FAT

The Menace Behind This Generation’s Liver Disease
By Alan Dove

Most people would need a search engine to identify the leading cause of chronic liver disease in the world today. A generation ago, alcohol or viruses would have been reasonable answers, but in recent years a new menace has supplanted both: fat.

Nonalcoholic fatty liver disease—NAFLD—is defined as an accumulation of lipids inside hepatocytes exceeding 5 percent of the weight of the liver. It now afflicts an estimated 25 percent of the global population. “It’s globally under-recognized,” says clinical investigator Julia Wattacheril, MD, director of the adult NAFLD program at Columbia.

Dr. Wattacheril leads a multidisciplinary team to confront this escalating public health crisis, covering everything from patient treatment and clinical trials to translational research, including genomics. It is a fertile field. “While there are some clear aspects of the disease and risk factors we know about, there’s also a huge amount of progression and regression of the disease that we fundamentally don’t understand. The unknowns are what make studying the disease so exciting–but also very urgent,” says Dr. Wattacheril.

One thing that is not a mystery is the cause of the epidemic, which has developed in lockstep with rising obesity rates. For most individuals, as body fat increases, some of the excess is stored in the liver, ultimately leading to NAFLD. In the majority of patients, that is as far as the liver pathology goes. In about 20 percent of cases, however, the fatty liver becomes inflamed and scarred, leading to much more serious nonalcoholic steatohepatitis, or NASH. NASH can even progress to cirrhosis and liver cancer, and some scientists project that these sequelae of NAFLD will become the top causes of liver transplants by 2020. Understanding how NASH progresses—and how to prevent or reverse it in a diverse group of patients —is a major focus for the Columbia team.

While excess weight is the major cause of NAFLD, exhortations to eat less have not accomplished much. “It’s not just a matter of excess calories, it’s also that the type of foods eaten generally lack the amount of natural antioxidants that would be present in a diet replete with vegetables and fruits,” says Joel Lavine, MD, PhD, vice chair of research in pediatrics and chief of pediatric gastroenterology, hepatology, and nutrition. Antioxidant-poor diets contribute to increased oxidative stress in the liver, causing damage to hepatocytes.

The damaged cells are the first link in a chain of problems. “They eventually die, and then there is release of inflammatory mediators by resident white blood cells and macrophages, resulting in scarring,” says Dr. Lavine. The scar tissue interferes with blood flow in the liver and results in the production of cirrhotic nodules.

 

FATTY LIVER IN CHILDREN

Perhaps the most distressing trend in the liver disease epidemic is the rise of NAFLD and NASH in children, which Dr. Lavine has observed firsthand. In some populations, patients as young as 2 years have fatty livers, and cirrhosis develops as early as age 8.

At the same time, children offer unique treatment opportunities. “Children could be more responsive to lifestyle interventions than adults,” says Dr. Lavine, “but they’re not the ones doing the shopping. If you can get the whole family to exercise together, to buy appropriate foods, and cook better meals, that matters.”

Ethnic differences in the disease’s prevalence also point to genetic factors, and researchers have zeroed in on two genes.

Certain vitamins also help. In two multicenter randomized controlled trials, Dr. Lavine and his colleagues found that natural vitamin E enhanced NASH resolution in children and adults, presumably by scavenging excess oxygen radicals in the patients’ livers. Findings from these studies, which were published in the New England Journal of Medicine and the Journal of the American Medical Association, have since been incorporated into standard treatment guidelines for both adults and children diagnosed with NASH.

Unfortunately, pediatric clinical trials are hard to orchestrate, especially for more powerful prescription drugs. One example is pioglitazone, a type 2 diabetes treatment that has significantly reduced progression from NAFLD to NASH in several studies. Because it has not been tested in children, though, its use is restricted to adult patients.

NASH and “All of Us”

The shortage of good treatments also has hampered efforts to screen for NAFLD and NASH. Currently, patients often find out they have NAFLD by accident, as a result of routine laboratory testing or imaging for other complaints. A definitive diagnosis of NASH, meanwhile, requires a liver biopsy. Research on improved diagnostic techniques is limited.

“There’s no point in having a screen for a disease that you can’t do anything about and there’s also no point in developing a therapy for a disease where you don’t find affected subjects,” says Dr. Lavine. He expects new therapies and new diagnostic tests, particularly for NASH, to evolve over the next few years. Indeed, he already sees signs of that happening, with several therapies now in late-stage clinical trials and more researchers and physicians recognizing the scope of the problem. As co-chair of the steering committee for the NIH NASH Clinical Research Network for the past 16 years, Dr. Lavine oversees many of the ongoing multicenter initiatives to develop such diagnostics and therapeutic trials.

HEPATOLOGY OUTREACH 

Broadening awareness to get more patients into treatment and clinical trials is a major focus for Columbia’s Hepatology Outreach program. “We set up satellite offices in neighborhoods in the tri-state area that have a high density of liver disease and that don’t really have any dedicated hepatologists,” says Paul Gaglio, MD, the program’s director. Satellite offices are in Chinatown in Manhattan, Hackensack in New Jersey, and in Cortlandt (NewYork-Presbyterian Hudson Valley Hospital), Eastchester, Somers, and Suffern in New York.

As a hepatology outreach map suggests, the geographic distribution of NAFLD is not random. Research has found strong correlations between fatty liver disease and ethnicity. For example, the rates of fatty liver disease in African-Americans are much lower than those in Hispanic-Americans for a given degree of obesity. Asian patients, meanwhile, appear to be the most susceptible, with many developing NAFLD and NASH after only a few pounds of weight gain.

The global melting pot of New York City provides an ideal environment for identifying these patterns and intervening appropriately. Early diagnosis can make a big difference, as dietary changes and exercise can stop the progression to NASH before it starts. “It’s a much more difficult thing to start thinking about how to manage somebody with fatty liver disease who now has cirrhosis,” says Dr. Gaglio.

Once the team gets patients connected with hepatologists, team members draw on the latest tools to track the disease’s progress. While liver biopsy has long been the definitive test for NASH, less invasive imaging and laboratory tests can now track pathogenesis in patients with milder liver disease. “The only patients who are getting biopsied are patients who you’re trying to determine if they have advanced fibrosis or if there is a potential alternative liver diagnosis,” says Dr. Gaglio.

Dr. Gaglio echoes Dr. Lavine’s assessment that improved diagnostic tools will help fuel improvements in treatment. That will be especially helpful for patients who have begun to progress to NASH or the majority for whom lifestyle interventions do not work. Because the disease advances through multiple mechanistic pathways, though, Dr. Gaglio does not expect a single “cure” to be the answer. Instead, physicians will likely need to determine the precise mechanisms at work in a given patient and select the treatment that works best against that phase of the pathology.

 

FROM LAB TO LIVER

Rapid advances in genomics and molecular biology are helping to move the field toward more tailored treatments. While environmental factors such as diet and lifestyle are major drivers of NAFLD and NASH, the ethnic differences in the disease’s prevalence also point to genetic factors. Through large population studies, investigators have zeroed in on two genes in particular: PNPLA3and TM6SF2. The former encodes a lipase that breaks down triacylglycerol in fat cells, while the latter encodes a transmembrane protein whose function remains unknown.

“The variant of interest for PNPLA3has been associated with the entire spectrum of fatty liver pathology, and TM6SF2 is associated mostly with lipid metabolism and aminotransferases and, in some populations, fibrosis,” says Dr. Wattacheril. Patients with specific variants of those two genes appear to be especially susceptible to NASH and other progressive forms of liver disease.

Dr. Wattacheril and her colleagues are interested in studying how those genetic factors interact with environmental influences. In collaboration with the Institute for Genomic Medicine, team members have performed exome sequencing on hundreds of their patients and are correlating results with the patients’ phenotypes. In collaboration with Dr. Lavine and the Nonalcoholic Steatohepatitis Clinical Research Network, an NIH-funded consortium, they have already analyzed pediatric patients with advanced fibrosis due to NAFLD and although no specific variant was strongly associated with advanced fibrosis, the sample size was one limitation. “We need more genomic information about individuals with NAFLD, especially those with particular phenotypes of interest.”

Dr. Wattacheril is also working with industry partners in the areas of biomarker discovery and precision medicine as part of a larger collaboration with the Irving Institute for Clinical and Translational Research. “Generally we think about 85 to 90 percent of individuals undergoing weight loss surgery should have nonalcoholic fatty liver disease,” says Dr. Wattacheril. “Individuals who do not are interesting; what is protecting their liver?” The general idea is to identify targets for therapeutic intervention as well as specific markers that could help separate patients into distinct risk groups for more precise treatment. Discovering at-risk groups can happen through traditional means—a clinician recognizing patients—but also via electronic health record phenotyping, something Dr. Wattacheril’s group is pursuing in collaboration with the Department of Biomedical Informatics.

Throughout Dr. Wattacheril’s program, the emphasis is on connecting patient care directly to cutting-edge research, a cross-disciplinary approach that is unusual for traditional clinics. “That’s something that doesn’t exist in other programs, and it’s actually why we’ve been able to recruit so many patients into the precision medicine initiative and sequencing projects. We discuss research at every visit.” says Dr. Wattacheril.

Generally we think about 85 to 90 percent of individuals undergoing weight loss surgery should have nonalcoholic fatty liver disease. Individuals who do not are interesting; what is protecting their liver?

The intense focus on translational research is no accident. Beginning in 2015, Dr. Wattacheril structured the NAFLD program to serve as a model for other efforts around the country, a concept that could scale quickly given a team-based approach. This integrated model works well: The NAFLD clinic and subsequently all of the Center for Liver Disease and Transplantation formed one of the beta launch sites for the All of Us Research Program, a $1.4 billion NIH-funded effort to gather health, environment, and genetic data from 1 million people as a base for future large-scale studies. A major part of that project is to engage patients directly with researchers. “Translational medicine comes alive when you have providers who are seeing patients, asking specific research questions, and communicating those results in real time to patients. The urgency of patient care keeps everyone motivated; the challenge is the pace with which data are emerging,” she says.

HEALING OUT OF CONTROL

At the other end of the translational pipeline are scientists such as Ira Tabas, MD, PhD, vice chair of research in the Department of Medicine. Dr. Tabas’ laboratory is trying to understand one of the central mysteries of fatty liver disease: Why do some patients progress to NASH while most do not? “The obvious answer is that it’s genetics, and there are some genes that are important, but they only define a minority of cases,” says Dr. Tabas.

The transition from NAFLD to NASH features three major changes in the liver: inflammation, cell death, and fibrosis. Fibrosis correlates most closely with the progression of the disease. To find the mechanisms driving it, he and his colleagues rely on a combination of human clinical data, experiments in cultured cells, and genetically engineered mice.

It takes several molecular steps to drive the complex pathogenesis of NASH. “When the early NASH process is beginning, proteins secreted by hepatocytes can act on cell surface receptors on hepatic stellate cells that turn on activation programs,” says Dr. Tabas. The stellate cells then begin forming scar tissue.

Dr. Tabas’ team has been working on two complementary processes related to NASH fibrosis. The first involves a protein made in liver cells called TAZ that Xiaobo Wang, PhD, in his lab discovered gets turned on when humans and experimental animals start to progress from fatty liver to NASH. Says Dr. Tabas: “TAZ activates a program that causes stellate cells to make fibrous tissue. When liver cell TAZ is silenced in animal models of NASH using a type of therapy that is currently approved for other uses in humans, NASH fibrosis can not only be prevented but also reversed.” He is collaborating with pharma to find ways to target TAZ in the NAFLD-to-NASH pathway.

Who’s Who

Paul Gaglio, MD, professor of medicine (in surgery) at CUMC

Joel Lavine, MD, PhD, professor of pediatrics (in the Institute of Human Nutrition)

Ira Tabas, MD, PhD, the Richard J. Stock Professor of Medicine (Immunology) and professor of pathology & cell biology (in physiology & cellular biophysics)

Julia Wattacheril, MD, assistant professor of medicine at CUMC

The second process involves a protein called MERTK, which when activated also causes activation of stellate cells and NASH fibrosis. The role of MERTK in NASH has a basis in human genetics. Interestingly, MERTK drives several aspects of wound healing in other settings. “The irony here is that this healing gene makes NASH worse,” says Dr. Tabas. He hypothesizes that the metabolic imbalance of NAFLD perverts the normal healing process. Scar formation would normally help a physically injured liver repair itself, but in NASH it gets out of control, leading to further injury instead.

Uncovering the underlying mechanisms of NASH is only the first part of the process for Dr. Tabas. “The proof of the pudding is what is relevant to people and most importantly what is tractable from a translational point of view,” he says. 

The translational research at Columbia is part of a broader push by scientists and physicians worldwide, all trying to tackle the immense public health threat of NAFLD and NASH. “Where else do you find a field with hundreds of millions of affected people and no FDA-approved drug?” asks Dr. Tabas. “Translational researchers and drug companies are stepping over themselves to try to come up with something.”