygen Species (ROS) scavenging: • - The flavonoid structure of silybin makes it easy to form an intracellular hydrogen bond, and thus be a free-radical (ROS) scavenger of active and stable oxygen radicals (Diagram 2). • - Alcohol produces ROS through the 5-lipooxygenase pathway and is thus able to be partially scavenged by the antioxidant properties of silybin. This reduces ROS in the liver (Diagram 1). • - Alcohol radicals are most effectively scavenged by silybin due to the structure of the hydrogen bonding abilities of silybin (5). • - Silymarin has shown to be an effective antioxidant in assays including, total antioxidant activity, reducing power, oxygen and hydrogen peroxide scavenging when compared to standard antioxidant compounds of BHA and BHT (6). Liver disorders are recent and frequent medical problems occurring in people for a variety of reasons including environmental factors, diet and excessive alcohol consumption.  There is an increased desire for natural remedies rather than pharmaceuticals for the treatment of liver diseases such as cirrhosis, hepatitis, and other alcoholic-related diseases. The following presentation looks at the benefits of milk thistle and its active role in the treatment and prevention of alcoholic liver disease.  Milk thistle (silybummarianum) contains several natural sources of antioxidants that are hepatoprotective.   These protective properties are effective in regulating cell membrane permeability, leukotriene inhibition and free radical (ROS) scavenging in the liver.  When taken properly silymarin can be effective in treating and preventing alcoholic liver disease. Abstract • Adapted from SallerR, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. DRUGS. November 2001; 61(14): 2035-2063. • Objective To explain the antioxidant effects of milk thistle (silymarin) and its benefits in the prevention and treatment of alcoholic liver disease. • Adapted from HaiyingF, Mingzhang L, Muroya Y et al. Free radical scavenging reactions and antioxidant activities of silybin: Mechanistic aspects and pulse radiolytic studies. free radical res. September 2009; 43(9): 887-897. • Conclusion Liver disease is one of the most common problems in human health. Common liver dysfunctions include alcoholic liver disease and its components of cirrhosis, and hepatitis (9).  As people are looking for other options besides pharmaceuticals, milk thistle is arising as a supplement shown to help fight liver disorders due to its protective effects on the liver (10).  Through supplementation milk thistle can help in regulating cell membrane permeability, leukotriene inhibition and free radical scavenging.  With these qualities and with its high safety factors, milk thistle can be effective in treating and preventing alcoholic liver disease.   • Application Milk thistle, also known as silymarin is composed of four different components: flavonolignans, silydinanin, silychristine and silybin.  An extraction of silymarin for milk thistle contains 70% silymarin and 30% active silymarin compounds. These active compounds of milk thistle are protective of the liver due to their increased lipid peroxidation (7).  Like most supplements, there is no FDA approval to account for all present items (3).  Between 20-50% of silymarin is absorbed after oral ingestion, 10% enters the bile and between 2-8% is then excreted through the urine. (8). Silymarin is safe to consume and there are very few small adverse effects in human trials.  Due to low solubility it is almost impossible for takers to consume toxic levels of silymarin (3).  In a study of 3500 patients that contained 2637 with liver disease the frequency of adverse effects was 1% with the most common complaints of bloating, nausea and diarrhea.  A safe dose is an oral dose between 240-900 mg/day taken in two to three doses.  There are different medications containing silymarin that have greater absorption in the body than supplement silymarin or milk thistle.  In Europe MadusLegalon is a water soluble derivative of silibin (a compound of silymarin) containing 70 or 140 mg silymarin and is given in one to two doses a day for a total of 420 mg a day.  Another medication is Silipide. Since silymarin and its compound silibin is not very bioavailable to the body, phosphatidycholine is used to increase absorption and bioavailibilty to the body.  Silipide is one part silibin and two parts phosphatidycholin and standardized in Silibin equivalents. This oral dose is ten times more bioavailable to the body than regular silymarin or silibin (8).  • References • 1. GramenziA, Caputo F, Bilelli M et al. Review article: alcoholic liver disease- pathophysiological aspects and risk factors. aliment pharm therap. 2006; 24: 1151-1161. • 2. KṝenV, Walterova D. Silybin and silymarin- new effects and applications. biomed pap. 2005; 149(1): 29-41. • 3. SallerR, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. DRUGS. November 2001; 61(14): 2035-2063. • (DIAGRAM 1) • 4. Beck I T, Boyd A J, Dinda P K. Evidence for the involvement of 5-lipoxgenase products in ethanol-induced intestinal plasma protein loss. am j physiol-gastr l. 1988; 254(4): G483-488. • 5. HaiyingF, Mingzhang L, Muroya Y et al. Free radical scavenging reactions and antioxidant activities of silybin: Mechanistic aspects and pulse radiolytic studies. free radical res. September 2009; 43(9): 887-897. • 6. KoksalE, Gulcin I, Beyza S, Sarikaya O, Bursal E. In vitro antioxidant activity of silymarin. j enzyminhib med ch.April 2009; 24(2): 395-405. • 7. Pares A, Planas M, Caballeria J, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial.j hepatol. 1998; 28: 615-621 • 8. AbenavoliL, Capasso C, Milic N, Capasso F. Milk thistle in liver disease: past, present and future. phytother res. June 2010; 24 : 1424-1432. • 9. Shaker E, Hahmound H, Mnaa S. Silymarin, the antioxidant component and Silybin marianum extracts prevent liver damage.food chemtoxicol. December 2009; 48: 803-806. • 10. BoerthJ, Strong K. The clinical utility of milk thistle (Silybummarianum) in cirrhosis of the liver. j herb pharmacother . June 2002; 2(2):7-11. Adapted from http://themadpriest.com/blog/?p=51 Adapted from http://cueflash.com/decks/pathology_chapter_18_images