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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 aŸ’”Á¼‹óà 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.
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 aŸ’”Á¼‹óà 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.
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