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.
Silent killer on the rise
Nonalcoholic fatty liver disease is on the rise nationally and globally. It affects some 80-100 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. 10-20% 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.
“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.”
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 Dr. Andrew Klein director of the Comprehensive Transplant Center at Cedars-Sinai.
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.”
A stealthy disease
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.
Innovations in treatment and diagnosis
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 Dr. Mazen Noureddin, 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, Dr. Shelly Lu, director of Digestive and Liver Diseases at Cedars-Sinai.
“There used to be very little hope for these patients with advanced fatty liver disease,” says Dr. 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, Dr. 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,” Dr. 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.”
“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.”
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,” Dr. 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 Dr. Nicholas N. Nissen, 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 Dr. 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,” Dr. 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, Dr. 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% 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.”
This article is re-published from Discoveries magazine, which covers medical research at Cedars-Sinai and its impact on patient care.