RESEARCH UPDATE

Non-Alcoholic Fatty Liver Disease (NAFLD)
Fat accumulation in the liver was recently recognized as the most common cause of chronic liver disease in the United States. The technical term, non-alcoholic fatty liver disease (NAFLD), refers to the replacement of more than 10% of the liver by fat. Some people with NAFLD get inflammation and scarring of the liver that is called non-alcoholic steatohepatitis (NASH). Patients with NASH can develop advanced scarring called cirrhosis and then are at risk for developing liver cancer and liver failure.

Intake of less than 1-2 drinks per day is contained in the definition of NAFLD, because excessive alcohol intake can also cause fat, inflammation and scarring in the liver. In the past, some people with NASH were accused of being alcoholics even though they did not drink alcohol, because the changes of NASH and alcoholic hepatitis tend to be indistinguishable on liver biopsy.

A liver biopsy from a patient with NASH is shown (upper left). Liver cells are stained pink. The clear spaces represent fat and inflammatory cells are blue.

What Causes NAFLD?
The most common factors associated with NAFLD include:

- Obesity
- Diabetes
- High triglycerides (fat droplets in the blood)

The high prevalence of NAFLD is related to the epidemic of obesity in this country. Obesity is defined by the body mass index (BMI), which is calculated as weight in kilograms divided by height in meters squared. A BMI > 25 is considered overweight and obesity is defined as a BMI >30. A recent survey found that 20% of the US population is obese and more than one half of Americans are overweight. Obesity in adults increased 60% from 1991 to 2000 and is rising dramatically in children as well.

People with adult onset diabetes and obesity have high blood sugar levels because their muscles and other tissues do not take up glucose in response to insulin. Resistance to insulin causes increased delivery of fat to the liver, increased production of fatty acids in the liver, and fat accumulation. High triglyceride levels are also associated with fatty liver disease.

NAFLD can develop in a number of other conditions. These include intravenous feeding with total parenteral nutrition, rapid weight loss or starvation, surgical removal of a large amount of the small intestine, and medications such as estrogens, tamoxifen, and amiodarone.

Fat accumulation in the liver is necessary, but not sufficient for the development of inflammation and scarring (NASH). There is intense interest in determining why some people with fat in the liver develop progressive liver disease. Metabolic pathways that are activated in the liver in patients with NASH produce oxygen species that can cause tissue damage. Certain chemical messengers called cytokines also appear to play a role in the development of inflammation and scarring in NASH.

Current treatment options for NAFLD are limited. The first step is to address any underlying causes that can be identified and to discontinue medications that cause fatty liver. In obese individuals, gradual, sustained weight loss of 10% of body weight can be beneficial. However, rapid weight loss can worsen the condition. When present, treatment of diabetes and high triglyceride levels should be optimized. Medications used to treat diabetes including pioglitazone and metformin are under study as potential therapies for NASH.

In the Department of Medicine, we are studying a number of aspects of NAFLD. We are working to develop noninvasive ways to measure fat in the liver that does not require a liver biopsy. We are examining the mechanisms that lead to liver damage in NASH. We are also studying new therapies for NASH. We hope that our research efforts will lead to a better understanding of, and better treatment for the most common cause of liver disease in the United States.