Making New Connections to Address the Silent Epidemic of Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease, or NAFLD1, is one of the most common and growing types of chronic liver disease in adults and children, marked by excess fat storage in the liver. An estimated quarter of people in the United States have NAFLD, and up to 70 percent of people with type 2 diabetes also have NAFLD, though it often goes undetected. The disease often accompanies obesity and type 2 diabetes as part of a cluster of conditions called metabolic syndrome, though NAFLD can occur even in people who are lean and do not have diabetes, including those who carry some genetic factors and/or whose ancestors are from regions of the world with higher risk. Its more severe form of nonalcoholic steatohepatitis, or NASH2, includes additional features of inflammation and scarring (fibrosis) that can lead, over many years, to compromised liver function; permanent damage, termed cirrhosis; liver cancer; and liver failure requiring a transplantation. There are currently no dedicated therapies approved by the U.S. Food and Drug Administration (FDA) for NAFLD and NASH. The current standard of care is weight loss through diet and exercise, which is challenging to achieve. Additionally, diagnosing these diseases is difficult because it relies on an invasive liver biopsy. New approaches are needed to prevent and treat NAFLD and NASH and to develop noninvasive means to identify people who could benefit from therapies as they become available.
NIDDK supports a long-standing, multifaceted, and highly collaborative research program to improve understanding of NAFLD/NASH disease processes and identify new treatment approaches. The progress achieved through these efforts is made possible through the collective efforts of research teams and study participants at institutions across the country, at NIH, and internationally.
Early Studies of Disease Development
NIDDK sponsored early research on NAFLD and NASH to identify the biologic processes involved and chart the course of disease development and progression. In the 1990s, studies of liver biopsies from patients with obesity (with or without diabetes) identified some of the key morphologic changes that take place in NASH. They also tracked disease progression in these patients, some of whom developed fibrosis, which can progress to cirrhosis. Furthermore, these studies pointed to a link between NASH and insulin resistance, a condition that is also associated with type 2 diabetes. Additional studies in the early 2000s confirmed the link between NASH and insulin resistance, as well as other metabolic abnormalities, such as increased fatty acid breakdown and oxidative stress in the liver. NIDDK also sponsored population-level studies in the United States documenting the prevalence and risk factors for these diseases in people of different ages, genders, and ancestry. For example, disease risk at the time was found to be higher in people with ancestry from Hispanic and South Asian countries than in people with ancestry from African or European countries.
Connecting Researchers to Accelerate New Approaches
In 2002, NIDDK dramatically ramped up these efforts by establishing the NASH Clinical Research Network (NASH CRN), which supports a collaborative group of clinical researchers at centers across the country focusing on adult and pediatric forms of NAFLD and NASH. Currently made up of teams and study participants at 17 participating clinical centers and a data coordinating center, the Network aims to advance understanding of disease causes and processes, and to also develop new approaches to diagnosing, treating, and managing these diseases. During the Network’s history, NIDDK has partnered with the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at NIH, and with the pharmaceutical industry, on clinical trials testing the safety and efficacy of new treatments for NAFLD/NASH. Over the past two decades, the Network has made many important contributions to the field, including developing a scoring system for diagnosing the disease and its progression, assessing genetic and other risk factors, and testing multiple candidate therapies.
To date, the Network has enrolled thousands of adults and children who have participated in its many observational studies and clinical trials. These include trials showing that a daily dose of the natural form of vitamin E improved NASH in adult study participants and in some children. Network trials tested other possible therapeutic approaches, including the diabetes drug pioglitazone in non-diabetic adults with NASH and the kidney disease drug cysteamine bitartrate in children with NAFLD, both of which improved some features, but did not reduce overall disease. In 2015, Network investigators released results of a trial finding that a small molecule drug called obeticholic acid improved liver health in people with NASH, though the drug was associated with some increases in itching and total cholesterol. These findings helped fuel an explosion of industry-sponsored NASH clinical trials of this drug and others. The NASH CRN collaborates with and complements industry partners by testing existing, low-cost agents that industry is unlikely to pursue, as well as conducting early phase studies of agents with novel mechanisms of action.
Recent findings flowing from Network studies have shown a direct link between disease stage and outcomes in adults, with severe, later-stage disease associated not only with a higher risk of liver-related complications and death, but also with complications in other organ systems. And Network studies have uncovered new knowledge about the underlying biology of this disease, such as new genetic factors associated with responsiveness to vitamin E treatment in adults with NASH. Network research on genetic factors in children with NAFLD showed that some gene variants increase risk of the disease, particularly its more severe form. Because the majority of study participants were children with ancestry from Hispanic countries, these findings are particularly valuable for this at-risk population. These findings add to the evidence base for determining prognosis and informing clinical care for both adults and children with NAFLD.
The goal of the Network’s current phase is to continue database-driven studies of disease processes and to conduct new trials of NASH therapies for children and adults, with a constant emphasis on low-cost agents that could be implemented across the population. In recent years, a Network study found that the anti- hypertension drug losartan did not reduce signs of liver disease in children with NAFLD. Another study is determining the minimum effective dose of vitamin E in adults with NAFLD needed to improve liver enzyme levels. And the Network’s impacts are further amplified through availability of its databases and vast repository of samples for additional studies by other scientists. For example, a current ancillary study is characterizing and testing treatments for the disease in people living with HIV, a population in which NAFLD is projected to become the leading cause of liver disease.
The Network also continues to develop and validate less invasive ways to diagnose NASH, such as by identifying biological markers of the disease and using imaging technologies. A recent ancillary study builds upon the NASH CRN to identify biomarkers in the blood that could be used in noninvasive tests related to NASH and NAFLD. Using data and samples from participants in four Network studies, the researchers provided evidence that these biomarkers could be used for noninvasive diagnosis of people at risk for NASH and for assessing the degree of fibrosis severity. This study was conducted through a collaborative project called Noninvasive Biomarkers of Metabolic Liver Disease, or NIMBLE, overseen by the Foundation for the NIH with participation from the FDA, academia, and industry partners, with partial funding provided by NIDDK and NIH’s National Center for Advancing Translational Sciences. If approved by the FDA, these markers could be used instead of biopsies to more easily screen and diagnose people with NAFLD and NASH as early as possible in their disease course—an important milestone in clinical care.
Investigator-generated Research Advances
In addition to the highly productive NASH CRN, a wealth of investigator-initiated research efforts supported by NIDDK have made important, complementary contributions to advancing knowledge in this area.
For example, NIDDK-sponsored investigators have performed clinical studies to identify genetic factors that could predispose some individuals to developing NAFLD. A 2008 study scanned the genomes of participants in a large population-based study to show that a variant in a gene called PNPLA3 was strongly associated with NAFLD and was more common among study participants of Hispanic ancestry with higher liver fat and inflammation. This was followed by a 2010 study conducted by NIDDK scientists working at the NIH Clinical Center to further analyze genomic data from participants in the NASH CRN, as well as from people with NASH who participated in non- Network studies at the Clinical Center. This study found that the PNPLA3 variant was associated with earlier disease development in children. Other studies, including international ones, are identifying additional regions of the genome associated with NAFLD and are determining their functional significance as prospective treatment targets across diverse populations.
Basic research in animal and cell models conducted by NIDDK-supported scientists has revealed new insights into disease development and possible treatment approaches. For example, a team of researchers supported by NIDDK and other NIH Institutes used mice and human liver cells to investigate how high amounts of fructose, a common ingredient in processed foods in the American diet, may promote NAFLD. They reported in 2020 that fructose can damage the intestinal barrier, which leads to inflammation and effects on the liver. Two teams of NIDDK-supported scientists tested lipid nanoparticles—used to deliver messenger RNA-based vaccines such as those developed against COVID-19— in mouse models to improve delivery of treatments for liver fibrosis and NAFLD. Researchers “eavesdropping” on how liver cells chemically talk amongst themselves in animal and cell models uncovered a host of new potential therapeutic targets for advanced-stage NAFLD. NIDDK is supporting ongoing research to develop innovative models for fostering new discoveries, such as stem cells, genetically altered cells in culture, and three-dimensional organoids (“mini- livers” grown in the lab) derived from people with NAFLD/NASH to develop personalized diagnostic biomarkers and treatments.
Imagining the Future of NAFLD/ NASH Treatment: Past Progress Fueling New Strategies
Recent years have witnessed the most rapid expansion yet of new treatment options under development for NAFLD and NASH. Many studies have focused on a new class of hormone-based drugs approved by the FDA for treating type 2 diabetes and obesity, such as semaglutide. These drugs work through a protein called the glucagon-like peptide 1 (GLP-1) receptor, and the development of these drugs stemmed from NIDDK-supported foundational research on GLP-1 and related factors. This class of drugs causes delayed stomach emptying, reduced appetite, increased satiety, and enhanced insulin release and lower blood glucose levels, in addition to significant weight loss.
In 2021, an industry-sponsored clinical trial featuring participation by NIDDK-supported scientists found that daily semaglutide treatment over a year and a half did improve disease resolution, based on the absence of inflammation or worsened liver fibrosis, but did not improve fibrosis stage in people with NASH but no cirrhosis. A 2023 study partially supported by NIDDK reported no improvement in disease, including resolution, in people with NASH and early cirrhosis who were treated weekly for a year with semaglutide, though the treatment did appear to be safe and have positive impacts on liver enzymes and liver fat. Researchers are conducting trials to determine whether longer-term treatment is required in people with cirrhosis resulting from NASH. NIDDK- supported researchers are currently conducting a clinical trial of semaglutide at the NIH Clinical Center in people with NAFLD/NASH to understand the mechanisms by which it may prove beneficial in treating the disease and identify predictors of clinical response. Additionally, NIDDK is supporting a new study testing another GLP-1 drug called liraglutide in young people with obesity, prediabetes or new onset type 2 diabetes, and NAFLD. And industry-sponsored trials are showing promising results in adults with obesity, type 2 diabetes, and fatty liver disease treated with similar drugs such as tirzepatide and testing other agents that target more than one receptor related to proteins like GLP-1.
Other novel treatment approaches are being investigated in parallel, including a study supported by NIDDK examining the impacts of intermittent fasting and aerobic exercise on NAFLD, which in combination were found to reduce liver fat more than either intervention alone. Another clinical trial is currently testing a low dose of the diabetes drug pioglitazone for improving signs of liver disease in people with both type 2 diabetes and NASH. NIDDK also supports many research projects overseen by industry scientists through the Small Business Innovation Research program that are testing new approaches to NAFLD/ NASH therapy.
Ongoing "Networking" to Facilitate Treatments
NIDDK continues to seek new opportunities to connect scientists studying NAFLD and catalyze research progress in this area, in addition to the ongoing NASH Clinical Research Network. In 2021, the Institute established the Liver Cirrhosis Network to conduct clinical and translational research toward expanding treatment options and transforming clinical care for cirrhosis caused by NAFLD and other forms of chronic liver disease. Network scientists are working in collaboration with a diverse population of adult study participants, some of whom have been underrepresented in past studies despite carrying a higher disease risk and burden. The Network is conducting an observational study, including on risk factors across racial and ethnic groups, to determine what drives cirrhosis progression and point to possible treatments. Current Network studies are also testing whether statins, which are drugs commonly taken for high cholesterol, can protect against cirrhosis progression. The goal of the Network’s studies is to usher in a new era of cirrhosis management, with a wider array of effective treatment options beyond liver transplantation, for NAFLD and other causes of severe liver disease.
For more information on NIDDK-sponsored research on NAFLD/NASH, such as the NASH Clinical Research Network, please see: www.niddk.nih.gov/health-information/liver-disease/nafld-nash/clinical-trials.
For more information on the NIDDK’s Liver Cirrhosis Network, please see: www.lcnstudy.org.
1 Also referred to as metabolic dysfunction-associated steatotic liver disease or MASLD
2 Also referred to as metabolic dysfunction-associated steatohepatitis or MASH