December 21, 2009

Obesity and Liver Disease
By Carolyn Gutierrez
For The Record
Vol. 21 No. 24 P. 24

Some medical experts believe poor dietary habits are playing a significant role in the increase of cases.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have increased dramatically in the United States but remain largely unrecognized as yet another repercussion of obesity, along with cardiovascular disease and diabetes. The rate of obesity among U.S. adults has doubled over the past 10 years; among children, the rate has tripled. According to Jeffrey Browning, MD, an assistant professor in the internal medicine, digestive, and liver diseases department at the University of Texas Southwestern Medical Center, the rate of infection for hepatitis C has relatively leveled off, but due to the obesity epidemic, physicians anticipate that “nonalcoholic fatty liver disease is going to become even more prevalent than it is now.”

In the 1960s, hepatologists became aware of a buildup of triglycerides in the livers of patients who had not been drinking alcohol. In an earlier era, it was assumed that these patients were simply not disclosing their alcohol use. But postwar changes to the American diet brought about by technology, burgeoning fast-food industries, and agribusiness resulted in a marked escalation of liver disease. In the early 1980s, NAFLD became an umbrella term used to differentiate the condition from liver disease brought on by alcohol, although physicians noted that the liver biopsies of those with NAFLD could not be differentiated from those with alcoholic liver disease.

According to Browning, NAFLD “is a spectrum of disorders. On the low end is what we currently think of as the safer end of the spectrum—just a liver that has a lot of fat in it, more so than there should be. On the far end, or the worst end of the spectrum, is what we call nonalcoholic steatohepatitis, which is basically fat in conjunction with inflammation.” Data suggest that approximately 30% of Americans have fatty liver disease and about 3% have NASH, but many liver specialists speculate that the numbers are actually higher. 

NASH is a more dangerous disease than fatty liver alone because the inflammation can build up scar tissue, known as fibrosis, that can lead to cirrhosis. A normal liver can regenerate itself, but with cirrhosis, “there is so much scar tissue that the normal framework is disrupted,” says Browning. “You do have regeneration going on, but it’s not normal, and so there are normal liver cells that are within the liver that can’t do what they’re supposed to do because of all of the scar tissue.” NASH can reverse itself but, when the scarring becomes advanced, it is difficult to halt the disease’s progression. When a patient’s liver becomes cirrhotic, the damage is irreversible and transplantation the only recourse.         

However, not all patients with NASH develop cirrhosis. According to Brent A. Neuschwander-Tetri, MD, an associate professor of internal medicine at St. Louis University School of Medicine, hepatologists “view NASH as the liver disease associated with obesity, and people don’t appreciate how common it really is. We see it in kids as well. And we don’t have good numbers on the prevalence in kids, but we know it’s out there—we see cirrhosis in teenagers from it.”

Even more troubling is the fact that NAFLD in the pediatric population progresses more rapidly than in adults. In fact, its progression is so quick, “you have children that have been obese for the majority of their life that require liver transplantation by the time they hit puberty,” Browning says. “I don’t think we entirely understand what makes fatty liver in children more aggressive than it is in adults.” When evaluating children who are obese, pediatricians are now being urged to include liver enzyme tests along with routine cholesterol screening.        

Neuschwander-Tetri blames the prevalence of NAFLD and NASH on poor dietary habits. “I focus [my patients] on healthy eating, and that’s really all it takes,” he explains. “Healthy eating habits and eliminating a lot of the bad things—the bad things being a high-fat diet, especially trans fats. We feed mice in our laboratory a high-trans fat diet and they get very severe liver disease. We basically feed mice a fast-food diet and they get severe liver disease.”

Another culprit is high-fructose corn syrup. The route to NAFLD and NASH is fairly simple and direct: A person consumes excess sugar, the liver turns that excess sugar into fat, and the fat inevitably accumulates in the liver and causes damage. Eliminating the consumption of sugar-sweetened beverages can make a huge difference. “A 12-oz can of Coke has the equivalent of about 10 sugar cubes, so I ask parents, ‘Would you give your child 10 sugar cubes to eat?’ Of course you wouldn’t,” notes Neuschwander-Tetri. “So why do you give them a can of Coke or Pepsi or Mountain Dew? It’s exactly the same thing.”

Risk Factors                                                              
According to Jose Franco, MD, an associate professor at the Medical College of Wisconsin, obesity is the major risk factor for NAFLD and NASH. As the average body mass index (BMI) has increased among Americans, so has the prevalence of liver disease. Most patients with a BMI greater than 30 have some degree of NAFLD, and with an increase in BMI comes a greater risk of diabetes, the second most common cause of NAFLD, according to Franco. The third risk factor is lipid disorders, triglyceride elevations in particular.

“There are other minor risk factors,” adds Franco, “such as certain forms of viral hepatitis, certain medications—for example, steroids that are used for various inflammatory conditions that can cause fatty liver—and so forth. But the main ones that stand out are obesity, diabetes, and lipid disorders. Fatty liver is, of course, also a risk factor for heart disease. You’re obese, diabetic, have lipid disorders—that’s like a time bomb from a cardiac standpoint. So not only are patients with NASH dying of liver disease, they’re also dying of heart disease.”  

Symptoms and Diagnosis                                    
Most patients with NAFLD are asymptomatic, making it a “silent” disease. However, some patients may develop upper right quadrant pain in the abdomen. “This is more than likely due to the fact that there’s so much fat in the liver, it’s actually distending or stretching the liver itself, which the liver will respond with a pain sensation as a result of that,” explains Browning.

Tests such as the alanine aminotransferase and the aspartate aminotransferase can detect whether a patient’s liver enzymes are elevated, and imaging tests such as ultrasound, CT, and MRI can reveal a fatty liver. However, these tests cannot determine whether there is scarring on the liver; for detecting inflammation and damage in the liver cells, a biopsy is required. In the early stages of NASH, a patient may feel well but, as the disease advances and approaches cirrhosis, fatigue and weakness may become apparent.

Treatment                                                                  
Although the mechanics of the disease are well understood, the FDA has not approved any medications specifically geared toward treating NAFLD or NASH. The key treatment for patients is to reverse the underlying causes of the disease, and for most that means losing weight. “By far, the No. 1 thing that has helped is weight loss,” Franco says. “It’s been shown that if you could lose just 10% of your body weight, that it significantly decreases the inflammation and results in less damage.”

Studies have shown that NAFLD patients who are obese and have undergone gastric bypass or lap-band surgery show a marked decrease in the progression of their liver disease and, in some cases, resolve it completely. “We believe that the fat has to be there for the disease to progress and so if you take the fat away, then you’ve basically reduced the risk of that individual,” Browning says. “In my practice, the mainstay is diet, weight loss, and exercise, which is generally hard for people to stick with.”

One of the main issues of NAFLD is insulin resistance, occurring when “the body makes enough insulin, but the receptors don’t seem to be reacting to it as well as they normally should,” Franco says. “There are medications that we use in diabetic patients that help those receptors sense insulin better. What’s interesting is that in some small studies, when they gave nondiabetic patients diabetes medications, it actually appeared to improve their liver disease, even though they weren’t diabetic. That’s a potential mechanism for future treatments.” In addition to the standard recommendation of weight loss and exercise, medications, including metformin, rosiglitazone, and pioglitazone, are currently being explored as treatment options.

Interestingly, statins, commonly thought to be dangerous to those sensitive to liver disease, may be beneficial for treating NAFLD. “Studies that have been done looking at statin toxicity have actually shown that, if you look at large groups, hundreds of thousands of people started on statins who also have elevated liver enzymes to begin with, on average, their liver enzymes improve on the statin,” Neuschwander-Tetri says. “Our concern about statins [causing harm] is pretty low.”

Although it seems counterintuitive, some liver specialists have been encouraging patients to take statins. “It appears that fatty liver is definitely associated with cardiovascular disease and cardiovascular risk, and it may be an independent risk factor for heart attack, stroke, and other things,” Browning notes. “At least in my practice, it’s very important to put these people on statins as a cardiovascular protective mechanism.”

Currently, transplantation is the only option for patients with advanced liver disease, but scientists are exploring the prospect of using skin cells reprogrammed into pluripotent stem cells that have the ability to develop into actual liver cells.

At the Medical College of Wisconsin, researchers were able to generate patient-specific liver cells in laboratory culture dishes. Although it sounds like the stuff of science fiction, the liver’s unique ability to regenerate lends itself well to these experiments, opening up the possibility that a mere piece of skin from a patient with liver disease could be utilized to generate new liver cells to replace the diseased organ with healthy tissue. Applying these experiments is still some time away but, as Franco notes, “In the future, if we were able to gain the ability to somehow transplant these liver cells—and they’d have to be in significant quantities—into patients with liver disease and get them to replicate and divide, essentially we could save millions of lives every year.”     

One major problem facing liver specialists seeking new therapies is the general lack of randomized, placebo-controlled trials. The studies addressing NAFLD and NASH that exist are extremely small, of a short duration, and are often contradictory. Much of the older data are based on trials in which no biopsies were obtained before and after treatment, limiting their accuracy.         

The overwhelming number of NAFLD and NASH cases shows no signs of slowing down. Hepatologists such as Neuschwander-Tetri wonder whether the obesity crisis is the only explanation. “One of the things with NASH is, we are really seeing an epidemic of this, and we see the epidemic of obesity, but a lot of us feel that there must be something else besides the obesity because a certain amount of obesity has always been there,” he says. “If you go back 40 or 50 years, people weren’t all rail thin, and I think we’re seeing more NASH than we’d expect, just based on obesity—so it does emphasize that there must be something else going on environmentally or dietarily. That’s why I raise the trans fats as a potential issue, and there may be other things as well, but we just don’t know.”

— Carolyn Gutierrez is a freelance writer based in New York City.