Guest guest Posted September 13, 2004 Report Share Posted September 13, 2004 http://www.lef.org/protocols/prtcls-txt/t-prtcl-068.html Liver Cirrhosis In the human, the liver is the second largest organ in the body (skin being the largest). The liver is about the size of a football and it weighs approximately 4 lbs. The liver is responsible for performing more functions than any other organ in the body, including metabolizing the food we eat by breaking it down to useful parts; filtering and detoxifying (neutralizing) poisons in our blood to remove numerous toxic compounds that we are exposed to on a daily basis, producing immune agents to control infection, and regenerating itself when part of it has been damaged (NIDDK 2000). Several times each day, our entire blood supply passes through the liver. At any given time, about a pint of blood is in the liver (or 10% of the total blood volume of an adult). Another important function of the liver is to produce prothrombin and fibrinogen (two blood-clotting factors) and heparin (a mucopolysaccharide sulfuric acid ester that helps prevent blood from clotting within the circulatory system). The liver also converts sugar into glycogen and stores it until the muscles need energy. The released glycogen becomes glucose in the blood stream. The liver also synthesizes proteins and cholesterol and converts carbohydrates and proteins into fats, which it also stores for later use. Additionally, the liver produces and secretes bile (that is stored in the gallbladder until needed), which is needed to break down and digest fatty acids. It also produces blood protein and hundreds of enzymes needed for digestion and other bodily functions. As the liver breaks down proteins, it produces urea, which it synthesizes from carbon dioxide and ammonia. (Urea is the primary solid component of urine and is eventually excreted by the kidneys.) Essential trace elements, such as iron and copper, as well as vitamins A, D, and B12 are also stored in the liver. Until recently, the most common cause of cirrhosis of the liver in the United States was attributed to alcohol abuse. Hepatitis C is now the number one cause of liver cirrhosis (26%), followed closely by alcohol abuse at 21% (NIDDK 2000). A cofactor such as the hepatitis C virus can increase the risk of cirrhosis in those who also consume alcohol in excess (NIDA 2002). Etiology of CirrhosIS Cirrhosis of the liver is a chronic, diffuse (widely spread throughout the organ), degenerative disease in which the parenchyma (the functional organ tissue) deteriorates; the lobules are infiltrated with fat and structurally altered; dense perilobular connective tissue forms; and often areas of regeneration develop. The surviving cells multiply in an attempt to regenerate and form " islands " of living cells that are separated by scar tissue. These islands of living cells have a reduced blood supply, resulting in impaired liver function. As the cirrhotic process continues, blood flow through the liver becomes blocked; portal hypertension may occur (high blood pressure in the veins connecting the liver with the intestines and spleen); glucose and vitamin absorption decrease; the manufacturing of hormones and stomach and bowel function are affected; and noticeable facial veins may appear. Most patients die from cirrhosis in the fifth or sixth decade of life (Wolf 2001). Approximately one-third of cirrhosis cases are " compensated, " meaning there are no clinical symptoms. Compensated cases are usually discovered during routine tests for other problems or during surgery or autopsy. Cirrhosis is irreversible. Unless the underlying cause of cirrhosis is removed and the person takes measures to treat the condition, the liver will continue to incur damage, eventually leading to liver failure, ammonia toxicity, gastrointestinal hemorrhage, kidney failure, hepatic coma, and death. For some people, the only chance for a long-term cure is a liver transplant. According the Centers for Disease Control (CDC), in the year 2000, preliminary data compiled by the Division of Vital Statistics revealed that even though cause of death from cirrhosis and chronic liver disease had fallen a rank from 7th to 12th, the number of people who died from liver disease was 26,219, almost the same as when cirrhosis was ranked 7th (Minino et al. 2001). Symptoms of CirrhosIS Common symptoms of cirrhosis include nausea or indigestion and vomiting; loss of appetite; weight loss; constipation or diarrhea; flatulence; ascites (the accumulation of serous fluids in the peritoneal cavity); edema (fluid retention in the legs); light-colored stools; weakness or chronic dyspepsia; dull abdominal aching; varicosities; nosebleeds, bleeding gums, or other internal and external bleeding; easy bruising; extreme skin dryness; intense skin itching; and spider angiomas (a central, raised, red dot about the size of a pin head from which small blood vessels radiate). In cirrhosis, healthy, functioning liver cells are destroyed, and scarring and distortion of the liver eventually takes place. As fewer liver cells function, smaller amounts of albumin (a protein) are manufactured. Lower albumin levels facilitate water retention (edema) in the legs and abdomen (ascites). Excessive bile product deposits cause intense skin itching, often accompanied by jaundice (yellowed skin). Other symptoms are testicular atrophy, gynecomastia (enlargement of the male breast), and loss of chest and armpit hair. Psychotic mental changes such as extreme paranoia can also occur in cases of advanced cirrhosis. Systemic Complications from CirrhosIS In the cirrhotic liver, when blood flow is restricted, blood can back up in the spleen, causing an enlarged spleen and sequestered blood cells. In this situation, the platelet count typically falls and abnormal bleeding results. In extreme cases, blood actually flows backward from the portal circulation to systemic circulation. In addition to esophageal varices, varicose veins can develop in the stomach (gastric varices) and rectum (hemorrhoids). Ruptured varices cause massive bleeding and are often fatal. Bilirubin levels may also build up in the blood, causing jaundice and bright yellow to dark brown urine. Additionally, insulin resistance and diabetes mellitus, kidney dysfunction, and congestive heart failure, as well as osteomalacia (the adult form of rickets, resulting in bone softening that often leaves them brittle) and osteoporosis (reduction in bone mass) are associated with cirrhosis (NIDDK 2000). If cirrhosis prevents bile, a green-brown fluid that is produced by the liver, from reaching the gallbladder, a person may develop gallstones (NIDDK 2000). It is then secreted through tiny channels within the liver into a duct to the gallbladder. Bile is stored in the gallbladder until it is needed for digestion of fats. Most gallstones are formed from cholesterol. If the liver is healthy, the bile contains the proper constituents to dissolve cholesterol excreted by the liver, but in a cirrhotic liver, the bile cannot adequately dissolve cholesterol. The cholesterol then forms crystals, which settle to the bottom of the gallbladder and eventually become stones (ALF 2002; MFMER 2002; WebMD 2002). A cross-sectional study was conducted in 1010 patients with cirrhosis related to alcohol abuse, chronic viral infection, or miscellaneous causes (42%, 48%, and 10%, respectively). Gallstone development was monitored by ultrasound in 618 patients who were free of gallstones at enrollment. The overall prevalence of gallstones was 29.5% and increased significantly with age without differences according to sex or cause of cirrhosis. During a mean ± SD follow-up of 50 months ± 9 months, 141 (22.8%) of 618 patients developed gallstones, with an estimated cumulative probability of 6.5%, 18.6%, 28.2%, and 40.9% at 2, 4, 6, and 8 years, respectively. Multivariate analysis showed that degree of cirrhosis and high body mass index carried a significantly greater risk of gallstone formation, leading the researchers to conclude: " Cirrhosis per se represents a major risk factor for gallstones whose prevalence and incidence were far higher than those reported in a general population from the same area " (Conte et al. 1999). * Note: Cholesterol in the bile has no relation to the cholesterol in the blood. Therefore cholesterol-lowering drugs do not prevent gallstones. Toxins that the liver normally removes build up in the blood, dulling mental function and leading to personality changes. The condition of the liver also affects how drugs are filtered from the body. Drugs the patient is taking that are normally filtered out by the liver and disposed of in the urine may remain in the bloodstream for a much longer period, acting longer than expected or even building up in body tissue. A cirrhotic liver is usually much larger than a healthy liver (Clayman 1989; Glanze 1996; NIDDK 2000; Wolf 2001). Treating the Complications In patients who have cirrhosis, complications from the disease must be treated. In particular, acute variceal bleeding is a very serious, life-threatening medical emergency. Infections such as spontaneous bacterial peritonitis must be promptly treated with appropriate antibiotics. Coagulation disorders will sometimes respond to vitamin K. However, drugs that are metabolized in the liver must be used with caution. Ascites Mild cases of ascites are treated with a salt-restricted diet (2000 mg of sodium daily or less in some cases). Cirrhosis patients often need guidance in planning a diet that has low sodium content without compromising caloric and nutritional requirements (NIDDK 2000). If salt restriction is not effective, diuretic drugs are the next treatment consideration (e.g., Aldactone or Lasix). In patients who continue to be resistant to drug therapy, peritoneovenous and portosystemic shunts (plastic tubing) are inserted subcutaneously to connect the peritoneal cavity or the portal system to an internal jugular or subclavian vein (Wolf 2001). Hepatic Encephalopathy Blood ammonia will be checked because an elevated serum ammonia level is a classic laboratory finding in hepatic encephalopathy. Lactulose is helpful in some patients to assist in removal of ammonia (Wolf 2001). Lactulose is a synthetic sugar that is not absorbed by the body and is used a laxative. Neomycin and other antibiotics are also used to decrease bacteria in the intestine that produce ammonia. Depending on nutritional status, dietary protein may be restricted in patients who are having an acute flare-up of hepatic encephalopathy (Wolf 2001). Esophageal Varices Restricted blood flow in the portal vein causes blood from the intestines and spleen to back up into stomach and esophagus blood vessels. These vessels are not intended to carry large amounts of blood and become enlarged. As these veins enlarge (varicose veins or varices), the walls become thin and are likely to burst as pressure increases. Variceal hemorrhaging is very serious and requires immediate medical attention. As part of routine monitoring, a diagnostic endoscopy will be done to determine if a patient has asymptomatic esophageal varices. If varices are present, treatment can include reducing salt intake; taking diuretics to eliminate excess salts and fluids from the body; taking a beta-blocker (propranolol, nadolol); injection of a clotting agent; injection of a scarring chemical (sclerotherapy); or rubber-band ligation (a surgical procedure using a device to compress the varices and stop bleeding) (Pugh et al. 1973; NIDDK 2000; Wolf 2001). In addition, there is a radiological procedure called transjugular intrahepatic protosystemic shunt (TIPS) that shows some promise. Hepatoma In the United States, hepatocellular carcinoma is observed in 10-20% of patients who have cirrhosis (Wolf 2001). The liver cells develop a malignant change leading to a type of cancer called hepatocellular carcinoma (HCC). As with other cancers, early detection and number and size of tumors influence survival. Treatment for HCC ranges from surgical removal of the HCC if the patient has good liver function to transplantation (NIDDK 2000; Columbo 2001; Wolf 2001). If the patient cannot have surgery (advanced age, other health conditions, poor liver function, large tumors, or tumors in strategic locations), possible treatment includes ultrasound-guided injection of solutions that cause necrosis of tumor cells in the cancerous area; using a catheter to eliminate blood supply to the tumor; injecting antitumor agents directly into the tumor; systemic chemotherapy; and radiation (Columbo 2001). Portal Hypertension A healthy liver can accommodate a wide range of changes in portal blood flow without alteration of portal blood pressure. However, when the portal vein is obstructed, portal hypertension (very high blood pressure) occurs (Clayman 1989; Wolf 2001). Factors causing increased resistance to blood flow are fibrotic changes in the liver caused by cirrhosis, compression of the nodules that are regenerating liver tissue, and increased collagen deposition and levels of chemicals that act to constrict the blood vessels in the liver. Other causes are a blood clot in the portal vein or congenital narrowing (Clayman 1989). Treatment can consist of controlling ascites with salt restriction and diuretics; treating varices; or surgically implanting a shunt to divert blood from the portal vein to another blood vessel to relieve some of the pressure on the portal vein (Clayman 1989). Cirrhosis and the Hepatitis C FactOR Until recently, the most common cause of cirrhosis of the liver in the United States was attributed to alcohol abuse. Because of the rapid increase of hepatitis C virus infection, hepatitis C has now taken over first place (26%), with alcohol abuse falling to second place, but only slightly behind at 21% (NIDDK 2000). There are vaccines for some of the hepatitis viruses, but at this time, there is no vaccine to prevent transmission of the hepatitis C virus. Preventive and deterrent practices are the only means to avoid it (Alter et al. 1998; Buggs 2002; NIDA 2002). The most common routes of infection with the hepatitis C virus are via needles, sexual contact, and blood transfusions, and from an infected pregnant female to her newborn (NIDA 2002) (see the protocol on Hepatitis C for a complete discussion of the hepatitis C virus). Hepatitis C is one of six viruses known to cause liver disease (Buggs 2001; NIDA 2002, Strickland 2002). Hepatitis C is very difficult for the immune system to overcome and often becomes chronic, leading to serious and permanent liver damage. Typically hepatitis C infection is mild in the early stages and rarely recognized until it has caused significant damage to the liver. From infection to noticeable or significant liver damage can take 20 years or more. The symptoms of hepatitis C are also very mild in the early stages. Fatigue, the most common symptom, may not appear for many years. Other symptoms are mild fever, muscle and joint aches, nausea and vomiting, poor appetite, and vague abdominal pains. Hepatitis C often goes undiagnosed because the symptoms come and go and are so suggestive of a flu-like illness. Its presence is usually identified during a routine blood test or because the hepatitis C antibody is positive at the time of a blood donation. A low level of infection with practically no symptoms can continue for years. The hepatitis C infection causes inflammation of the liver, with chronic infection resulting in cirrhotic-like scarring. Unfortunately, more than 80% of infected individuals eventually progress to the chronic stage of hepatitis C which results in cirrhosis (severe scarring of liver tissue). Persons with the late stages of hepatitis C can also develop liver cancer. When the hepatitis C virus is a cofactor, there is an increased risk of cirrhosis in those who also consume alcohol in excess (NIDA 2002). Cirrhosis and the Alcohol FactOR Although alcohol affects many organs in the body, it is especially harmful to the liver. Alcohol is metabolized in the body, and the liver performs most of that work, potentially incurring serious damage in the process. Not only does alcohol destroy liver cells, it also destroys their ability to regenerate, leading to a syndrome of progressive inflammatory injury to the liver. In the United States, approximately 1% of the population (more than 2 million people) has alcoholic liver disease. Additional cases go undetected because patients are asymptomatic and never seek medical treatment. Alcoholism and alcoholic liver disease are higher in minorities. Women are also more susceptible to the adverse effects of alcohol than men. Women develop alcoholic hepatitis in a shorter time frame and from smaller amounts of alcohol than men (Day 2000). The survival rate after 5 years is also lower for women than for men (30% compared to 70%). There seems to be no single factor to account for increased susceptibility to alcoholic liver damage in females, but the effect of hormones on the metabolism of alcohol may play an important role (Day 2000; Mihas et al. 2002). Symptoms Although mild forms of alcoholic liver disease are often completely symptom-free, the symptoms are quite similar to cirrhosis: nausea, generally feeling unwell, a low-grade fever, impaired liver function, altered mental state, gastrointestinal bleeding, abdominal bloating, and seizures (Mihas et al. 2002). As long as consumption of alcohol continues, alcoholic inflammation of the liver will usually continue. Alcoholic inflammation of the liver will often eventually progress to cirrhosis. If use of alcohol ceases, inflammation of the liver generally resolves slowly over several weeks to months to years. Some improvement can continue for several years. Unfortunately, if cirrhotic damage has already occurred, there will be residual cirrhosis (Mihas et al. 2002). How Much Alcohol Causes Cirrhosis? When relating alcohol consumption to those persons who will actually go on to develop cirrhosis, the amount of alcohol consumption required varies widely. In less than 10% of drinkers who do develop cirrhosis, many factors that may be causally related to the development of cirrhosis remain unknown (e.g., genetic, malnutrition, toxic effects of ethanol, free radicals generated as byproducts of ethanol, and immune mechanisms) (Day 2000). In fact, in alcoholics there is actually a rather weak relationship between the amount of alcohol consumed and the risk of developing cirrhosis, and many alcoholics will not develop severe or progressive liver injury (Mihas et al. 2002). Is There a Genetic Factor? Since ancient times, common belief has been that alcoholism runs in families. For decades, researchers have investigated this folk opinion with scientific studies. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institutes of Health (NIH), as early as the 1970s, studies documented that alcoholism does occur in families. However, studies do not answer questions such as: does alcoholism occur in families because children observe the parents drinking, does the environment in the home play a role, do children inherit genes that create a predisposition for alcoholism, or does alcoholism result from a combination of factors? Continued studies have investigated these questions as well as the possibility that there is an underlying vulnerability to incur organ damage from alcohol that is under genetic control (Gordis 1992, 2000). Progress has been made using genetic, biochemical, and behavioral characteristics; population, family, and twin studies (male and female; identical and fraternal); and studies of adopted children; however, results have been difficult to interpret because of study variables. It is the opinion of the NIAAA that " more than one gene is likely to be responsible " for the vulnerability to alcoholism and that " it is probable that environmental influences are at least as important, and possibly more important, than genetic influences " (Gordis 1992; 2000). If research is successful in revealing the genes that are involved in increasing an individual's vulnerability to become an alcoholic, physicians will be better able to identify individuals who are at high risk for alcoholism and perhaps develop more effective treatment for alcohol-related health conditions such as cirrhosis of the liver (Day 2000). What Role Does Diet Play? It has been estimated that chronic alcoholics receive at least half of their daily caloric intake in the form of alcohol. Additionally, chronic abusers of alcohol often have vitamin deficiencies caused by self-neglect and poor eating habits, and it is not unusual for them to need significant vitamin supplementation to correct these vitamin deficiencies. Acute thiamin (vitamin B1) deficiency is typical. Patients with alcoholic inflammation of the liver also have protein/calorie malnutrition. Even though early studies in baboons demonstrated that cirrhosis can develop in subjects with good dietary nutrition, improved nutritional status does have positive effects for patients with alcoholic inflammation of the liver (Lieber et al. 1970). Nutrition should be improved with a healthy diet. Counting calories is a useful method to ensure adequate intake. Nutritional supplements and appetite stimulants should be used when appropriate (Mihas et al. 2002). Interestingly, obesity can exist even in persons who have poor nutritional status. In alcoholics, the presence of obesity increases the risk of cirrhosis development, probably because obesity also contributes to an earlier development of fatty liver (steatosis), now known to facilitate liver damage and make the liver more susceptible to a variety of insults, including alcohol consumption, infections, toxins, medicines, and so forth. (Day 2000). Fatty liver causes scarring of the liver. Diagnosing Alcoholic Liver Disease Tests to confirm a diagnosis of alcoholic inflammation of the liver include a complete blood count (CBC); liver enzyme, liver function, and electrolyte testing; and screening for other health conditions (presence of hepatitis B and C viruses, liver cancer, gallstones). Imaging studies are rarely used for diagnosis. (Sometimes they are used to exclude other potential causes such as gallstones, obstructions, or abnormal tissue or to evaluate the extent of existing conditions.) In some cases, a liver biopsy is used to confirm the diagnosis, the presence or absence of cirrhosis, and to exclude other causes (Mihas et al. 2002). Treatment There is no specific treatment paradigm for mild cases of alcoholic hepatitis. The common sense approach is to follow the instructions of your physician; stop all use of alcohol; ensure good dietary nutrition; and take supplements that enhance liver functioning such as N-acetyl-cysteine and lecithin. More severe cases may benefit from hospitalization to stabilize complications of the disease. The most predictive indicators for eventual outcome are willingness of the patient to not drink alcohol, the severity of any encephalopathy, levels of serum bilirubin and albumin, prothrombin time; the patient's age, and existing kidney function (Mihas et al. 2002). Other Causes of CirrhosIS Additional causes or conditions that can lead to cirrhosis are congestive heart failure, genetic disorders such as hemochromatosis (excessive iron accumulation) or Wilson's disease (excessive copper accumulation in the liver), advanced syphilis, exposure to parasitic flatworms or infections, exposure to heavy metals, ingestion of poisons (alcohol, phosphorus, carbon tetrachloride), cystic fibrosis, a severe reaction to an over-the-counter, prescriptive, or " recreational " drug, and injury to the liver from an accident (NIDDK 2000). Research also suggests that the hepatic stellate cell might play an important role in the development of cirrhosis. Hepatic stellate cells normally reside in the liver in a quiet or inactive state and function normally in a balanced process of extracellular matrix production (the structure between cells) and degradation. Development of fibrosis indicates that the balance of this process has been altered. When exposed to certain factors (such as alcohol, chronic hepatitis C, cirrhosis), stellate cells can undergo a complex activation process that causes them to become activated into collagen-forming cells. If these changes continue to be stimulated, a proliferation of fibrosis continues in hepatic stellate cells and normal tissue is replaced with abnormal, fibrotic liver tissue (Wolf 2001). This cirrhotic change may be caused by a transformational cell from the hepatic adipocyte (a fat cell) (Miyahara et al. 2000). There are natural therapies that deactivate the stellate cell. In one study, the reduction in the activation of the stellate cells by dilinoleoyl-phosphatidylcholine (DLPC) may be responsible for, or at least contribute to, the prevention of fibrosis (Poniachik et al. 1999). Risk Factors to the Cirrhotic PatieNT Patients with cirrhosis are at high risk for poor nutritional status (either obesity or weight loss); poor response to bacterial and viral infections; stomach ulcers, kidney disorders, and gallstones; liver cancer; and diabetes mellitus. Poor nutritional status often includes deficiencies in proteins, vitamins, choline, trace elements, or methionine. Additionally, cirrhosis patients may also exhibit enhanced or even severe reactions to prescription or " recreational " drugs. Interestingly, vitamin B1 (thiamin) deficiency may actually be a direct cause of alcoholic cirrhosis. Often persons who have cirrhosis are poor surgical candidates. General anesthesia during surgery reduces cardiac output, causes pooling of blood in the blood vessels in the stomach cavity, and reduces hepatic blood flow, putting the patient's liver at even greater risk for additional damage from reduced blood flow (Glanze 1996; Wolf 2001). Persons with well-compensated cirrhosis (few or mild clinical symptoms) have an increased but acceptable risk when surgery is required, but surgery should be avoided in cirrhotic patients unless absolutely necessary. Diagnosis of CirrhosIS Early diagnosis is critical in cirrhosis to establish the cause of the disease and to determine the amount of existing liver damage. A positive diagnosis of cirrhosis requires the use of several laboratory tests; imaging procedures (computerized axial tomography scans, radioisotope liver scans, ultrasound); physical examination; liver biopsy; and observation of the patient's symptoms (Nidus 1999a; NIDDK 2000). Treatment of CirrhosIS Cirrhosis of the liver is an irreversible process, but treatment of the underlying liver disease and determining its possible causes can slow or stop the progression of cirrhosis (Wolf 2001). One causal factor is alcohol: stopping the intake of alcohol will stop progression of alcoholic cirrhosis. Ending the use of hepatoxic drugs and removing sources of environmental toxins will also stop progression. The possible presence of metabolic diseases (hemochromatosis, Wilson's disease) should be investigated. Identifying the presence of hepatitis viruses is essential. Some chronic hepatitis viruses (B and C) may respond to treatment with interferon. Treatment for cirrhosis requires skilled medical management including appropriate drug therapy, monitoring and treatment of possible side effects, and supportive treatment, such as ensuring appropriate nutrition and using supplemental vitamins and minerals. In general, there is little conventional medical treatment for the basic mechanisms that cause cirrhosis (Nidus 1999b). Once cirrhosis has developed, any damage to the liver that has already occurred cannot be reversed. Liver transplantation is considered a last resort for a failing or non-functioning liver (NIDDK 2000). Drug Therapies In patients with cirrhosis of the liver, drug treatments are aimed at the disease and its complications. Drugs that are metabolized by the liver must be used with caution. Infections must be treated promptly with appropriate antibiotics. Antiviral drugs are a mainstay in hepatitis C virus (HCV) therapy. Conventional Colchicine, a generic drug used to treat gout, also inhibits collagen (a protein in the body the makes up scar tissue) and has produced some improvement in liver function and patient survival. Nausea and gastrointestinal imbalances are common side effects. Ursodiol (or ursodeoxycholic acid, Actigall), a drug generally used to dissolve or prevent gallstones, improves symptoms of cirrhosis and side effects are minor. Actigall is a very expensive drug. Unfortunately, it does not seem to prolong patient survival. Tauroursodeoxycholate is a similar drug that appears to be more effective. Drugs that suppress the immune system such as cyclosporine, methotrexate, and azathioprine have been shown to provide some benefit for patient survival. These drugs have severe side effects (Nidus 1999b). Drugs that reduce inflammation such as corticosteroids have been helpful in improving liver function and symptoms, but these drugs have potentially serious side effects as well. If a patient takes a corticosteroid, measures must be taken to monitor adverse side effects (edema, hypertension, diabetes mellitus, ulcers) (Glanze 1996). Osteoporosis is another side effect of both cirrhosis and corticosteroids. Cholestyramine (taken with food) and Naltrexone can relieve the itching caused by primary biliary cirrhosis. Naltrexone in high doses is toxic for the liver, but low doses appear to be safe. Some persons have found phototherapy (light therapy) helpful in reducing itching in one study (Nidus 1999b). In Japan, researchers have found evidence that malotilate prevented both damage to liver cells and cirrhosis that they attempted to induce in rats. Malotilate is a drug developed by a Japanese pharmaceutical company that has been shown by several researchers to prevent induced liver damage and the accumulation of collagen and morphologic changes (such as accumulation of inflammatory cells and fibrosis and reductions in ethanol-induced lesions) (Takase et al. 1989; Mirossay et al. 1996; Ryhanen et al. 1996). It has been shown in one study to perfectly inhibit liver cirrhosis (Suzuki 1992). In studies as early as 1987, Ala-Kokko et al. found that malotilate had preventive effects on liver fibrosis in the rat. Continuing studies by Ala-Kokko et al. (1989) reported that malotilate was able to reduce liver damage in rats even when started 14 days after the damage occurred. Ala-Kokko et al. (1989) suggested that the effect of malotilate was likely the result of inhibiting inflammation. In another study, malotilate had a 96% protective effect on ethanol-induced gastric damage (Mirossay et al. 1999). Antiviral Antiviral drugs are also used in treating cirrhosis and are a mainstay for some persons (NIDA 2002). However, some patients are not responsive or experience relapse after the antiviral drugs are discontinued. Some have great difficulty handling the side effects of antiviral drugs (Strickland 2002). Commonly used antiviral drugs are interferon-alpha (Intron A) and ribavirin (Rebetol and Virazole). Intron A may have potential to reduce the risk of cancer development in some cirrhosis patients. Intron A is a powerful antiviral protein that is found in cells when they are exposed to a virus. Newer drugs are pegylated, meaning they contain polyethylene glycol combined with interferon. At this writing, only one pegylated drug has been approved by the FDA. In January 2001, the FDA approved PEG-Intron for once-a-week therapy for HCV. Investigative PEGASYS (Hoffman-La Roche) is another antiviral drug that is under consideration for approval by the FDA ( www.fda.gov ). PEGASYS is primarily directed at the antiviral treatment of HCV, but appears to also have benefits for persons with cirrhosis and chronic liver disease. PEGASYS contains a pegylated form (or longer-lasting form) of interferon. Hoffman-La Roche states that their clinical studies in persons with HCV showed a significantly better sustained response rate for PEGASYS compared to interferon alone (35% versus 19%); a better response rate (30% versus 5%) in cirrhosis patients; the drug can be injected one time each week for a year (interferon is given three times a week); and side effects are similar to interferon. The National Institutes of Health (NIH) will study the role of PEGASYS to determine if it can reduce the progression of cirrhosis, liver disease, and hepatocellular carcinoma in patients with HCV, fibrosis, and cirrhosis. Hoffman-La Roche has submitted an application for approval to the FDA to market PEGASYS. PEGASYS is in Phase III clinical trials, awaiting approval by the FDA. Researchers are testing drugs that will have a greater ability to correct circulation imbalances that lead to portal hypertension and ascites. V2 receptor antagonists are of great interest to researchers. These V2 receptor antagonists have potential to reverse the dilation in blood vessels that leads to salt and fluid retention (Nidus 1999b). Gene therapy as a treatment option is the subject of research, but even if research indicates that gene therapy appears feasible, human trials are years away. Outlook Unfortunately, there are no commonly accepted, effective, conventional drug therapy regimes to reverse liver damage that has been caused by cirrhosis, HCV, and alcoholic liver disease. However, humans are fortunate because our bodies can still function with only about 10% of the liver, providing the liver is intact and undamaged. As with some other organs, the liver has been designed with a redundancy (excess or backup) of tissue to protect it from damage or loss of function. The healthy parts of the liver have an amazing capacity to regenerate new, healthy liver tissue to replace liver tissue that has been damaged. This information, however, should not be taken as advice or sanction to continue behavior that causes undue stress upon the liver. Once the liver has been damaged, the person will be in a situation of playing " catch-up, " trying to assist the liver to repair the tissue that has been damaged while maintaining the day-to-day work done by the liver. Compared to having a normal, optimally functioning, healthy liver, being in a " catch-up " situation is a greatly disadvantaged position. Therefore, even though the liver can incur considerable damage and still function with some success, we only have one liver and it must be cared for appropriately. Because drug therapies for cirrhosis have limited effectiveness and new drugs have not shown great promise, studies regarding natural, supportive, and alternative therapies should be considered to be especially important sources of information concerning adjunct care of the liver and protection from cirrhosis. Liver Transplantation Liver transplantation is the now an accepted conventional medical treatment for a liver that is severely damaged or failing. The liver is the second most transplanted organ (Thomas et al. 2001). Survival rates improve each year because of drugs to prevent infection and suppress rejection of the new liver. More than 80% of liver transplant patients are still alive 5 years after their surgery. HCV is the most common reason for chronic liver disease and the need for liver transplantation in the United States (NIDA 2002). In some transplant patients (8%), hepatitis C can return to infect the transplanted liver and subsequently progress to cirrhosis (Nidus 1999b). Alcohol abuse is the second most common cause of cirrhosis, just slightly behind HCV. Active use of alcohol is a contraindication for a liver transplant. In the United States, most patients must have abstained from drinking alcohol for at least 6 months and have received a thorough psychological evaluation to determine if they are committed to abstaining before they will be considered for a liver transplant (Mihas et al. 2002). End-stage cirrhosis is a common cause of liver failure. A liver transplant may be the only option for persons who have end-stage cirrhosis resulting from alcoholic cirrhosis or chronic hepatitis (Nidus 1999b; Workman 1999). A transplant may also be a necessity for survival when the complications of cirrhosis (encephalopathy, ascites, or bleeding varices) are uncontrollable or when liver function is severely reduced (Thomas et al. 2001). Liver cancer is usually a contraindication to transplantation, but in certain experimental situations, some patients with small, localized liver cancers might be suitable candidates. According to the American Liver Foundation, if a liver cancer is in an early stage and it is localized, a liver transplant might result in long-term survival for a patient. If a cancer in the liver has already spread to other parts of the body by the time it is discovered, a liver transplant will not cure the patient of cancer. Once it has been determined that a patient with cirrhosis needs a liver transplant for survival, there are many considerations: the patient's health status (determined by extensive testing); placement on the liver transplant waiting list (greatest need is considered first; the list is maintained by UNOS, the United Network for Organ Sharing); location of the donor and recipient (greatest need first; then locally; then regionally; then nationally); and matching of the donor and recipient (blood type and body size). The Benefit of Natural TherapiES Due to the small number of conventional drug therapies presently used to treat cirrhosis, alternative therapies must be considered. Note that the vast majority of natural or alternative treatments act by having an antioxidant or anti-inflammatory effect. As with almost all disease processes, research has demonstrated that good antioxidant levels are necessary for optimum health and to protect us from the physical assaults of trauma and disease. Some of the therapies listed in this section also act by having an effect on the immune system (an immune modulating effect). Because the liver can often continue to perform essential functions in spite of serious damage, it is important to eat foods and take proper nutrients to retain its regeneration and detoxification abilities. B Vitamins and Metabolic Functioning Vitamin B Complex Vitamin B complex is a group of vitamins (B1, thiamine; B2, riboflavin; B3, niacin; B5, pantothenic acid; B6, pyridoxine; folic acid; betaine; inositol; and B12, cyanocobalamin) that differ from each other in structure and the effect they have on the human body. The B vitamins (thiamine, riboflavin, niacin, pantothenic acid, pyridoxine) play a vital role in numerous metabolic functions including enzyme activities. These enzyme activities have many roles and are involved in the metabolism of carbohydrates and fats, functioning of the nervous and digestive systems, production of red blood cells, and having a synergistic effect with each other (Clayman 1989). The B vitamins are found in large quantities in the human liver. Dietary sources of vitamin B are wheat germ, bran, whole grain cereals and bread, brown rice, pasta, fish, lean meats, beans, nuts, bananas, green leafy vegetables, and eggs (Clayman 1989). Heat and overcooking destroys the B vitamins (Glanze 1996). Folic Acid Folic acid (vitamin B4) is an important member of the B complex family, known for reducing harmful levels of homocysteine (a sulfur-containing amino acid) known to be a major culprit in heart disease. At normal levels, homocysteine plays a vital role in the biosynthesis of cysteine, which assists glutathione in the liver to detoxify carcinogens and other toxins, but without adequate methylation, which is provided by folic acid and other B vitamins, biochemical reactions generated from beneficial byproducts of homocysteine cannot occur. Decreases in folate (folic acid) are also associated with increased levels of lipoperoxidases, that is, an indicator of increased oxidative stress. Therefore, folic acid is potentially beneficial in the early stages of cirrhosis or for the ongoing oxidative damage seen in the cirrhotic process. In humans with viral hepatitis, treatment with folic acid improved liver chemistry measurements in the recovery period following the illness. This improvement was thought to be due to an effect on nucleotide (genetic building block) synthesis (Zviarynski et al. 1999). In an experiment using rats, the occurrence of decreased folate and elevated homocysteine documented the strong association of decreased folate with increased oxidative stress and liver peroxidation (Huang et al. 2001). Dietary sources of folic acid are green, leafy vegetables such as broccoli and spinach; mushrooms; liver; nuts; dried beans and peas; egg yolk; and whole-wheat breads and cereals (Clayman 1989; Glanze 1996). A varied diet that includes fruits and vegetables will usually provide sufficient folic acid, but mild to moderate deficiencies are not uncommon. More severe deficiencies result from certain blood disorders, malabsorption disorders, alcohol dependence, and certain drugs (oral contraceptives, anticonvulsants, antimalarials, analgesics, corticosteroids, and sulfonamides) (Clayman 1989). Choline Choline is another of the B complex vitamins, essential for the use of fats in the body. It is a precursor to acetylcholine, a nerve signal carrier in the brain. Choline also stops fats from being deposited in the liver and help move fats into the cells. Deficiency of choline can lead to cirrhosis with associated conditions such as bleeding; kidney damage hypertension (high blood pressure); cholesterolemia (high blood levels of cholesterol); and atherosclerosis (occulsive deposits in blood vessels) (Glanze 1996). Sources of dietary choline are liver, wheat germ, legumes, brewer's yeast, and egg yolk. The Synergistic Effects of Vitamins C and E Vitamins C and E Vitamins C and E used in combination have been demonstrated to improve liver function in chronic liver disease patients. Both vitamins C and E act as antioxidants. Vitamin C is a potent antioxidant that is found naturally in many fruits and vegetables. Researchers have found inadequate levels of vitamin C in patients with degenerative diseases. According to Garg et al. (2000), vitamin C has protective effects against liver oxidative damage, particularly when used in combination with vitamin E. Garg et al. (2000) found that supplementation in rats lowered plasma and liver lipid peroxidation, normalized plasma vitamin C levels, and raised vitamin E above normal levels, suggesting that the improved levels of lipid peroxidation products in the plasma and liver with vitamin C and E supplementation and the activities of antioxidant enzymes in the liver indicated that vitamins C and E reduced lipid peroxidation by quenching free radicals. Sources of dietary vitamin C are fresh fruits and vegetables. Particularly good sources are citrus fruits, tomatoes, green leafy vegetables, potatoes, green peppers, strawberries, and cantaloupe. Vitamin E is found in vegetable oils, nuts, meats, green leafy vegetables, whole grain cereals, wheat germ, and egg yolk (Clayman 1989). Essential Trace Minerals Selenium Selenium is a trace element that acts by several mechanisms, including detoxifying liver enzymes, exerting anti-inflammatory effects, and providing antioxidant defense. Selenium is found in minute amounts in foods (Glanze 1996), with the richest sources being from meats, fish, whole grains, and dairy products. The selenium content of vegetables is dependent on the soil in which they are grown (Clayman 1989). Using selenium-deficient rats, experiments have shown that selenium deficiency causes oxidative stress (Ueda et al. 2000). The presence of selenium helps induce and maintain the glutathione antioxidant system. Epidemiological studies in China have also shown that selenium provides protection against both hepatitis B and C and liver cancer. In a 4-year trial on 130,471 Chinese individuals, those who were given selenium-spiked table salt showed a 35.1% reduction in primary liver cancer, compared with the group given salt without selenium added. A clinical study of 226 hepatitis B-positive people showed that one 200-mcg tablet daily of selenium reduced the incidence of primary liver cancer to zero. Upon cessation of selenium supplementation, primary liver cancer incidences began to rise, indicating that viral hepatitis patients should take selenium on a continuous basis (Yu et al. 1997). Zinc Zinc is used in numerous drugs and preparations that are protective: zinc oxide in skin ointments; zinc stearate in acne and eczema preparations; and zinc permanganate to treat bladder inflammation. Zinc deficiency features weakness, decreased taste and appetite, lengthy wound healing, and risk of infection. Zinc levels that are low have also been related to the progression of cirrhosis to hepatic encephalopathy (Romero-Gomez et al. 2001). An earlier study in rats (Okegbile et al. 1998) demonstrated that the amount of dietary zinc dramatically affected the ability of the rats' livers to synthesize cellular components (nucleic acid building blocks) and maintain normal alkaline phosphatase (indicated by a blood test of liver function, which is related to cholestasis or accumulation of bile acids). Cholestasis has been shown to play a role in facilitating the development of cirrhosis.) Dietary sources of zinc are meats, eggs, liver, seafood, vegetables with pods, nuts, peanut butter, and whole-grain cereals (Glanze 1996). Zinc supplementation can vary from 25-90 mg daily. Multifaceted Effects of CoQ10 Coenzyme Q10 (CoQ10) is an excellent antioxidant that is protective for a liver that has been damaged by ischemia (reduced blood flow). CoQ10 is also an important component of healthy metabolism. It protects the mitochondria and cell membrane from oxidative damage and helps generate ATP, the energy source for cells. CoQ10 is absorbed by the lymphatic system and distributed throughout the body. Japanese researchers studied the effects of the toxic drug hydrazine on liver cells. They administered hydrazine to rats to study the effect of free radicals on liver cells (hepatocytes). One group of rats was given hydrazine only; a second group of rats was given CoQ10 in addition to the hydrazine. Hepatocyte cell mitochondria from the hydrazine-only group were found to be extremely enlarged, a state often preceding cell death from oxidative stress. The mitochondria of rats given CoQ10 along with hydrazine were nearly normal, showing only slight enlargement. * Note: Cachexia is a condition of general poor health and dietary state associated with wasting diseases. Hydrazine sulfate is an anticachexia drug. Hydrazine sulfate is also used to reverse the metabolic processes of debilitation and weight loss in some cancer patients (NCI 2001). Other researchers have reported that hydrazine sulfate also acts to stabilize or cause some types of tumors to regress in some patients, but this benefit has been contested (Green 1997). Therefore, drugs containing hydrazine may be required in a treatment plan even when the liver is weakened or at risk. In other studies in rats, liver ischemia (poor blood supply) was induced surgically to investigate the effects of CoQ10 on oxidative stress (Yamamura et al. 1980; Genova et al. 1999). In the study by Genova et al. (1999), lipid peroxidation occurred as a result of ischemia. However, when the rats were pretreated with CoQ10 for 14 days, the liver peroxidation parameters were normalized. The CoQ10-treated rats were also more resistant than nontreated rats to oxidative stress by free radicals. According to Genova et al. (1999), their preliminary study suggests that pretreatment with CoQ10 can have a beneficial effect against oxidative damage during surgical liver transplantation. Ito et al. (1999) induced hepatic ischemia by clamping the liver artery, portal vein, and bile duct. After 15 minutes, the levels of glutathione rapidly decreased. When reperfusion was started, the glutathione levels promptly increased for about an hour before they began to decline. When Ito et al. administered CoQ10 to the rats prior to ischemia, the reduction of glutathione levels induced by ischemia/reperfusion was protected. Our bodies can produce some of the CoQ10 that we need. The rest is synthesized from our diet. The best dietary sources of CoQ10 are fresh sardines and mackerel; heart and liver of beef, pork, and lamb; meat from beef and pork; and eggs. Vegetable sources of CoQ10 are spinach, broccoli, peanuts, wheat germ, and whole grains. Meat sources of CoQ10 are higher than vegetable and grain sources. It is important to remember that foods must be fresh and unprocessed (no milling, canning, freezing, preserving, etc.) and grown in unpolluted areas to be considered as viable sources (Bliznakov 1987). Protecting and Improving Liver Function N-Acetyl-Cysteine (NAC) N-acetyl-cysteine (NAC) is a substance that acts as an antioxidant or free-radical scavenger. Most scientific articles related to liver protection with NAC emphasize this effect. NAC is frequently used in medical settings to treat liver toxicity associated with ingesting Tylenol (also poisonous mushrooms). In this situation, NAC is given orally or intravenously. In liver transplantation, NAC reduces liver injury associated with reperfusion (resumption of blood flow after transplant) (Taut et al. 2001; Weinbroum et al. 2001). NAC also has been found to improve liver blood flow and liver function in patients who have extremely critical infections such as septic shock (Rank et al 2000). In ingestion of methanol (a very toxic form of alcohol different from the ethanol in alcoholic drinks), NAC partially prevented liver damage from methanol (Dobrzynska et al. 2000). Another study also showed that NAC slowed liver damage caused by methanol (Dobrzynska et al. 2000). In another experiment that used cocaine as a pro-oxidant, NAC was found to exert a protective effect by acting as a precursor for glutathione, a vitally important antioxidant and free-radical scavenger (Zaragoza et al. 2000). The best dietary sources of NAC are meat, fish, poultry, eggs, and dairy products (Young et al. 1994). S-Adenosyl Methionine (SAMe) SAMe is a methylation agent (a methyl group donor) and is necessary for the synthesis of glutathione, necessary for liver health. Medical studies have shown that SAMe has beneficial antioxidant effects on the liver and other tissues, particularly in protecting and restoring liver cell function destroyed by the hepatitis C virus. When mice were given paracetamol (a hepatotoxic substance), SAMe was found to be as effective as N-acetyl-cysteine (NAC) in preventing liver damage. Additionally, SAMe has a positive effect on the fluidity of the cell membrane, as demonstrated in red blood cells from patients with cirrhosis (Turchetti et al. 2000). However, in a major review that was limited to alcoholic liver disease and cirrhosis (Rambaldi et al. 2001), researchers concluded that there were no significant effects of SAMe on mortality, liver-related mortality, liver transplantation, or liver complications in patients with alcoholic liver disease. This review concluded that SAMe should not be used routinely in alcoholic liver disease. In critical care medicine, it is occasionally necessary to provide total nutrition via special IV solutions to patients who are unable to eat for a prolonged period of time (i.e., several months). This process is called total parenteral nutrition (TPN). Various complications are associated with the parenteral method of providing calories and nutrients, including liver cholestasis (interruption or blockage of the bile ducts). When studying extremely ill pediatric surgical patients, Amii et al. (1999) stated, " SAMe is the most promising treatment of total parenteral nutrition-associated cholestasis. " In another study on hepatic cholestasis and oxidative stress in rats, Lopez et al. (2000) concluded, " the results confirmed the function of SAMe as an antioxidant and hepatoprotector. " SAMe is found naturally in every cell of the body. It is synthesized from a combination of the amino acid L-methionine, folic acid, vitamin B12, and trimethylglycine, provided all these ingredients are present and performing (Anon. 2002). Polyenylphosphatidylcholine (PC) PC is one of the most important substances for liver protection and health and is a primary constituent of the cell membrane. As such, PC is necessary for integrity of liver cells. In studies in rats, PC has prolonged the survival of rat liver cells in culture by stabilizing the cell membrane (Miyazak et al. 1991). Liver cells that have been damaged by alcohol or cirrhosis are unable to meet the ongoing demands of the liver for phospholipid synthesis. Adding phospholipids such as PC via oral intake played an important role in regeneration of damaged liver cells (Horejsova et al. 1994). In an early study, Neuberger (1983) stated: " It has been shown that orally administered polyunsaturated PC can be incorporated into the liver cell membrane. " Other studies have shown the antifibrotic effect of PC. Not only does PC inhibit the development of hepatic fibrosis, it actually accelerates the regression of existing fibrosis (Ma et al. 1996). Part of this effect is probably due to PC promoting the breakdown of collagen (Lieber 1999), but it may also be due to an inhibitory effect on the stellate cell (Poniachik et al. 1999). In experimental studies, PC was also found to protect against alcoholic cirrhosis in baboons and against carbon tetrachloride-induced cirrhosis in rats (Aleynik et al. 1997). In another study (Navder et al. 1997), PC was shown to prevent earlier changes induced in the alcoholic liver before cirrhosis even develops. When liver cells are damaged, apoptosis (programmed cell death) is activated. If apoptosis can be decreased, more liver cells (hepatocytes) can be preserved and actually still function. PC decreases apoptosis, but alcohol consumption increases the rate of apoptosis in liver cells (Mi et al. 2000). The positive effect of PC on hepatocyte apoptosis is probably via an antioxidant mechanism. As a result, the antioxidative hepatoprotective mechanism of PC is one of the most studied mechanisms. Numerous medical articles have noted the antioxidant properties of PC and other related phospholipid compounds and how toxic metabolites associated with liver injury are decreased when they are used (Navder et al. 1999). The best dietary sources of phosphatidylcholine are beef steak, liver, organ meats, egg yolks, spinach, soybeans, cauliflower, germ, peanuts, and brewer's yeast. Smaller amounts are found in oranges, apples, potatoes, lettuce, and whole-wheat bread (Canty et al. 1994). Alpha-Lipoic Acid (ALA) Alpha-lipoic acid is an antioxidant that has been shown to decrease the amount of hepatic fibrosis associated with liver injury. Both of these mechanisms suggest it has promise for cirrhosis. Alpha-lipoic acid is considered to be the universal antioxidant by Dr. Lester Packer, who has studied the effects of ALA extensively (Constantinescu et al. 1994; Packer 1994, 1997; Podda et al. 1994). Because alpha-lipoic acid is fat-soluble, it can penetrate the cell membrane to exert therapeutic action. It has been shown to effectively scavenge harmful free radicals, chelate toxic heavy metals, and help to prevent mutated gene expression (Biewenga et al. 1997). Another of its most beneficial functions is to enhance the effects of other essential antioxidants including glutathione, which is vital to the health of the liver (Lykkesfeld et al. 1998; Khanna et al. 1999). The effects of ALA have been studied in rats and mice. In studies in rats, when the rat liver was insulted with a chemical agent, dietary alpha-lipoic acid encouraged healing (Arend et al. 2000). Alpha-lipoic acid also demonstrated promise in the treatment of sepsis (a life-threatening systemic infection) (Liang et al. 2000) in septic mice. In septic mice, alpha-lipoic acid improved carbohydrate metabolism in liver cells by its effect on nitric oxide pathways. The body can make some of its own lipoic acid, but most must be obtained from dietary sources, either from food or supplements. Dietary sources of alpha-lipoic acid include yeast, liver, and spinach, potatoes, and carrots. Unfortunately, the best sources of dietary alpha-lipoic acid are red meats, which also contain high levels of saturated fats, and it would require huge amounts of spinach to consume the amount of alpha-lipoic acid conveniently obtained from the supplementation of 1 capsule. Improving Cellular Metabolism Acetyl-L-Carnitine Acetyl-L-carnitine has been shown to convert some hepatic parameters to more youthful levels. Acetyl-L-carnitine is the biologically active form of the amino acid L-carnitine that has been shown to protect cells throughout the body from age-related degeneration. By facilitating the youthful transport of fatty acids into the cell mitochondria, acetyl-L-carnitine facilitates conversion of dietary fats to energy and muscle. Acetyl-L-carnitine has also been shown to regenerate nerves (Fernandez et al. 1997); provide protection against glutamate and ammonia-induced toxicity to the brain (Rao et al. 1999); and to reverse the effects of heart aging in animals (Paradies et al. 1999). In an aging mouse model, two studies (Hagen et al. 1998a, b) illustrated the ability of acetyl-L-carnitine to increase cellular respiration. The first study at the University of California (Berkeley) examined liver parenchymal cells in old mice after feeding them a 1.5% solution of acetyl-L-carnitine for 1 month (Hagen et al. 1998a). The results showed that acetyl-L-carnitine supplementation significantly reversed the age-associated decline of mitochondrial membrane function. In the second study, also at Berkeley, researchers again confirmed the ability of acetyl-L-carnitine to reverse age-related mitochondrial decay (Hagan et al. 1998b). In another study, also conducted with old rats, acetyl-L-carnitine improved liver metabolism and slowed age-related decline in metabolism and biosynthetic function (Mollica et al. 2001). Primary dietary sources of L-carnitine are meats (especially beef and lamb) and dairy products. The liver and kidneys can also synthesize L-carnitine from the amino acids lysine and methionine (Plawecki 2001). Amino Acids that Support Liver Health Taurine Taurine is a conditionally essential amino acid produced from cysteine by the body. It is abundantly found in the body, particularly the central nervous system where it is thought to have a regulating influence. Taurine is a crystallized acid that comes from bile, which is produced by the liver. Sources of dietary taurine are cow's milk, meats, seafood, and poultry. Plants have virtually no taurine. Taurine can be deficient in our daily diet and can also be insufficiently produced by the body in certain disease states. Taurine exerts a protective effect against liver cirrhosis, working by a mechanism that decreases oxidative stress (Balkan et al. 2001). L-Arginine L-arginine is an essential amino acid. L-arginine is also a key building block for repair of damaged tissue. Numerous studies have documented enhanced wound healing in response to L-arginine supplements. Dietary sources of L-arginine are high-protein foods (meats, eggs, nuts and nut products), seeds, brown rice, whole-wheat grains, oatmeal, raisins, and legumes. Persons with diabetes (or borderline diabetics), persons who do not have complete bone growth (children and teenagers), pregnant women, persons who have a latent herpes virus, or persons with psychoses should consult their physician before taking L-arginine. Antioxidants should always be taken with L-arginine. L-Glutamine L-glutamine is a nonessential amino acid that has benefits for the liver and intestines, particularly for those who use NSAIDs (nonsteroidal anti-inflammatory drugs). L-glutamine may also be useful in neutralizing the effects of alcohol and strengthening the immune system. Sources of dietary L-glutamine are plant (e.g., nuts and nut products, seeds, and brown rice) and animal protein (e.g., meats and eggs). Branched-Chain Amino Acids BCAAs are leucine, isoleucine, and valine. They are considered to be essential amino acids because humans cannot survive unless these amino acids are present in the diet. BCAAs are needed for the maintenance of muscle tissue and appear to preserve muscle stores of glycogen (stored form of carbohydrates that can be converted into energy). Dietary sources of BCAAs are dairy products and red meat. Whey protein and egg protein supplements are other sources. Most diets provide the daily requirement of BCAAs for healthy people. However, in cases of physical stress, we have increased energy requirements, in particular in persons with cirrhosis. Studies on alcoholic cirrhosis patients have shown benefits from supplementing valine, leucine, and isoleucine. These branched-chain amino acids can enhance protein synthesis in liver and muscle cells, help restore liver function, and prevent chronic encephalopathy (Shimazu 1990; Chalasani et al. 1996). In studies, BCAAs have also been shown to have therapeutic value in adults with cirrhosis of the liver. According to the researchers, BCAAs seem to be the preferred substrate to meet this requirement (Kato et al. 1998). Herbal Extracts Silymarin Silymarin (also known as milk thistle or Silybum marinum) is a member of the aster family (Asteraceae) that has been used as a medicinal plant since ancient times and is widely used in traditional European medicine. The active extract of milk thistle is silymarin (Bosisio et al. 1992), a mixture of flavolignans, including silydianin, silychristine, and silibinin, with silibinin being the most biologically active. Although the mechanisms are not yet fully understood, silymarin has proven to be one of the most potent liver-protecting substances known. Its main routes of protection appear to be the prevention of free-radical damage, stabilization of plasma membranes, and stimulation of new liver cell production. According to several early studies, silymarin acts as an antioxidant and free-radical scavenger that is many times more potent than vitamin E (Hikino et al. 1984) and has also been shown to inhibit lipid peroxidation and to prevent glutathione depletion induced by alcohol and other liver toxins, even increasing total glutathione levels in the liver by 35% over controls (Valenzuela et al. 1989). However, perhaps the most interesting effect from the early studies of silymarin was its ability to stimulate protein synthesis, resulting in production of new liver cells to replace older, damaged ones (Sonnenbichler et al. 1986). Studies also demonstrate the benefits of silymarin for protection from numerous toxic chemicals such as carbon tetrachloride, ethanol, poisonous mushrooms (Desplaces et al. 1975); alcohol and chronic alcoholic hepatitis (Salmi et al. 1982); cirrhosis (Ferenci et al. 1989); acute and chronic hepatitis (Berenguer et al. 1977); and hypercholesterolemia (high cholesterol) (Krecman et al. 1998). Most medical studies cover the use of silymarin in the early forms of liver degeneration, which occur prior to the development of cirrhosis. However, ongoing research indicates that the development of cirrhosis is a continuum, beginning with damaged liver cells and progressing on to an intermediate stage such as fatty liver before actual development of cirrhosis. Therefore, the potential for obtaining protective benefits from silymarin is worth consideration. Green Tea Green tea has been in widespread, common use in China for thousands of years. In the last several decades, green tea has also been widely used in the treatment of hepatic disease in Europe. Green tea has active ingredients called catechin polyphenols. Catechins in green tea have potential therapeutic significance because of their potent antioxidants, which have an ability to neutralize free radicals and act as free-radical scavengers. Green tea has been shown to have antiviral activity and immune-stimulating properties (Kaul et al. 1985); protective benefits from hepatotoxicity caused by carbon tetrachloride, ethanol, and 2-nitropropane (a common industrial solvent also found in tobacco smoke) (Lewis et al. 1979); promise for treatment of many types of hepatic disease, particularly acute and chronic viral hepatitis; and fibrosis (overgrowth of collagen) (Pontz et al.1982). Additionally, green tea has hepatoprotective qualities that include killing dangerous intestinal bacterial strains (Clostridium and Escherichia coli) and promoting the growth of friendly bacteria in the intestine; inhibiting several viruses, including viral hepatitis; and lowering excessive iron levels in the liver that would interfere with ribavirin and interferon treatment for hepatitis C. For most people, drinking green tea daily seems to be a most practical, readily available means for providing protective liver benefits and preventing chronic toxicity induced by oxidative stress from environmental chemicals. The dose used for hepatic diseases in clinical studies has typically been 1 gram of green tea three times daily. Artichoke Artichoke (Cynara scolymus) is an herb with antioxidant properties that are similar to silymarin. Artichoke is used in Eastern parts of the world for its hepatoprotective qualities. Like silymarin, it is a member of the aster family (Asteraceae). It is native to the Mediterranean, where it has been in common use for more than 2000 years. Also similar to silymarin, artichoke extract has demonstrated strong antioxidant potential and a hepatoprotective effect, protecting the liver from the damaging effects of toxins, such as carbon tetrachloride and other environmental chemicals (Adzet et al. 1987; Gebhardt 1995). Artichoke extract is also able to stimulate regeneration of damaged liver tissue (Maros et al. 1966). The usefulness of artichoke to prevent or reduce buildup of fat in the liver from chronic alcohol consumption is noteworthy (Samochowiec et al. 1971; Wojciki 1978). Experimental studies of hepatoprotective mechanisms have only been conducted in animals because the procedure involves exposure to toxins. The basic research method in this type of investigation is to administer the test substance, in this case artichoke leaf extract, to the animal prior to or simultaneously with, administration of a toxic substance and observe the results. Gebhardt (1995) demonstrated hepatoprotective effects against carbon tetrachloride-induced toxicity on liver cells from rats. When studying rat liver cells exposed to t-BHP (tertiary butylhydroperoxide), they found that artichoke leaf extract significantly prevented damage. Living with CirrhosIS There is no cure for cirrhosis at this time. However, physicians attempt to delay its progress, minimize liver cell damage, and reduce the complications of the disease through the use of drugs and dietary and lifestyle recommendations. Once cirrhosis has been diagnosed, sodium and fluids should be restricted and all alcohol consumption must cease. Antiemetics, diuretics, and supplemental vitamins are often prescribed. Because of the potential of bleeding, persons with cirrhosis should avoid straining at the bowel and use stool softeners as directed by a qualified medical caregiver. Violent sneezing, coughing, and nose blowing should also be avoided. Untreated cirrhosis can be fatal. Patients should avoid exposure to infections. They should eat small but frequent meals of nutritious foods. They should also carefully follow caregiver instructions from a medical professional. More than half of all liver disease could be prevented if only we simply acted on knowledge we already have! Avoiding or limiting the use of alcoholic beverages is an excellent place to start because it is well documented that alcohol destroys liver cells. Man-made chemicals also pose an extreme threat to the liver. Always follow recommended standard safety precautions for handling man-made chemicals. All ingested, inhaled, and absorbed chemicals and toxins must be processed by the liver. If you have cirrhosis, stay one step ahead of the disease by watching for the appearance of additional symptoms of cirrhosis or a change in the symptoms you already have (e.g., increasing fatigue, worsening appetite, nausea and vomiting, itching, jaundice, abdominal pain, abdominal swelling, ankle swelling, bleeding or bruising more easily). Report them to your physician immediately. Cirrhosis causes the filtering process in the liver to slow down so its ability to handle medication will be affected. The liver will probably not remove drugs from the blood at the expected rate, causing prescription drugs to act longer than expected. Report any drug reactions to your physician immediately. Do not add any new medicine (including over-the-counter medicines) without consulting your physician. It is essential that your physician is always aware of all medicines you take. The liver is the only organ that can generate healthy, new tissue in response to injury or disease. However, the exact moment at which fibrosis becomes irreversible is not known. Cirrhosis with nodule formation, portal hypertension, and early liver failure is generally considered irreversible, but less advanced lesions can show remarkable reversibility when the underlying cause of the liver injury is controlled. Therefore, it is possible to regenerate a cirrhosis-damaged liver if extraordinary therapies are followed and the underlying cause of the cirrhosis is eliminated. SUMMARY If you have cirrhosis, consult a qualified physician who is experienced in treating liver disease and who will coordinate your treatment and manage the complications. Supplementation with antioxidants, branched-chain amino acids, and all of the B complex of vitamins except B3 (niacin) has been shown to have protective qualities and to be beneficial for the liver. (For specific antiviral therapies to help eradicate hepatitis B or C, refer to the Hepatitis B and Hepatitis C protocols. Also see the protocols on Hepatitis C and Liver Degenerative Disease for additional information.) Maintain a nutritionally balanced diet that includes fruits, vegetables, and appropriate levels of fats, carbohydrates, and protein. 1. B vitamins are important for healthy metabolism and liver health. Daily recommendations include: * B1 (thiamine), 500 mg * B2 (riboflavin), 75 mg * B5 (pantothenic acid), 1500 mg * B6 (pyridoxine), 200 mg * B12 (cobalamin), sublingual methylcobalamin is recommended for better absorption, one 5 mg lozenge 1-5 times daily * Folic acid, 800 mcg daily * Vitamin B3 (niacin) should be avoided by people with liver conditions. 2. Choline helps reduce the amount of fat deposited in the liver, 1500 mg daily. 3. Antioxidant vitamins C and E work together to help prevent free-radical damage to the liver. * Take at least 500 mg of vitamin C daily. * Gamma E Tocopherol/Tocotrienols provide the most broad-spectrum antioxidant protection, 1-2 capsules daily. 4. The trace mineral selenium has shown antioxidant protection in the liver. Zinc is often deficient in the cirrhotic liver. Take selenium, 200 mcg daily, and zinc, up to 90 mg daily. 5. CoQ10 protects the mitochondria from oxidative damage and provides cellular energy, 300 mg daily. 6. N-acetyl-cysteine (NAC) enhances the production of glutathione and has protective benefits for the liver from toxins. Take two 600-mg doses daily of NAC. 7. S-adenosylmethionine (SAMe) can be effective for protecting and restoring liver cell function. The suggested dose of SAMe is 400 mg 3 times daily. 8. A cost-effective alternative to SAMe supplementation is TMG (trimethylglycine). Take two 500 mg tablets of TMG after meals twice daily or as directed by a physician. 9. Polyunsaturated phosphatidylcholine (PPC) has been shown to prevent the development of fibrosis and cirrhosis and to prevent lipid peroxidation and associated liver damage from alcohol consumption. GastroPro contains pure pharmaceutical-grade polyunsaturated phosphatidylcholine (also known as polyenylphosphatidylcholine). Take two to three 900-mg capsules daily. 10. Alpha-lipoic acid may help to decrease hepatic fibrosis and increase glutathione production, two to four 250 mg capsules daily. 11. Acetyl-L-carnitine will help to maintain mitochondrial health. Take 2 daily doses of 1000 mg. 12. Amino acids are required for protein synthesis and metabolism. Certain amino acids are particularly beneficial for diseased liver states: * Taurine decreases oxidative stress in the cirrhotic liver; 1-4 grams daily are recommended. * L-arginine (5-10 grams daily) and L-glutamine (2000 mg daily) may help lower blood levels of toxic ammonia that build up when the liver is damaged. L-arginine can also help facilitate regeneration of the liver, providing the liver still has at least a 20% functional capacity. 13. Alcoholic cirrhosis patients can benefit from valine, leucine, and isoleucine supplements. These branched-chain amino acids can enhance protein synthesis in the liver and are especially beneficial in alcoholic cirrhosis. The suggested dose is 2-4 capsules daily between meals with fruit juice or before eating. Each capsule should contain 300 mg of leucine, 150 mg of isoleucine, and 150 mg of valine. 14. Green tea (95%) extract will lower toxic levels of iron and provide protection from oxidation; take four to ten 350-mg capsules daily. Each capsule should contain at least 100 mg of epigallocatechin gallate (EGCG). Alcoholic liver disease patients should consider taking silymarin extract from milk thistle. The most active flavonoid in silymarin is silybinin. Silibinin Plus is formulated to the same potency as European prescription drugs. One 325-mg capsule taken twice daily is recommended for healthy people. Under a physician's supervision, patients with liver disease may take up to 6 capsules daily. 15. Artichoke extract will stimulate damaged liver tissue and provide continued protection. One to three 300-mg doses of Artichoke Leaf Extract are recommended. For specific antiviral therapies for the treatment of hepatitis B or C, refer to the Hepatitis B and Hepatitis C protocols (see the Liver Degenerative Disease protocol for additional information). The protocol on Heavy Metal Toxicity contains extensive information about conditions related to exposure to heavy metals. For more informatION Contact the American Liver Foundation, (800) 465-4837 ( www.liverfoundation.org ); Hepatitis Foundation International, (800) 891-0707 ( www.hepfi.org ); United Network for Organ Sharing (UNOS), (800) 330-8500 ( www.unos.org ); or the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (www.niddk.nih.gov). Product availability Polyenylphosphatidylcholine (sold under the name GastroPro), Silibinin Plus, branched-chain amino acids, B vitamins, SAMe, TMG, vitamin C, Gamma E Tocopherol/Tocotrienols, vitamin C, selenium, zinc, coenzyme Q10, taurine, L-arginine, L-glutamine, acetyl-L-carnitine, alpha-lipoic acid, N-acetyl-cysteine, green tea extract, and artichoke leaf extract may be ordered by calling (800) 544-4440 or by ordering online. Disclaimer This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional. The information published in the protocols is only as current as the day the book was sent to the printer. This protocol raises many issues that are subject to change as new data emerge. None of our suggested treatment regimens can guarantee a cure for these diseases. Quote Link to comment Share on other sites More sharing options...
Recommended Posts
Join the conversation
You are posting as a guest. If you have an account, sign in now to post with your account.
Note: Your post will require moderator approval before it will be visible.