Point-Counter Point: Should NAFLD change to reflect on dysregulated metabolism?
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We need better defined disease criteria, a more accurate definition and a better name for what we call nonalcoholic fatty liver disease.
In the past, we did not really know what caused nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The major cause of liver problems at that point was alcohol, yet clinicians were observing cases of steatohepatitis or cirrhosis among people who were not excessive alcohol drinkers. That is how a name with “nonalcoholic” emerged. Even 30 years ago, obesity was not as prevalent as it is today.
As time progressed, more people developed fatty liver disease unrelated to alcohol use, with most of the cases managed by hepatologists. Yet these advanced cases were just the tip of the iceberg. Slowly, we started adding other exclusion criteria for nonalcoholic fatty liver disease (NAFLD), in addition to no excessive alcohol use and no hepatitis. We also realized we needed to rule out other forms of liver disease caused by autoimmune conditions and iron deficiency. Some people also debate whether genetic forms of fatty liver disease should be included.
Today, we understand NAFLD better. It is a disease of excess fat in the liver in amounts that should not be deposited in the liver. Each of us is endowed, genetically or epigenetically, with a certain amount of fat storage. As we exercise less or have an abnormal diet, some exceed this storage space; some may even have obesity but have the excess fat stored in adipose tissue. Some have a genetic predisposition that regulates fat metabolism in the liver, but in any case NAFLD is a mainly metabolic problem.
Initially, we proposed the name metabolic-associated fatty liver disease, or MAFLD. However, this is not a disease reflecting metabolism; it is a disease caused by dysregulated metabolism. That is why I propose dysmetabolism-associated fatty liver disease, or DAFLD, and dysmetabolism-associated steatohepatitis, or DASH as the new names for this prevalent disease state.
In changing the name to “DAFLD,” we can also change the approach to the disease. We do not use names without meaning. We want to convey a meaning to clinicians and to the greater public for prevention purposes, highlighting this is a disease of dysmetabolism. A name change is also important for pharmaceutical companies and the FDA. If you have what are essentially different diseases — people with fatty liver due to autoimmune or iron conditions — lumped under one name and one category, you tend to increase the noise in a drug trial. The effect of a potentially effective drug is diluted.
Some experts agree change is needed, but caution a change is premature. Previous and ongoing drug trials are based on the name “NAFLD” and current disease criteria. What would become of those data? I propose there are ways to move forward that not only preserve older data, but allow us to reevaluate the data with new exclusion criteria. All past phase 3 drug trials for NAFLD have been negative. Is it possible that if we go back and reanalyze old data, without the noise, we may have a different finding?
Right now, this is just a debate at scientific meetings and in papers. Progress toward a better characterization of the disease and its subtypes may be slow, but I believe this will happen. However, this does not eliminate the value of international efforts toward eventual harmonization. We must prompt people to think about this and make the appropriate change at the right time.
- Reference:
- Polyzos SA, et al. Metabolism. 2020;doi:10.1016/j.metabol.2020.154318.
- For more information:
- Christos S. Mantzoros, MD, DSc, PhD, is a professor of medicine at Harvard Medical School and Chief of Endocrinology at VA Boston Healthcare System.
A name change, without understanding its broad implications, can have a negative impact on the field.
NAFLD is a term that has been around for decades. It took about 20 years for the disease itself to become fully accepted among gastroenterologists and hepatologists as an important cause of liver disease. Awareness of the disease remains limited among primary care physicians, endocrinologists and cardiologists, yet they see many of these patients, not recognizing them. Awareness also remains low among patients. Our recent analysis of National Health and Nutrition Examination Survey data assessed liver disease knowledge. Among U.S. adults with NAFLD, less than 5% were aware they even had liver disease. In contrast, among U.S. adults with chronic viral hepatitis, 38% already knew they had liver disease. We also recently published a global survey of approximately 2,200 practitioners. Across specialties — gastroenterology, hepatology, primary care and endocrinology — PCPs and endocrinologists had the biggest knowledge gap about NAFLD.
Today, we have a greater understanding of NAFLD and its root causes, namely, obesity and type 2 diabetes. To emphasize the metabolic causes, some have proposed a new name for the disease that takes the emphasis away from alcohol use.
When one is studying a disease and considering a change of terminology, several issues must be considered: accuracy, acceptability, negative consequences of a change and clarity.
It would be accurate to clarify the name “NAFLD” and highlight its association with metabolic syndrome or metabolic dysfunction. However, there is a relatively small subgroup of patients with NAFLD who do not have overt metabolic abnormality. Furthermore, it is important to assess the unintended consequences of a name change. A change to metabolic-associated fatty liver disease, or MAFLD, or dysmetabolism-associated fatty liver disease, or DAFLD, will not help the current challenges of low disease awareness. The term is still suboptimal, leaving a great deal of ambiguity. People will be confused.
Major industry challenges persist with developing new drugs to treat NAFLD. Industry, the FDA and European Medicines Agency agreed on certain surrogate outcomes for drug trials, one of them being nonalcoholic steatohepatitis (NASH) resolution. New terminology eliminating “nonalcoholic” will also eliminate “NASH” as a term. Trialists would have to go back and agree with regulators and industry on what any new term would be and how to adopt it for clinical trials. This will place significant challenge to a field already plagued by many failures of tested regimens.
Additionally, current epidemiologic data for this disease are for those who meet the definition of NAFLD. One cannot automatically assume any data will still be applicable with a change to MAFLD or DAFLD. It just does not work that way. We have to study and provide evidence about the epidemiology and disease burden of the new entity.
On the lay side, when many people hear “liver disease,” the assumption is it is due to alcohol use. There is already a bias toward liver disease. Some could argue that, although a negative term, the name “nonalcoholic” fatty liver disease may remove some stigma associated with liver disease.
- Reference:
- Younossi ZM, et al. Hepatology. 2021;doi:10.1002/hep.31420.
- For more information:
- Zobair M. Younossi, MD, MPH, FACP, FACG, AGAF, is chairman, department of medicine at Inova Fairfax Medical Campus and professor of medicine at Virginia Commonwealth University, Inova Campus, and an Affiliate Professor of Biomedical Sciences at George Mason University.
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