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).
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.
- Genetic Factor
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).
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).
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.
- Drug Therapies
- Liver Transplantation
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).
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.
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 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.
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.
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 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).
Continued: The Benefit of Natural Therapies
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