Disease: Fatty Liver
(Nonalcoholic Fatty Liver Disease [NAFLD] and Nonalcoholic Steatohepatitis [NASH])

    Nonalcoholic fatty liver facts

    • Nonalcoholic fatty liver (NAFLD) is the accumulation of abnormal amounts of fat within the liver.
    • NAFLD can be divided into isolated fatty liver in which there is only accumulation of fat, and nonalcoholic steatohepatitis (NASH) in which there is fat and damage to liver cells.
    • NASH progresses to scarring and ultimately to cirrhosis, with all the complications of cirrhosis, for example, gastrointestinal bleeding, liver failure, and liver cancer.
    • Isolated fatty liver does not progress to NASH or cirrhosis.
    • The development of NAFLD is intimately associated with and is probably caused by obesity and diabetes.
    • NAFLD is considered a manifestation of the metabolic syndrome.
    • The symptoms of NAFLD are primarily those of the complications of cirrhosis in patients with NASH; isolated fatty liver infrequently causes symptoms and usually is discovered incidentally.
    • The differentiation of isolated fatty liver from NASH requires a liver biopsy.
    • The most promising treatments for NAFLD are weight loss including bariatric surgery and exercise.
    • Several drugs have been studied in the treatment of NASH. There is little evidence that any drug is effective in slowing the disease progression of NASH.
    • Many diseases are associated with NASH and are part of the metabolic syndrome. These diseases should be screened for and treated, for example, high blood pressure, dyslipidemia and diabetes.
    • NAFLD, including NASH affects young children as well.
    • NASH will become the number one reason for liver transplantation unless effective and safe treatments are found.

    What are nonalcoholic fatty liver disease and steatohepatitis?

    Fatty liver is a condition in which the cells of the liver accumulate abnormally increased amounts of fat. Although excessive consumption of alcohol is a very common cause of fatty liver (alcoholic fatty liver), there is another form of fatty liver, termed nonalcoholic fatty liver disease (NAFLD), in which alcohol has been excluded as a cause. In NAFLD, other recognized causes of fatty liver that are less common causes than alcohol also are excluded.

    NAFLD is a manifestation of an abnormality of metabolism within the liver. The liver is an important organ in the metabolism (handling) of fat. The liver makes and exports fat to other parts of the body. It also removes fat from the blood that has been released by other tissues in the body, for example, by fat cells, or absorbed from the food we eat. In NAFLD, the handling of fat by liver cells is disturbed. Increased amounts of fat are removed from the blood and/or are produced by liver cells, and not enough is disposed of or exported by the cells. As a result, fat accumulates in the liver.

    NAFLD is classified as either fatty liver (sometimes referred to as isolated fatty liver or IFL) or steatohepatitis (NASH). In both isolated fatty liver and NASH there is an abnormal amount of fat in the liver cells, but, in addition, in NASH there is inflammation within the liver, and, as a result, the liver cells are damaged, they die, and are replaced by scar tissue.

    Why is nonalcoholic fatty liver disease important?

    NAFLD is important for several reasons. First, it is a common disease, and is increasing in prevalence. Second, NASH is an important cause of serious liver disease, leading to cirrhosis and the complications of cirrhosis--liver failure, gastrointestinal bleeding, and liver cancer. Third, NAFLD is associated with other very common and serious non-liver diseases, perhaps the most important being cardiovascular disease that leads to heart disease and strokes. Fatty liver probably is not the cause of these other diseases, but is a manifestation of an underlying cause that the diseases share. Fatty liver, therefore, is a clue to the presence of these other serious diseases which need to be addressed.

    What causes nonalcoholic fatty liver disease?

    The cause of NAFLD is complex and not completely understood. The most important factors appear to be the presence of obesity and diabetes. It used to be thought that obesity was nothing more than the simple accumulation of fat in the body. Fat tissues were thought to be inert, that is, they served as simply storage sites for fat and had little activity or interactions with other tissues. We now know that fat tissue is very active metabolically and has interactions and effects on tissues throughout the body.

    When large amounts of fat are present as they are in obesity, the fat becomes metabolically active (actually inflamed) and gives rise to the production of many hormones and proteins that are released into the blood and have effects on cells throughout the body. One of the many effects of these hormones and proteins is to promote insulin resistance in cells.

    Insulin resistance is a state in which the cells of the body do not respond adequately to insulin, a hormone produced by the pancreas. Insulin is important because it is a major promoter of glucose (sugar) uptake from the blood by cells. At first, the pancreas compensates for the insensitivity to insulin by making and releasing more insulin, but eventually it can no longer produce sufficient quantities of insulin and, in fact, may begin to produce decreasing amounts. At this point, not enough sugar enters cells, and it begins to accumulate in the blood, a state known as diabetes. Although sugar in the blood is present in large amounts, the insensitivity to insulin prevents the cells from receiving enough sugar. Since sugar is an important source of energy for cells and allows them to carry out their specialized functions, the lack of sugar begins to alter the way in which the cells function.

    In addition to releasing hormones and proteins, the fat cells also begin to release some of the fat that is being stored in them in the form of fatty acids. As a result, there is an increase in the blood levels of fatty acids. This is important because large amounts of certain types of fatty acids are toxic to cells.

    The release of hormones, proteins, and fatty acids from fat cells affects cells throughout the body in different ways. Liver cells, like many other cells in the body, become insulin resistant, and their metabolic processes, including their handling of fat, become altered. The liver cells increase their uptake of fatty acids from the blood where fatty acids are in abundance. Within the liver cells, the fatty acids are changed into storage fat, and the fat accumulates. At the same time, the ability of the liver to dispose of or export the accumulated fat is reduced. In addition, the liver itself continues to produce fat and to receive fat from the diet. The result is that fat accumulates to an even greater extent.

    What is the difference between nonalcoholic fatty liver and steatohepatitis?

    As discussed previously, the difference between isolated, nonalcoholic fatty liver and steatohepatitis (NASH) is the presence of inflammation and damage to the liver cells in NASH; in both, the liver has increased amounts of fat. Although about a third of the general population has fatty liver, approximately 10% have NASH. Approximately one third of patients with NAFLD have NASH. Although fatty liver and NASH appear to arise under the same conditions, it does not appear that fatty liver progresses to NASH. Thus, whether a patient is to develop fatty liver versus NASH is determined very early during the accumulation of fat, although it is unclear what factors determine this. It is believed that the inflammation and damage of liver cells are caused by the toxic effects of the fatty acids released by fat cells, but fatty acids in the blood are elevated in both fatty liver and NASH. Perhaps the difference is explained by genetic susceptibility as suggested by preliminary data.

    The consequences of fat in the liver depend greatly on the presence or absence of inflammation and damage in the liver, i.e., whether there is fat alone or NASH is present. Isolated fatty liver does not progress to important liver disease. NASH, on the other hand, can progress through the formation of scar (fibrous tissue) to cirrhosis. The complications of cirrhosis, primarily gastrointestinal bleeding, liver failure, and liver cancer, then may occur.

    What is the relationship between nonalcoholic fatty liver disease, obesity, and diabetes?

    As discussed previously, obesity and diabetes have important roles in the development of fatty liver. Whereas one third of the general population (which includes obese and people with diabetes) may develop NAFLD, more than two thirds of people with diabetes develop NAFLD. Among patients who are very obese and undergoing surgery for their obesity, the majority have NAFLD. Moreover, whereas the risk of NASH is less than 5% among lean persons, the risk is more than a third among the obese. Fatty liver increases both in prevalence as well as severity as the degree of obesity increases. The increases begin at weights that are considered overweight - i.e., less than obese.

    What is the relationship between nonalcoholic fatty liver disease and the metabolic syndrome?

    The metabolic syndrome is a syndrome defined by the association of several metabolic abnormalities that are believed to have a common cause. These metabolic abnormalities result in obesity, elevated blood triglycerides, low high density lipoprotein (HDL) cholesterol, high blood pressure, and elevated blood sugar (diabetes). NAFLD is considered a manifestation of the metabolic syndrome and thus occurs frequently with the other manifestations of the syndrome. Occasionally it may occur without the other abnormalities of the syndrome.

    What are the symptoms of fatty liver?

    Fatty liver disease rarely causes symptoms until the liver disease is far advanced. At most, there is enlargement of the liver which may give rise to mild right, upper abdominal discomfort.

    Patients with advanced fatty liver disease - which means that the liver has developed large amounts of scar tissue or cirrhosis - have all of the well-known complications of advanced liver disease of any cause. The complications result from 1) loss of liver cells and their ability to perform their normal functions, and 2) blockage of the flow of blood from the intestines through the scarred liver.

    Specifically, liver cells produce critical proteins, for example, proteins necessary for blood to clot, and advanced liver disease can result in excessive bleeding. The liver also removes waste products from the blood, for example, bilirubin and advanced liver disease can result in retention of bilirubin and jaundice (yellow skin due to the accumulation of bilirubin in tissues).

    The blockage of the flow of blood through the liver causes the blood to go around (bypass) the liver. The pressure within the bypassing blood vessels increases and the vessels enlarge, particularly in the esophagus, and these vessels can rupture and bleed profusely. The flow of blood from the intestine that bypasses the liver prevents the liver from removing toxic chemicals produced in the intestine. These toxins are shunted to the brain where they interfere with all of the brain's functions, ultimately leading to coma.

    In addition, because of the increase in pressure within blood vessels, fluid leaks from the vessels. It may leak into the abdomen (ascites) or into the tissues, particularly of the legs (edema).

    How is nonalcoholic fatty liver disease diagnosed?

    Fatty liver generally does not cause symptoms, and any symptoms if present are more likely to be due to the accompanying diseases such as obesity, diabetes, vascular disease, etc. In anyone with obesity or diabetes, fatty liver should be suspected. In a minority of patients, abnormal liver tests are found on routine blood testing although the abnormalities usually are mild. Probably the most common method by which NAFLD is diagnosed is by imaging studies - ultrasonography, computerized tomography (CT), magnetic resonance imaging (MRI)--that are obtained for reasons other than diagnosing NAFLD. NAFLD also may be discovered when patients develop complications of the liver disease - cirrhosis, liver failure and liver cancer - due to the presence of NASH.

    It is not possible to distinguish between isolated fatty liver and NASH with imaging studies. Although a combination of several blood tests has been suggested as a means of separating the two, and tests are being developed to identify NASH, biopsy of the liver is the best means to differentiate between the presence of fat, or fat and inflammation (NASH). Although the majority of individuals will have isolated fatty liver and not NASH, it is important to identify patients with NASH, because of the need to look for complications of liver disease and to enter these patients into trials of treatment with the hope of preventing progression of the liver disease. Patients with the metabolic syndrome, obesity, and diabetes are good candidates to undergo biopsy of the liver since the incidence of NASH is higher among these groups.

    One of the difficulties in diagnosing NASH as the cause of severe scaring or cirrhosis is that as the scaring progresses to cirrhosis, the fat disappears. This results in a condition that is referred to as cryptogenic cirrhosis, cirrhosis in which there is no clear cause. (Specifically, in cryptogenic cirrhosis the two most common causes of cirrhosis - alcohol and viral hepatitis - are not involved.) Cryptogenic cirrhosis has puzzled physicians for many years as to its cause. However, it now appears that half of cryptogenic cirrhosis occurs in patients with obesity and/or diabetes and probably is due to NASH.

    What are the other causes of fatty liver?

    There are several identifiable causes of fatty liver that are not NAFLD but may cause confusion. The most common are excessive alcohol consumption and hepatitis C. Other causes include Wilson's disease, lipodystrophy (a disease of fat storage), starvation, intravenous nutrition, and abetalipoproteinemia (a disease of fat transport). In addition, several drugs cause fatty liver, including corticosteroids, tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall).

    What are the complications of nonalcoholic fatty liver disease?

    The complications of nonalcoholic liver disease are essentially those of NASH that has progressed to cirrhosis and include liver failure, gastrointestinal bleeding, and liver cancer.

    How is nonalcoholic fatty liver disease treated?

    Treatment for nonalcoholic fatty liver disease include lifestyle changes (exercise, weight loss, diet), medications, supplements (antioxidants), omega-3 fatty acids, surgery, and liver transplant.

    Weight loss and exercise

    Since the serious complications of NAFLD are primarily seen in patients with NASH, treatment of NASH is of great importance. Unfortunately there are no clearly effective treatments for these patients. One of the difficulties in identifying effective treatments is the need for long-term studies since the progression of NASH to cirrhosis and its complications occurs slowly. Several treatments have resulted in a reduction of fat in the liver, but few have shown that the progression of NASH is slowed.

    Weight loss and exercise are among the most promising of treatments for NAFLD. It does not take large amounts of weight loss to result in a decrease in liver fat. A less than 10% decrease in weight may be enough. Vigorous exercise results in a reduction of liver fat and also may reduce the inflammation of NASH. The long-term effects of weight loss and exercise on the important development of cirrhosis and its complications are unknown. Nevertheless, at the present time, the best theoretical approach to NAFLD is weight loss and vigorous exercise. Unfortunately, only a minority of patients are able to accomplish these.

    Diet

    NAFLD has been associated in human or animal studies with reduced amounts of unsaturated fats (a diet high in saturated fat) and increased amounts of fructose (which is most commonly added to the diet as high-fructose corn syrup). Benefits of increasing unsaturated fat (a diet lower in saturated fat, and higher unsaturated fat) and reducing high fructose corn syrup on NAFLD have not been demonstrated; however, there is little harm in doing so, especially since there may be benefits of these dietary modifications unrelated to the liver.

    An interesting observation - though unexplained - is that there is less scarring (fibrosis) in the livers of patients with NASH who drink more than two cups of coffee per day. (Scarring or fibrosis is the process that ultimately leads to cirrhosis.) Similar benefits of coffee have been associated with lesser degrees of liver disease in both alcoholic cirrhosis and hepatitis C. It is not unreasonable to recommend drinking coffee in moderate amounts in view of the lack of harmful side effects.

    Vitamin D deficiency is associated with NAFLD. Although there is no reason to think that this deficiency contributes to NAFLD, it is reasonable to measure vitamin D levels in patients with NAFLD and treat them with vitamin D if they are deficient.

    There is no evidence of harmful effects of light alcohol consumption (two or fewer drinks per day) on NAFLD though there also is no evidence that it is safe! Larger amounts of alcohol consumption should be avoided by everyone, including individuals with NAFLD.

    Medications and other treatment options

    Insulin sensitizers

    Metformin (Glucophage) is a drug used for treating diabetes. It works by increasing the insulin sensitivity of cells, directly counteracting the insulin resistance that accompanies NAFLD as well as the metabolic syndrome. It has been studied but, unfortunately, has not been found to improve the liver injury associated with NASH.

    Pioglitazone (Actos) and rosiglitazone (Avandia) are drugs that also are used for treating diabetes because they increase insulin sensitivity. There has been a reduction in liver fat and signs of liver injury with both drugs, and pioglitazone might reduce the scarring that results from the inflammation of NASH. Two problems that occur with treatment are weight gain and, with rosiglitazone, an increase in heart attacks. Pioglitazone may be used to treat NASH; however, it needs to be recognized that its long-term effectiveness and safety have not been well-established.

    Antioxidants

    Vitamin E has been studied in NASH because of its general effects of opposing inflammation. It has been shown to reduce liver fat and inflammation and possibly fibrosis, but its long-term effectiveness and safety have not been well-studied. Moreover, treatment of patients with vitamin E who do not have NASH is associated with a higher mortality. Vitamin E can be used for treating NASH, but it should be used selectively (not in all patients), and patients should understand the potential risk.

    Pentoxyfylline

    Pentoxyfylline (Trental) has been studied for the treatment of NASH in small groups of patients with encouraging results; however, there is not enough experience or knowledge of its effectiveness and safety to recommend treatment outside of research studies.

    Omega-3-fatty acids

    Small studies have shown some benefit with omega-3-fatty acids in reducing liver fat in NAFLD, and larger studies are underway. In large groups of individuals (not selected because of the presence or absence of NAFLD), omega-3-fatty acids were shown to reduce cardiovascular events such as heart attacks and overall mortality. Therefore, omega-3-fatty acids may be appropriate treatment for patients with NAFLD and the metabolic syndrome because these patients have a high incidence of cardiovascular disease and death.

    Lipid-lowering drugs

    Lipid-lowering drugs, specifically the statins and ezetimibe (Zetia), have been used to treat the abnormal blood lipids associated with the metabolic syndrome. Although there is evidence of beneficial effects of these drugs on the liver in NAFLD, there is not enough experience to recommend them in patients with NAFLD unless they are primarily being used for treating abnormal blood lipids.

    Ursodeoxycholic acid

    Ursodeoxycholic acid (Ursodiol) has been studied in NAFLD but has been abandoned because of its ineffectiveness and concerns about toxicity at very high doses.

    What are nonalcoholic fatty liver disease and steatohepatitis?

    Fatty liver is a condition in which the cells of the liver accumulate abnormally increased amounts of fat. Although excessive consumption of alcohol is a very common cause of fatty liver (alcoholic fatty liver), there is another form of fatty liver, termed nonalcoholic fatty liver disease (NAFLD), in which alcohol has been excluded as a cause. In NAFLD, other recognized causes of fatty liver that are less common causes than alcohol also are excluded.

    NAFLD is a manifestation of an abnormality of metabolism within the liver. The liver is an important organ in the metabolism (handling) of fat. The liver makes and exports fat to other parts of the body. It also removes fat from the blood that has been released by other tissues in the body, for example, by fat cells, or absorbed from the food we eat. In NAFLD, the handling of fat by liver cells is disturbed. Increased amounts of fat are removed from the blood and/or are produced by liver cells, and not enough is disposed of or exported by the cells. As a result, fat accumulates in the liver.

    NAFLD is classified as either fatty liver (sometimes referred to as isolated fatty liver or IFL) or steatohepatitis (NASH). In both isolated fatty liver and NASH there is an abnormal amount of fat in the liver cells, but, in addition, in NASH there is inflammation within the liver, and, as a result, the liver cells are damaged, they die, and are replaced by scar tissue.

    Why is nonalcoholic fatty liver disease important?

    NAFLD is important for several reasons. First, it is a common disease, and is increasing in prevalence. Second, NASH is an important cause of serious liver disease, leading to cirrhosis and the complications of cirrhosis--liver failure, gastrointestinal bleeding, and liver cancer. Third, NAFLD is associated with other very common and serious non-liver diseases, perhaps the most important being cardiovascular disease that leads to heart disease and strokes. Fatty liver probably is not the cause of these other diseases, but is a manifestation of an underlying cause that the diseases share. Fatty liver, therefore, is a clue to the presence of these other serious diseases which need to be addressed.

    What causes nonalcoholic fatty liver disease?

    The cause of NAFLD is complex and not completely understood. The most important factors appear to be the presence of obesity and diabetes. It used to be thought that obesity was nothing more than the simple accumulation of fat in the body. Fat tissues were thought to be inert, that is, they served as simply storage sites for fat and had little activity or interactions with other tissues. We now know that fat tissue is very active metabolically and has interactions and effects on tissues throughout the body.

    When large amounts of fat are present as they are in obesity, the fat becomes metabolically active (actually inflamed) and gives rise to the production of many hormones and proteins that are released into the blood and have effects on cells throughout the body. One of the many effects of these hormones and proteins is to promote insulin resistance in cells.

    Insulin resistance is a state in which the cells of the body do not respond adequately to insulin, a hormone produced by the pancreas. Insulin is important because it is a major promoter of glucose (sugar) uptake from the blood by cells. At first, the pancreas compensates for the insensitivity to insulin by making and releasing more insulin, but eventually it can no longer produce sufficient quantities of insulin and, in fact, may begin to produce decreasing amounts. At this point, not enough sugar enters cells, and it begins to accumulate in the blood, a state known as diabetes. Although sugar in the blood is present in large amounts, the insensitivity to insulin prevents the cells from receiving enough sugar. Since sugar is an important source of energy for cells and allows them to carry out their specialized functions, the lack of sugar begins to alter the way in which the cells function.

    In addition to releasing hormones and proteins, the fat cells also begin to release some of the fat that is being stored in them in the form of fatty acids. As a result, there is an increase in the blood levels of fatty acids. This is important because large amounts of certain types of fatty acids are toxic to cells.

    The release of hormones, proteins, and fatty acids from fat cells affects cells throughout the body in different ways. Liver cells, like many other cells in the body, become insulin resistant, and their metabolic processes, including their handling of fat, become altered. The liver cells increase their uptake of fatty acids from the blood where fatty acids are in abundance. Within the liver cells, the fatty acids are changed into storage fat, and the fat accumulates. At the same time, the ability of the liver to dispose of or export the accumulated fat is reduced. In addition, the liver itself continues to produce fat and to receive fat from the diet. The result is that fat accumulates to an even greater extent.

    What is the difference between nonalcoholic fatty liver and steatohepatitis?

    As discussed previously, the difference between isolated, nonalcoholic fatty liver and steatohepatitis (NASH) is the presence of inflammation and damage to the liver cells in NASH; in both, the liver has increased amounts of fat. Although about a third of the general population has fatty liver, approximately 10% have NASH. Approximately one third of patients with NAFLD have NASH. Although fatty liver and NASH appear to arise under the same conditions, it does not appear that fatty liver progresses to NASH. Thus, whether a patient is to develop fatty liver versus NASH is determined very early during the accumulation of fat, although it is unclear what factors determine this. It is believed that the inflammation and damage of liver cells are caused by the toxic effects of the fatty acids released by fat cells, but fatty acids in the blood are elevated in both fatty liver and NASH. Perhaps the difference is explained by genetic susceptibility as suggested by preliminary data.

    The consequences of fat in the liver depend greatly on the presence or absence of inflammation and damage in the liver, i.e., whether there is fat alone or NASH is present. Isolated fatty liver does not progress to important liver disease. NASH, on the other hand, can progress through the formation of scar (fibrous tissue) to cirrhosis. The complications of cirrhosis, primarily gastrointestinal bleeding, liver failure, and liver cancer, then may occur.

    What is the relationship between nonalcoholic fatty liver disease, obesity, and diabetes?

    As discussed previously, obesity and diabetes have important roles in the development of fatty liver. Whereas one third of the general population (which includes obese and people with diabetes) may develop NAFLD, more than two thirds of people with diabetes develop NAFLD. Among patients who are very obese and undergoing surgery for their obesity, the majority have NAFLD. Moreover, whereas the risk of NASH is less than 5% among lean persons, the risk is more than a third among the obese. Fatty liver increases both in prevalence as well as severity as the degree of obesity increases. The increases begin at weights that are considered overweight - i.e., less than obese.

    What is the relationship between nonalcoholic fatty liver disease and the metabolic syndrome?

    The metabolic syndrome is a syndrome defined by the association of several metabolic abnormalities that are believed to have a common cause. These metabolic abnormalities result in obesity, elevated blood triglycerides, low high density lipoprotein (HDL) cholesterol, high blood pressure, and elevated blood sugar (diabetes). NAFLD is considered a manifestation of the metabolic syndrome and thus occurs frequently with the other manifestations of the syndrome. Occasionally it may occur without the other abnormalities of the syndrome.

    What are the symptoms of fatty liver?

    Fatty liver disease rarely causes symptoms until the liver disease is far advanced. At most, there is enlargement of the liver which may give rise to mild right, upper abdominal discomfort.

    Patients with advanced fatty liver disease - which means that the liver has developed large amounts of scar tissue or cirrhosis - have all of the well-known complications of advanced liver disease of any cause. The complications result from 1) loss of liver cells and their ability to perform their normal functions, and 2) blockage of the flow of blood from the intestines through the scarred liver.

    Specifically, liver cells produce critical proteins, for example, proteins necessary for blood to clot, and advanced liver disease can result in excessive bleeding. The liver also removes waste products from the blood, for example, bilirubin and advanced liver disease can result in retention of bilirubin and jaundice (yellow skin due to the accumulation of bilirubin in tissues).

    The blockage of the flow of blood through the liver causes the blood to go around (bypass) the liver. The pressure within the bypassing blood vessels increases and the vessels enlarge, particularly in the esophagus, and these vessels can rupture and bleed profusely. The flow of blood from the intestine that bypasses the liver prevents the liver from removing toxic chemicals produced in the intestine. These toxins are shunted to the brain where they interfere with all of the brain's functions, ultimately leading to coma.

    In addition, because of the increase in pressure within blood vessels, fluid leaks from the vessels. It may leak into the abdomen (ascites) or into the tissues, particularly of the legs (edema).

    How is nonalcoholic fatty liver disease diagnosed?

    Fatty liver generally does not cause symptoms, and any symptoms if present are more likely to be due to the accompanying diseases such as obesity, diabetes, vascular disease, etc. In anyone with obesity or diabetes, fatty liver should be suspected. In a minority of patients, abnormal liver tests are found on routine blood testing although the abnormalities usually are mild. Probably the most common method by which NAFLD is diagnosed is by imaging studies - ultrasonography, computerized tomography (CT), magnetic resonance imaging (MRI)--that are obtained for reasons other than diagnosing NAFLD. NAFLD also may be discovered when patients develop complications of the liver disease - cirrhosis, liver failure and liver cancer - due to the presence of NASH.

    It is not possible to distinguish between isolated fatty liver and NASH with imaging studies. Although a combination of several blood tests has been suggested as a means of separating the two, and tests are being developed to identify NASH, biopsy of the liver is the best means to differentiate between the presence of fat, or fat and inflammation (NASH). Although the majority of individuals will have isolated fatty liver and not NASH, it is important to identify patients with NASH, because of the need to look for complications of liver disease and to enter these patients into trials of treatment with the hope of preventing progression of the liver disease. Patients with the metabolic syndrome, obesity, and diabetes are good candidates to undergo biopsy of the liver since the incidence of NASH is higher among these groups.

    One of the difficulties in diagnosing NASH as the cause of severe scaring or cirrhosis is that as the scaring progresses to cirrhosis, the fat disappears. This results in a condition that is referred to as cryptogenic cirrhosis, cirrhosis in which there is no clear cause. (Specifically, in cryptogenic cirrhosis the two most common causes of cirrhosis - alcohol and viral hepatitis - are not involved.) Cryptogenic cirrhosis has puzzled physicians for many years as to its cause. However, it now appears that half of cryptogenic cirrhosis occurs in patients with obesity and/or diabetes and probably is due to NASH.

    What are the other causes of fatty liver?

    There are several identifiable causes of fatty liver that are not NAFLD but may cause confusion. The most common are excessive alcohol consumption and hepatitis C. Other causes include Wilson's disease, lipodystrophy (a disease of fat storage), starvation, intravenous nutrition, and abetalipoproteinemia (a disease of fat transport). In addition, several drugs cause fatty liver, including corticosteroids, tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall).

    What are the complications of nonalcoholic fatty liver disease?

    The complications of nonalcoholic liver disease are essentially those of NASH that has progressed to cirrhosis and include liver failure, gastrointestinal bleeding, and liver cancer.

    How is nonalcoholic fatty liver disease treated?

    Treatment for nonalcoholic fatty liver disease include lifestyle changes (exercise, weight loss, diet), medications, supplements (antioxidants), omega-3 fatty acids, surgery, and liver transplant.

    Weight loss and exercise

    Since the serious complications of NAFLD are primarily seen in patients with NASH, treatment of NASH is of great importance. Unfortunately there are no clearly effective treatments for these patients. One of the difficulties in identifying effective treatments is the need for long-term studies since the progression of NASH to cirrhosis and its complications occurs slowly. Several treatments have resulted in a reduction of fat in the liver, but few have shown that the progression of NASH is slowed.

    Weight loss and exercise are among the most promising of treatments for NAFLD. It does not take large amounts of weight loss to result in a decrease in liver fat. A less than 10% decrease in weight may be enough. Vigorous exercise results in a reduction of liver fat and also may reduce the inflammation of NASH. The long-term effects of weight loss and exercise on the important development of cirrhosis and its complications are unknown. Nevertheless, at the present time, the best theoretical approach to NAFLD is weight loss and vigorous exercise. Unfortunately, only a minority of patients are able to accomplish these.

    Diet

    NAFLD has been associated in human or animal studies with reduced amounts of unsaturated fats (a diet high in saturated fat) and increased amounts of fructose (which is most commonly added to the diet as high-fructose corn syrup). Benefits of increasing unsaturated fat (a diet lower in saturated fat, and higher unsaturated fat) and reducing high fructose corn syrup on NAFLD have not been demonstrated; however, there is little harm in doing so, especially since there may be benefits of these dietary modifications unrelated to the liver.

    An interesting observation - though unexplained - is that there is less scarring (fibrosis) in the livers of patients with NASH who drink more than two cups of coffee per day. (Scarring or fibrosis is the process that ultimately leads to cirrhosis.) Similar benefits of coffee have been associated with lesser degrees of liver disease in both alcoholic cirrhosis and hepatitis C. It is not unreasonable to recommend drinking coffee in moderate amounts in view of the lack of harmful side effects.

    Vitamin D deficiency is associated with NAFLD. Although there is no reason to think that this deficiency contributes to NAFLD, it is reasonable to measure vitamin D levels in patients with NAFLD and treat them with vitamin D if they are deficient.

    There is no evidence of harmful effects of light alcohol consumption (two or fewer drinks per day) on NAFLD though there also is no evidence that it is safe! Larger amounts of alcohol consumption should be avoided by everyone, including individuals with NAFLD.

    Medications and other treatment options

    Insulin sensitizers

    Metformin (Glucophage) is a drug used for treating diabetes. It works by increasing the insulin sensitivity of cells, directly counteracting the insulin resistance that accompanies NAFLD as well as the metabolic syndrome. It has been studied but, unfortunately, has not been found to improve the liver injury associated with NASH.

    Pioglitazone (Actos) and rosiglitazone (Avandia) are drugs that also are used for treating diabetes because they increase insulin sensitivity. There has been a reduction in liver fat and signs of liver injury with both drugs, and pioglitazone might reduce the scarring that results from the inflammation of NASH. Two problems that occur with treatment are weight gain and, with rosiglitazone, an increase in heart attacks. Pioglitazone may be used to treat NASH; however, it needs to be recognized that its long-term effectiveness and safety have not been well-established.

    Antioxidants

    Vitamin E has been studied in NASH because of its general effects of opposing inflammation. It has been shown to reduce liver fat and inflammation and possibly fibrosis, but its long-term effectiveness and safety have not been well-studied. Moreover, treatment of patients with vitamin E who do not have NASH is associated with a higher mortality. Vitamin E can be used for treating NASH, but it should be used selectively (not in all patients), and patients should understand the potential risk.

    Pentoxyfylline

    Pentoxyfylline (Trental) has been studied for the treatment of NASH in small groups of patients with encouraging results; however, there is not enough experience or knowledge of its effectiveness and safety to recommend treatment outside of research studies.

    Omega-3-fatty acids

    Small studies have shown some benefit with omega-3-fatty acids in reducing liver fat in NAFLD, and larger studies are underway. In large groups of individuals (not selected because of the presence or absence of NAFLD), omega-3-fatty acids were shown to reduce cardiovascular events such as heart attacks and overall mortality. Therefore, omega-3-fatty acids may be appropriate treatment for patients with NAFLD and the metabolic syndrome because these patients have a high incidence of cardiovascular disease and death.

    Lipid-lowering drugs

    Lipid-lowering drugs, specifically the statins and ezetimibe (Zetia), have been used to treat the abnormal blood lipids associated with the metabolic syndrome. Although there is evidence of beneficial effects of these drugs on the liver in NAFLD, there is not enough experience to recommend them in patients with NAFLD unless they are primarily being used for treating abnormal blood lipids.

    Ursodeoxycholic acid

    Ursodeoxycholic acid (Ursodiol) has been studied in NAFLD but has been abandoned because of its ineffectiveness and concerns about toxicity at very high doses.

    Source: http://www.rxlist.com

    There are several identifiable causes of fatty liver that are not NAFLD but may cause confusion. The most common are excessive alcohol consumption and hepatitis C. Other causes include Wilson's disease, lipodystrophy (a disease of fat storage), starvation, intravenous nutrition, and abetalipoproteinemia (a disease of fat transport). In addition, several drugs cause fatty liver, including corticosteroids, tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall).

    Source: http://www.rxlist.com

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