NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND NONALCOHOLIC STEATOHEPATITIS (NASH)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States.  It consists of two stages – a fatty liver and NASH (nonalcoholic steatohepatitis). The only way to distinguish between these two stages is by looking at a sample of liver tissue under a microscope after a liver biopsy has been performed.  The medical term for a fatty liver is hepatic (liver) steatosis (fat). A fatty liver is considered a benign (harmless) condition characterized by fat deposits in liver cells (hepatocytes). This is a reversible condition, and does not have the potential to lead to cirrhosis, liver failure or liver cancer.  NASH is when a fatty liver has progressed to something worse ---namely inflammation (steatohepatitis) and scarring (steatonecrosis) of the liver.      Unlike a fatty liver, NASH is not considered a harmless condition, but rather a liver disease with the potential to cause cirrhosis, liver failure, and liver cancer.

     The reason that NAFLD is prefaced by the word “nonalcoholic” is because the results of liver biopsies from people with NAFLD are frequently identical to those from people with alcoholic liver disease. Yet people with NAFLD do not have a history of excessive alcohol use. Excessive use is commonly defined as greater than 80 grams per day for men and greater than 20 grams per day for women. (See Chapter 17 for more information about alcohol and the liver.)

    So, what causes NAFLD?  Well, medical authorities currently believe that most cases of NAFLD are caused by a condition known as insulin resistance.  But, more about this later in the chapter. What types of people are most at risk for getting NAFLD?  People with type 2 diabetes (adult onset diabetes), obese people and people with hypertriglyceridemia (high level of fats {triglycerides}) in the blood) are at risk for getting NAFLD. What role do weight and diet play in NAFLD?  Weight and diet play an important role in NAFLD.  Excessive weight greatly increases the likelihood of someone getting NAFLD.  Ditto for an unhealthy diet, especially one which is high in fats and sugars. Does lifestyle also play a role? Yes, a sedentary lifestyle will probably increase one’s chance of getting NAFLD.  Contrarily, regular exercise may reduce ones chances of getting NAFLD.

INSULIN RESISTANCE AND NAFLD

Emerging trends in the study of NAFLD have supported the concept that most people who develop NAFLD have an insulin resistance. As such, in order to understand NAFLD, you will need to become familiar with the concept of insulin resistance. Insulin is an important hormone, and is made by the pancreas.  Insulin is released into the bloodstream in response to elevated glucose (blood sugar) levels which occurs for example, after eating a meal.  Insulin keeps the glucose levels from becoming too elevated. To do this, insulin pushes glucose out of the bloodstream and into the cells of the body. The cells that are mainly involved with insulin are the fat cells, the muscle cells, and the liver cells (hepatocytes). When these cells receive glucose, it enables them to convert it to energy. When glucose is not metabolized properly, ( when the cells are insulin-resistant), energy production is diminished resulting in fatigue.

     On the surface of the cells are little doors known medically as “insulin receptors”.  These doors (receptors) regulate the entrance of glucose into cells by opening and closing.  People who are insulin-resistant cannot utilize insulin efficiently.  As such, they have poorly functioning cell doors- some of which open sluggishly and some of which do not open at all. With less doors open, glucose is unable to enter the cells and therefore accumulates in the blood. In order to try to clear excess glucose from the blood, the body signals the pancreas to produce additional insulin. This results in an overabundance of insulin in the blood, a condition referred to as hyperinsulinemia. By a complex mechanism, high levels of insulin in the blood also cause high levels of fatty acids -in the form of triglycerides (hypertriglyceridemia), to accumulate in the blood.  This in turn causes fatty acids to be deposited in the liver. The result of all of these events—NAFLD! Approximately 10-25 percent of the population is insulin- resistant, and almost all people with NAFLD are insulin-resistant. However, it is believed that only a small percentage of people who are insulin-resistant have NAFLD.

     People who are overweight are more likely show signs of insulin resistance than people who are of normal weight.  But keep in mind that a sedentary lifestyle and a diet rich in sugars and fat may promote insulin resistance --even among people who are not overweight.  Thus, NAFLD can occur even in people of normal body weight. In fact, it is thought that most people with NAFLD have insulin resistance independent of weight.

     In extreme cases of insulin resistance, a medical condition of glucose overload, known as diabetes mellitus, develops. It has been found that approximately 70 percent of diabetic people have some form of NAFLD, and that approximately 5 to 20 percent of people with diabetes have cirrhosis due to NASH. In fact, diabetes in itself is believed to be a risk factor for development of cirrhosis. 

WHAT IS THE “METABOLIC SYNDROME”?

The combination of the findings of obesity, hyperinsulinemia, insulin resistance, diabetes, hypertriglyceridemia, and hypertension has been referred to as a “metabolic syndrome’ or “syndrome X”. Recent research has determined that people with syndrome X also have a liver disease. NAFLD appears to be the liver component of this syndrome. In fact, people with syndrome X often have more advanced forms of NAFLD – i.e. fibrosis or cirrhosis.

TREATMENT OF NAFLD

The following section discusses the treatments for NAFLD.  It should be noted that there is no specific therapy for NAFLD that has clearly been proven effective.  Treatment has focused on weight reduction and liver-protective (hepatoprotective) medications. As with all liver diseases, avoidance of alcohol, before, during, and after treatment, is essential. This is especially true for people with NAFLD, as alcohol may worsen the severity of fat deposits, fatty inflammation, and fatty scarring in the liver.

Weight Management

Overweight or obese people with NAFLD can usually normalize the elevations in liver enzymes, decrease some of the enlargement of their livers, and diminish the amount of fat in their livers merely through weight reduction. A weight loss of approximately 10 percent can significantly correct these abnormalities. If weight reduction is achieved early in the disease, progression to scarring and cirrhosis can possibly be prevented altogether. In fact, in one study, weight reduction actually reversed some scarring (fibrosis, not cirrhosis).

     Three points need to be emphasized concerning weight reduction. First, weight loss must be sustained, or the disease will recur. Second, weight reduction must be achieved through reasonable methods, and it must occur at a slow pace. This means that people should aim for a 1-2 pound weight loss per week. Excessively rapid weight reduction or starvation techniques can actually worsen or even precipitate progression to cirrhosis and liver failure. Obviously, this is at odds with the purpose of the weight reduction. Furthermore, rapid weight loss has been shown to put people at risk for gallstone disease.  In addition, it can adversely affect a person’s overall health. Finally, an exercise routine must be incorporated into any weight-reduction routine.

     There are numerous weight- loss diets on the market. However, their effects on NAFLD are unknown. Any diet should be evaluated by a knowledgeable hepatologist as to its likely effectiveness as a tool against NAFLD. In general, a diet low in saturated fat, low in simple carbohydrates, and high in fiber should be used. This type of diet may improve insulin resistance. Supplementation with polyunsaturated fatty acids has also been shown to improve insulin resistance, in addition to decreasing the risk for coronary artery disease. However, the effect of this type of supplementation on NAFLD needs to be studied.

     Weight reduction is particularly important for those overweight people who have both NAFLD  and an additional liver disease—for example, hepatitis C. In these people, a 10-percent weight loss will also lower elevated liver enzymes although liver enzymes, may not revert to totally normal levels. It has been shown that people with chronic hepatitis C who also have excessive fat deposits (seen most commonly among people with genotype 3) are especially likely to experience a quick progression to cirrhosis.

Treatment of NAFLD With Medications or Supplements

Many medications are presently being evaluated for people with NAFLD. The most promising one appears to be ursodeoxycholic acid (UDCA). UDCA, also known by the brand names Actigall, URSO, and Ursodiol, is a naturally occurring bile acid, that, unlike many other bile acids in the body, is not toxic to the liver. It is found in a small quantity in the human body, but in a large quantity in a bear’s body. UDCA was initially used to dissolve gallstones, but is now commonly used to treat many different liver diseases, specifically primary biliary cirrhosis (see Chapter 15 of my book or discussion of URSO on this website). Initial studies involving people with NASH have shown that treatment with UDCA can lead to improvements in liver enzymes and to a reduction in the severity of fatty deposits in the liver. UDCA may possibly decrease the risk of developing gallstones during weight reduction. Further studies are ongoing as to the effects of UDCA on NAFLD.

     Metformin (Glucophage) and rosiglitazone (Avandia) are oral glucose-lowering (also known as hypoglycemic) medications used to treat type II diabetes.  These medications work by correcting insulin resistance.  Therefore, these types of drugs may potentially benefit people with NAFLD and insulin resistance. In fact, preliminary studies have shown that treatment with metformin can improve liver enzyme elevations in people with NAFLD.  However, improvement in the amount of fat and inflammation in the liver have thus far been established only in studies involving animals. Studies on humans will be required before these medications can be recommended  for people with NAFLD.

     Clofibrate, a triglyceride-lowering drug, has been tested as a treatment but has not shown to be beneficial. Gemfibrozil, another triglyceride-lowering medication was able to improve liver enzyme elevations in a small group of people with NAFLD, but its effects on liver fat and scarring was not tested.  Further study is needed on gemfibrozil. Polymixin B is an antibiotic that can reduce the amount of bacteria in the intestines. This medication may be characterized as a form of “bowel decontaminate.” Studies have shown that administering polymixin B to people on intravenous feedings (total parenteral nutrition (TPN)) can reduce the amount of fat in their livers. This treatment option needs further study before definite conclusions can be drawn about its effectiveness in treating people with NAFLD.

     Betaine is a precursor of S-adenosyl methionine (SAMe), a derivative of the amino acid methionine.  S-AMe is purported to promote the health of the liver.  In two studies, some patients who were treated with betaine experienced decreased liver enzyme elevations and a decreased  amount of fatty deposits in their livers.  The mechanism by which betaine exerts its beneficial effect on the liver, is not clear, but it is believed that it may assist in transporting fat away from the liver. More research is needed in this area.

      Certain nutritional deficiencies which are common among  people with NAFLD may provide a clue in the search for a successful treatment. Some people who receive intravenous feedings for prolonged periods of time develop fatty liver in addition to a choline deficiency. (Choline is a B vitamin.) Correcting the choline deficiency in these people has been shown to resolve the fatty liver as well. Choline supplementation in people with NAFLD is a promising treatment option, but is one which requires further study. Coenzyme A is a substance that is essential for the metabolism of carbohydrates, fats, and certain amino acids. It contains pantothenic acid, a B vitamin which is necessary for growth.  In some studies, people with NAFLD were supplemented with a form of coenzyme A, and this caused the extent of fat deposits in the liver to decrease. More research must be done to confirm the efficacy of this type of nutritional supplementation.

One preliminary study has indicated that vitamin E (alpha-tocopherol) supplementation may be a beneficial adjunctive treatment for people with NAFLD, but more research is needed in this area.  Biotin, a B vitamin has been shown to decrease insulin resistance.  Studies on people with NAFLD have not been conducted at this time, but biotin supplementation would be an interesting area of exploration for people with NAFLD.

All contents of this article are Copyright © Melissa Palmer, MD

Melissa Palmer, MD is the author of " Dr. Melissa Palmer's Guide of Hepatitis and Liver Disease". (Published 2004. Penguin Putnam).

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