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Cedars-Sinai

The Worst Disease You’ve Never Heard Of

It often appears without symptoms and is frequently misdiagnosed. It affects nearly a third of all adults and can quietly progress to a life-threatening state. Nonalcoholic fatty liver disease is on the rise.

Photo: Ann Cutting

Stepping off the treadmill, Jim Trevino looks lean and fit. A wide, generous smile flashes from underneath his grey-flecked mustache. Over the past year, Jim has worked hard to get healthy, adopting a strict workout regimen of weight training three times a week and an hour on the treadmill every morning. Though he admits it was tough at first, his persistence has paid off — not only has he dropped 34 pounds but he also now looks forward to his exercise routine. And while he used to be a weekend beer drinker, a diabetes diagnosis 14 years ago turned him into a teetotaler. “I stopped the day they told me I had diabetes and had to straighten up,” he says.

At 57 and recently retired, Jim cherishes his “leisure” lifestyle in Palmdale, California, where he resides with his wife, Linda, a water conservationist. But last year, the endocrinologist he regularly sees for his diabetes detected a rise in his liver enzymes and referred him to a hepatologist. Jim soon learned he has advanced liver disease. Though he is asymptomatic and feels healthy, his diagnosis was “nonalcoholic fatty liver disease,” a wordy moniker for a potentially fatal condition that wreaks as much damage to his liver as would a bottle of vodka a day.

Nonalcoholic fatty liver disease is on the rise nationally and globally. It affects some 80 million to 100 million Americans, according to the National Institute of Diabetes and Digestive and Kidney Diseases. About 16 million of these have more advanced inflammation and NASH — nonalcoholic steatohepatitis — a more aggressive form of the condition, often called a “silent killer” because it causes liver scarring and inflammation and can develop into cirrhosis. Between 10 and 20 percent of these cases will develop into liver cancer. Like Jim, most of those affected consume very little alcohol or don’t drink at all. Many are non-obese. Some are even famous: Singer George Michael’s untimely death was, in part, related to fatty liver.

While researchers believe the epidemic is driven by skyrocketing rates of obesity, diabetes, and high cholesterol, an absence of treatments other than exercise and weight control make the rise of the fatty liver tantamount to a public health powder keg.

“Nonalcoholic fatty liver disease is predicted to eclipse hepatitis C as the leading cause of liver transplants by 2020, but I expect it may happen before then,” says Andrew Klein, MD, director of the Comprehensive Transplant Center at Cedars-Sinai and the Esther and Mark Shulman Chair in Surgery and Transplantation Medicine.

Though medical centers around the country are beginning to address the looming crisis, Cedars-Sinai’s Fatty Liver Disease Program is on the forefront, tackling it through a combination of research to uncover the underlying mechanisms of the disease, clinical trials to test potential new therapies, advanced imaging techniques for diagnosis, and lifestyle treatments for patients with an early-stage fatty liver.

Characterized by accumulated fat in the liver, the condition ranges in severity from a small and relatively benign amount of liver fat to the more serious scarring and inflammation of NASH, the permanent damage of cirrhosis, and then, finally, end-stage liver disease — requiring a transplant — or possibly even liver cancer. Jim is in the NASH/cirrhotic stage, with inflammation and scarring called fibrosis. Investigators now believe that nonalcoholic fatty liver disease runs in families but often goes undetected for many years in nondrinkers. Looking back, Jim believes that his mother, who died at 59, had it.

“I think my mom probably had cirrhosis,” Jim says. “She was a nondrinker. I know in my heart it was fatty liver.”

“More organ donors have fatty liver disease and so we’re seeing a lesser quality of donor livers. But we’re also going to see an increased need for transplants.” — Nicholas N. Nissen, MD

Alarmingly, even an annual checkup may not yield a diagnosis unless a physician detects rising liver enzyme levels, which may be the tip-off that leads to further testing. Because of the disease’s stealthiness, it often can go undetected for years. Though it occurs in every age group, fatty liver typically shows up in people in their 40s and 50s, and researchers are beginning to document its prevalence among certain ethnic groups.

At Cedars-Sinai, Jim is enrolled in a double-blind trial of an investigational drug that targets fibrosis. It is one of six clinical trials now in progress under the supervision of Mazen Noureddin, MD, director of Cedars-Sinai’s Fatty Liver Disease Program, who was lured away from USC a year and a half ago to continue his research under his mentor, Shelly Lu, MD, director of Digestive and Liver Diseases at Cedars-Sinai and the Women’s Guild Chair in Gastroenterology.

“There used to be very little hope for these patients with advanced fatty liver disease,” says Lu, whose National Institutes of Health-funded research focuses on how a particular molecule impacts the development of liver disease. “But there is emerging evidence that fibrosis and even cirrhosis can be reversed. In the next two to three years, we should see something reach fruition.”

In addition to the drug trials, Noureddin hopes to launch a clinical trial of S-adenosylmethionine (SAM-e), which has been used in a number of foreign countries to treat liver disease. SAM-e is found in the body but deficient or absent in people with the condition.

“SAM-e may be groundbreaking,” Noureddin says. “It’s been around for many years, but animal data from trials show it can reverse liver disease. My goal is to one day help patients avoid transplants and even cure the disease.”

Meanwhile, to aid in diagnosis and evaluation, state-of-the- art imaging technologies make it possible for the first time to noninvasively measure levels of liver scarring and fat. They help cut down the number of biopsies performed to assess the extent of damage in patients in the Fatty Liver Disease Program.

“Biopsy has always been the gold standard, but it’s invasive,” Noureddin says. “We’re also trying to come up with a blood test that differentiates stages of the disease. With these imaging techniques, and by taking a blood sample back to the lab, we can study the physiology of the disease and try to find the predisposition in some individuals. We take a precision approach to find the specific physiology and target treatment to the individual.”

That entails working in concert with Cedars-Sinai’s Liver Transplant Program. According to Nicholas N. Nissen, MD, director of Liver Transplant and Hepato-Pancreato-Biliary Surgery, the statistics on fatty liver impact both ends of the transplant equation — donors as well as recipients.

“We look at the numbers, and they’re staggering. More and more organ donors have fatty liver disease and so we’re seeing a lesser quality of livers,” says Nissen, whose team performs about 80 transplants each year. “But we’re also going to see an increased need for transplants due to that same disease.”

A shortage of organs results in the use of more marginal livers that may contain higher levels of fat. To counter this, experts at Cedars-Sinai are investigating techniques for rejuvenating imperfect donor livers so they can be used for transplantation.

“It’s experimental but already being studied in Europe,” Nissen says. “A liver has the ability to recover and regenerate. It’s an interesting way to approach the problem and take a liver that might otherwise be discarded and bring it back to life, so to speak.”

In part, this reflects a growing awareness of — and concern for — the magnitude and potential impact of nonalcoholic fatty liver disease. It has led to recognition that what physicians historically labeled “unexplained liver failure” in patients who were not drinkers but presented with advanced liver disease may, in fact, have been this quiet affliction. In part, Noureddin’s life’s work stems from curiosity about his own grandmother’s premature death, which he now believes may have been the result of undiagnosed liver disease.

For now, Jim doesn’t require a transplant. He works hard to stay in shape and maintain good health, ever hopeful that his NASH will be kept in check. After 33 years working for Southern California Gas Company, the retiree appreciates not having to drive 160 miles round-trip each day to his job. Instead, he drives to Cedars-Sinai twice a month for the clinical trial in which 66 percent of participants are infused with GR-MD-02 — an experimental drug that targets liver fibrosis.

Jim is hopeful that the study drug will help improve his disease. But a deep sense of altruism also motivates his participation in the trial, along with a conviction that it will pay off, one way or another. “If I can help someone else down the line, I’m good with that.”

From Fatty to Fatal

When extra fat builds up in liver cells, it can cause progressive damage over time.
  • Stage 1
    Simple Fatty Liver
    The first stage of nonalcoholic fatty liver disease is characterized by fat accumulation in the liver without inflammation. It may remain relatively harmless and typically is asymptomatic.
  • Stage 2
    NASH
    Nonalcoholic steatohepatitis (NASH) is a more aggressive and serious form, in which the liver is inflamed and scarring starts. While NASH’s effects are similar to the damage caused by alcohol, people affected by NASH tend to drink very little or not at all. NASH often is called a silent killer because it can lead to permanent liver damage and scarring and prevent the liver from working properly.
  • Stage 3
    NASH with Fibrosis
    Some people with fatty liver develop fibrosis, scarring around liver cells caused by continual inflammation. Though scarring may replace some healthy tissue, the liver can still function normally.
  • Stage 4
    Cirrhosis
    At its most severe, a fatty liver may develop into cirrhosis, which causes permanent liver damage. The liver may become enlarged or shrink, liver cells are replaced by scar tissue, and the liver cannot function properly. Cirrhosis can be fatal and is typically the final stage before a transplant becomes necessary. Patients with cirrhosis can develop liver cancer as well.
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