It’s estimated that almost 80 million Americans have nonalcoholic fatty liver disease (NAFLD), in which fat accumulates in the liver cells (steatosis).

A small fraction of patients progress to a more serious form of the disease, called nonalcoholic steatohepatitis (NASH), in which inflammation and some cell death occurs, and a minority of patients with NASH progress to liver fibrosis (scarring) and even cirrhosis and liver cancer. NASH ranks as one of the major causes of cirrhosis in the United States, behind hepatitis C and alcoholic liver disease.

DukeMed Magazine talked with two Duke clinician-scientists who study the causes of NAFLD and each day translate what they learn to the patients they treat.

Anna Mae Diehl, MD, is chief of the Division of Gastroenterology and a researcher who conducts animal studies of NAFLD as well as human clinical studies.

Manal F. Abdelmalek, MD, is an associate professor of medicine in the Division of Gastroenterology; she’s an epidemiologist and researcher who conducts clinical trials and studies NAFLD from a public health standpoint.

Which patients are at risk for NAFLD?

Abdelmalek: Patients who have obesity, high cholesterol, insulin resistance, and hypertension should be considered at high risk. Because most patients with NAFLD do not have symptoms until the disease is more advanced, periodic evaluation of liver enzymes in patients at high risk should be considered.

Elevated liver enzymes on routine blood tests can be a sign of NASH if there is no other reason for liver disease, such as viral hepatitis or excessive alcohol use. A “bright” liver on abdominal ultrasound might suggest the presence of a fatty liver.

If my patient has NAFLD that has not yet progressed to NASH, when should I consider referring him to another specialist?

Abdelmalek: The most accurate method to differentiate simple fatty liver from NASH is liver biopsy. Therefore, if there is any suspicion of possible fatty liver disease based on the presence of multiple risk factors, features of fatty liver on an imaging study, or unexplained elevation of liver enzymes, patients may be referred to a specialist for further evaluation, counseling, and possibly staging of underlying liver disease.

Although no pharmacologic therapies are approved for the treatment of NASH, antioxidants such as vitamin E, lifestyle and dietary modification, and medications such as pioglitazone or metformin -- medications typically used to treat risk factors which may contribute to disease progression -- may be warranted.

Patients with more advanced forms of NAFLD would require further care and monitoring for potential complications of cirrhosis. At Duke, we individualize treatment depending on the risk factors that patients have which may contribute to disease and its progression. We also provide follow-up when needed, which may be necessary for patients with NASH and/or advanced fibrosis or cirrhosis from NAFLD.

We will also determine those patients who have steatohepatitis [NASH] and who may be considered for treatment studies.

Are there specific dietary interventions that can help?

Abdelmalek: In addition to treatment of risk factors such as high cholesterol and diabetes, we have learned that diet matters.

We have recently reported that increased consumption of fructose is a risk factor for fatty liver, independent of obesity. In that study, patients who had fatty liver disease were more likely to consume high levels of fructose compared to patients of the same age, gender, and body mass index who didn’t have fatty liver disease.

In a different study, published in June 2010 in Hepatology, we found that among patients with fatty liver, those who consumed the most fructose were more likely to have advanced disease. In that study, we evaluated a very large cohort of patients from the NASH Clinical Research Network, and we found that the more fructose that patients with fatty liver disease consumed, the higher their risk of liver inflammation, swollen liver cells (also called ballooned cells), and even fibrosis, despite controlling for other factors that may contribute to those outcomes.

This was a very interesting discovery because up until that study, we hadn’t been able to tell patients what dietary factors may contribute to NAFLD or disease progression in those with NAFLD. With more confidence, we can now inform patients with fatty liver disease to follow a diet low in refined sugars, avoid extra sugar, and to be careful about fructose, particularly in the form of high-fructose corn syrup, such as in sodas and fruit drinks. I advise them to start reading food packages and labels.

What are the best options for medical management of NASH?

Diehl: Lifestyle modifications (diet and exercise) remain the mainstay of treatment for NAFLD. Studies are being done to identify drugs that help to reduce liver damage and prevent disease progression in NAFLD.

The first multicenter, prospective controlled clinical trial comparing two treatments -- vitamin E and the insulin-sensitizing medication pioglitazone -- to placebo was published May 2010 in the New England Journal of Medicine. Duke enrolled many patients in that trial as part of an NIH-supported consortium called the NASH Clinical Research Network.

In non-diabetic patients who had had a liver biopsy that showed NASH, both treatments were found to be effective: 18 months of treatment with either vitamin E or pioglitazone improved the histologic features of NASH (fatty cells in the liver and inflammation and swelling of liver cells).

As a result of this recent study, therefore, we now have two potential treatments for NASH in non-diabetic patients. More studies are planned to identify agents that will help NASH patients who do not improve with pioglitazone or vitamin E treatment, and to determine the best treatments for NASH patients who also have diabetes. The latter trials will be particularly important because it appears that diabetic patients with NASH are likely to develop cirrhosis.

Why do some patients with fatty liver disease get cirrhosis while others don’t?

Diehl: From our research at Duke in animal models and in people, we find that some people tolerate fat accumulation in the liver without activating signaling pathways that lead to serious injury. Hence, they stay at early disease.

Other people, for reasons that we don’t understand (some may be genetic, some may be environmental) go down a path that’s going to lead them to cirrhosis and liver cancer. We’re trying to understand why some people go one way and some people go the other.

Ultimately, as we learn more about the mechanisms that cause progression to more serious disease, we aim to not only develop therapeutics, but also blood tests to identify who’s at risk of progressing to more advanced stages of NAFLD. The latter will enable us to focus our attention on those patients who are at greatest need for treatment.

We have made progress in identifying proteins and pathways that play a role when patients develop the most serious forms of NAFLD. One of those is the Hedgehog signaling pathway, which is known to provide cells with information that is used to repair tissues, and which has been implicated in some cancers.

Hedgehog had never been identified before as playing a role in NAFLD, but we found that its activity correlates with NAFLD progression in animals and in people [published July 2009, Gastroenterology]. Now we’ve shown that manipulating the Hedgehog pathway in animals actually modifies disease progression in NAFLD. That’s exciting because some companies have already developed Hedgehog inhibitor drugs for use in other diseases. This is a totally new treatment area for NASH that hasn’t been explored before. Right now, it’s still at the pre-clinical stage, however.

We have also learned more about how the Hedgehog pathway works and interacts with other molecules. For instance, we have found that the Hedgehog pathway stimulates immune cells and certain types of liver cells to produce a molecule called osteopontin.

Other researchers at Duke in the Department of Surgery (Drs. Bruce Sullenger and Paul Kuo) have developed agents that block the actions of osteopontin. Using their agents in our animal models of NASH, we showed that inhibiting osteopontin blocked fibrogenesis [production of scar tissue in the liver].

Then we examined liver tissue samples that we have collected from our patients at Duke who have NAFLD. We found that osteopontin is turned on in NASH, and it’s at higher levels in people who have fibrosis than in people who don’t [published in the September 2010 Hepatology].

So, osteopontin may be a serum biomarker that helps us to recognize which NAFLD patients have more advanced liver disease. In addition, osteopontin might be another new therapeutic target in NASH. Studies are being planned to evaluate the safety and efficacy of osteopontin blockers in patients with NASH.

Duke Tissue Repository

Duke has created its own nonalcoholic fatty liver disease database and tissue repository with more than 1,200 patients currently enrolled. Participants donate small blood and tissue samples that Duke scientists use to develop new diagnostic tests and treatments for the disease.

Trials Currently Recruiting at Duke

A center of excellence in NAFLD, Duke offers patients comprehensive medical evaluations and management plans, as well as access to clinical trials of new treatments.

Duke is one of only eight clinical centers in the NASH Clinical Research Network, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Clinical studies focus on prevention and treatment of NASH.

Current trials include:

• A single-center trial to find out if the diabetes medication metformin in combination with vitamin E can improve NASH in non-diabetic patients.
• A multicenter trial evaluating the role of a highly refined fish oil for treatment of NASH in diabetic and non-diabetic patients.

Additional diagnostic and treatment studies will be open for enrollment in early 2011.

For enrollment information, visit ClinicalTrials.gov.