Jay W. Marks, MD, is a board-certified internist and gastroenterologist. He graduated from Yale University School of Medicine and trained in internal medicine and gastroenterology at UCLA/Cedars-Sinai Medical Center in Los Angeles.
Nonalcoholic fatty liver disease (non-alcoholic fatty liver disease, NAFLD) is the accumulation of abnormal amounts of fat within the liver. Nonalcoholic fatty liver disease can be divided into isolated fatty liver in which there is only accumulation of fat, and nonalcoholic steatohepatitis (NASH) in which there is fat, inflammation, 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. The development of nonalcoholic fatty liver disease is intimately associated with and is probably caused by obesity and diabetes. Nonalcoholic fatty liver disease is considered a manifestation of the metabolic syndrome.
The symptoms of nonalcoholic fatty liver disease are primarily those of the complications of cirrhosis in patients with NASH; isolated fatty liver infrequently causes symptoms and usually is discovered incidentally. The complications of cirrhosis include gastrointestinal (GI) bleeding, mental changes (encephalopathy), accumulation of fluid (ascites, edema) and, liver cancer.
Usually, to differentiate isolated fatty liver from NASH requires a liver biopsy The most promising treatments for nonalcoholic fatty liver disease are diet, exercise, weight loss, and possibly bariatric surgery. 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. Isolated fatty liver rarely progresses to NASH or cirrhosis. Nonalcoholic fatty liver disease, including NASH affects young children as well. NASH will become the number one reason for liver transplantation unless effective and safe treatments are found.
Classic symptoms of liver disease include:
Fatigue, weakness and weight loss may also occur.
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 (nonalcoholic fatty liver disease), in which alcohol has been excluded as a cause. In nonalcoholic fatty liver disease, other recognized causes of fatty liver that are less common causes than alcohol also are excluded.
Nonalcoholic fatty liver disease 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 nonalcoholic fatty liver disease, 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.
Nonalcoholic fatty liver disease 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.
Fatty liver disease rarely causes symptoms until the liver disease is far advanced. Fatty liver usually is found or suspected when abnormal liver tests are found on routine blood testing, fat is seen ultrasonographically when ultrasonography of the abdomen is performed for other reasons, for example, the diagnosis of gallstones, infrequently when the liver is enlarged on physical examination of a patient.
When the liver disease is far advanced (cirrhosis), signs and symptoms of cirrhosis predominate. These include:
The cause of nonalcoholic fatty liver disease 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.
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 nonalcoholic fatty liver disease, more than two thirds of people with diabetes develop nonalcoholic fatty liver disease. Among patients who are very obese and undergoing surgery for their obesity, the majority have nonalcoholic fatty liver disease. 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.
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 density lipoprotein (LDL or “bad” cholesterol) and high density lipoprotein (HDL) cholesterol, high blood pressure, andelevated blood sugar (diabetes).
Nonalcoholic fatty liver disease is considered a manifestation of metabolic syndrome and thus occurs frequently with the other manifestations of the syndrome. Occasionally, it may occur without the other abnormalities of the syndrome.
Several identifiable causes of fatty liver that are not nonalcoholic fatty liver disease so often causes confusion. The most common causes of nonalcoholic fatty liver disease are excessive alcohol consumption and hepatitis C. Other causes of non alcoholic fatty liver disease include Wilson's disease, ipodystrophy (a disease of fat storage), starvation, intravenous nutrition, and abetalipoproteinemia (a disease of fat transport).
Several drugs also cause nonalcoholic fatty liver disease, for example corticosteroids, tamoxifen (Nolvadex), and methotrexate (Rheumatrex, Trexall).
Since the current epidemic of obesity begins in childhood, it is not surprising to find that nonalcoholic fatty liver disease occurs in children. Only a few studies are available, but the estimated prevalence among children 2-19 years of age is approximately 10%, the prevalence increases with the degree of obesity, and there is progression to cirrhosis. Although there is concern about nonalcoholic fatty liver disease among children, there is not enough evidence of benefit of treatment, and, therefore, no general recommendation has been made to screen overweight and obese children for nonalcoholic fatty liver disease. It is recommended, however, that children with suspected nonalcoholic fatty liver disease in whom the diagnosis is not clear should have a liver biopsy. Children should not be started on any drug treatment for nonalcoholic fatty liver disease without a biopsy showing NASH. Although there have not been studies in children to support the recommendations, loss of weight and exercise are the recommended treatment for children with nonalcoholic fatty liver disease.
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Nonalcoholic fatty liver disease is important for several reasons,
it is a common disease, and is increasing in prevalence, NASH is an important cause of serious liver disease, leading to cirrhosis and the complications of cirrhosis - liver failure, gastrointestinal bleeding, and liver cancer. Nonalcoholic fatty liver disease 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 medical conditions, which need to be addressed.
Fatty liver generally does not cause symptoms or signs, and any symptoms and signs 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 nonalcoholic fatty liver disease is diagnosed is by imaging studies like ultrasonography, computerized tomography (CT), and magnetic resonance imaging (MRI); that are obtained for reasons other than diagnosing nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease 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.
Treatment for nonalcoholic fatty liver disease includes lifestyle changes (exercise, weight loss, diet), medications, supplements and antioxidantsOmega-3 fatty acids, surgery, and liver transplantation.
Nonalcoholic fatty liver disease 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 nonalcoholic fatty liver disease 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 nonalcoholic fatty liver disease. Although there is no reason to think that this deficiency contributes to nonalcoholic fatty liver disease, it is reasonable to measure vitamin D levels in patients with nonalcoholic fatty liver disease 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 for men, one or fewer for women) on nonalcoholic fatty liver disease though there also is no evidence that it is safe. Everyone, including individuals with nonalcoholic fatty liver disease should avoid drinking large amounts of alcohol.
Since the serious complications of nonalcoholic fatty liver disease 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 nonalcoholic fatty liver disease. 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 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, now, the best theoretical approach to nonalcoholic fatty liver disease is weight loss and vigorous exercise. Unfortunately, only a minority of patients are able to accomplish these.
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 nonalcoholic fatty liver disease as well as the metabolic syndrome. It has been studied but, unfortunately, has not been found clearly 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.
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.
Pentoxifylline (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.
Small studies have shown some benefit with omega-3-fatty acids in reducing liver fat in nonalcoholic fatty liver disease, and larger studies are underway. In large groups of individuals (not selected because of the presence or absence of nonalcoholic fatty liver disease), 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 nonalcoholic fatty liver disease and the metabolic syndrome because these patients have a high incidence of cardiovascular disease and death.
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 nonalcoholic fatty liver disease, there is not enough experience to recommend them in patients with nonalcoholic fatty liver disease unless they are primarily being used for treating abnormal blood lipids.
Ursodeoxycholic acid (Ursodiol) has been studied in nonalcoholic fatty liver disease but has been abandoned because of its ineffectiveness and concerns about toxicity at very high doses.
Bariatric surgery is surgery of the gastrointestinal tract that results in loss of weight, and there are several different types of bariatric surgery. Since obesity is believed to be an important factor in the causation of nonalcoholic fatty liver disease and loss of weight has been shown to have beneficial effects on nonalcoholic fatty liver disease, it is not surprising that bariatric surgery has been considered as a potential treatment for nonalcoholic fatty liver disease. Only one study has reported the effects of bariatric surgery on nonalcoholic fatty liver disease and has demonstrated that fat and inflammation decrease, and progression from mild fibrosis to more severe fibrosis is arrested. (Patients with more severe fibrosis were not studied and, therefore it is not known if the progression from more severe fibrosis also is arrested.) Nevertheless, because appropriate studies to determine both the benefits and risks of bariatric surgery have not been done, it is recommended that bariatric surgery should not be used as a treatment for NASH. Instead, patients should be selected for surgery irrespective of the presence or absence of NASH.
Once a liver has become cirrhotic and complications have developed, the options for treatment are either treating the complications as they arise or to replace the diseased liver with a transplanted liver. In fact, NASH has become the third most common cause of transplanting livers, only surpassed by alcoholic liver disease and hepatitis C, but it is expected to climb to the number one position due to the epidemic of obesity and diabetes that is occurring in the U.S. Unfortunately, NASH recurs frequently in the transplanted liver and then progresses to cirrhosis, presumably because the underlying causes - obesity and diabetes continue.
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.
The diseases of the metabolic syndrome that are associated with nonalcoholic fatty liver disease have already been discussed. Other associations exist including fatty pancreas, hypothyroidism, colon polyps, elevated blood uric acid, vitamin D deficiency, polycystic ovary disease (PCOD), and obstructive sleep apnea.
For example, half of patients with nonalcoholic fatty liver disease have obstructive sleep apnea, and most patients with obstructive sleep apnea have nonalcoholic fatty liver disease. Associations do not prove causation, and in most cases, it is not clear why the associations exist--whether the associations are due to a causal relationship or they reflect an underlying common cause.
Cardiovascular disease, especially heart attacks and strokes, is commonly seen in patients with fatty liver. In fact, cardiovascular causes of death occur more frequently than liver-related deaths. Whereas the components of the metabolic syndrome are risk factors for cardiovascular disease, nonalcoholic fatty liver disease has been found to be a risk factor that is independent of the metabolic syndrome, increasing the risk two-fold. Since the means of treating nonalcoholic fatty liver disease are limited, it is important that the manifestations of the metabolic syndrome - obesity, diabetes, high blood pressure, dyslipidemia (abnormalities of fats or lipids in the blood) be aggressively treated.
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 nonalcoholic fatty liver disease 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.
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