Diseases

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.

As previously discussed, 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.

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.

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:

• Excessive bleeding due to the inability of the liver to make blood-clotting proteins
• Jaundice due to the inability of the liver to eliminate bilirubin from the blood
• Gastrointestinal bleeding due to portal hypertension that increases the pressure in intestinal blood vessels
• Fluid accumulation due to portal hypertension that causes fluid to leak from blood vessels and the inability of the liver to make the major blood protein, albumin
• Mental changes (encephalopathy) due to the liver's inability to eliminate chemicals from the body that are toxic to the brain. Coma may occur.
• Liver cancer

What is the difference between nonalcoholic fatty liver and steatohepatitis (NASH)?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.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 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.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).

Nonalcoholic fatty liver disease 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.

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.What are the other causes of fatty liver?There are several identifiable causes of fatty liver that are not nonalcoholic fatty liver disease 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).

Several drugs also cause fatty liver, including

• corticosteroids,
• tamoxifen (Nolvadex), and
• methotrexate (Rheumatrex, Trexall).

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 ovaries, 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.

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.Why is nonalcoholic fatty liver disease important?Nonalcoholic fatty liver disease 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, 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 diseases which need to be addressed.

As mentioned previously, 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.

Treatment for nonalcoholic fatty liver disease includes

• lifestyle changes (exercise, weight loss, diet),
• medications,
• supplements (antioxidants),
• omega-3 fatty acids,
• surgery, and
• liver transplantation.