No patient left behind: MASLD rebranding provides ‘affirmative diagnosis’ without stigma
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In June 2023, 74% of respondents from a multinational, multisociety Delphi process agreed that the term nonalcoholic fatty liver disease was “sufficiently flawed” and 89% preferred nomenclature that described the underlying cause of disease.
Members from international liver societies, along with patient advocacy organizations, have since chosen steatotic liver disease (SLD) as the new overarching term.
Source: Norah Terrault, MD, MPH, FAASLD
“The reason we undertook this systematic and global approach is because it is a common condition,” Fasiha Kanwal, MD, MSHS, professor and section chief of gastroenterology at Baylor College of Medicine and member of the Delphi consensus panel, told Healio Gastroenterology. “The main considerations were that the previous nomenclature, NAFLD, was an exclusionary diagnosis where you had to exclude things to identify or diagnose patients.”
Kanwal continued: “For the first time, we have a positive and affirmative diagnosis that can be made using information that is readily available in clinical practice.”
Additional changes to the nomenclature brought about by the Delphi consensus group, which included 236 panelists from 56 countries, included renaming NAFLD to metabolic dysfunction-associated steatotic liver disease (MASLD). Metabolic dysfunction-associated steatohepatitis (MASH) replaced nonalcoholic steatohepatitis, or NASH.
“The advantage of this nomenclature change is that it connects the disease to its underlying pathogenesis,” Zobair M. Younossi, MD, MPH, professor and chairman in the department of medicine at Inova Fairfax Medical Campus and chairman of the Global NASH Council, said. “There is also the additional advantage that it has the potential to reduce stigma, which can impact patients’ quality of life.”
Aside from eliminating the terms “nonalcoholic” and “fatty,” which around two-thirds of panelists felt were stigmatizing, the new nomenclature also pushes diagnosis in a “simpler” direction by moving away from a required liver biopsy, Norah Terrault, MD, MPH, FAASLD, chief of gastroenterology and hepatology at Keck Medical Center at USC and president of AASLD, said. Instead, providers can rely on this new algorithm to determine whether their patients fit MASLD diagnostic criteria.
“We are relying on noninvasive imaging tests and the presence of metabolic risk factors, which is the simplicity piece we do not get with invasive tests,” Terrault added. “This simplification will hopefully also raise awareness about the frequency at which MASLD is present in the population and encourage more evaluation.”
Healio Gastroenterology spoke with experts across the field to understand the new nomenclature, how it simplifies diagnostic criteria and aims to squash existing stigma, as well as its implications on prior research.
Defining Metabolic Liver Disease, Diagnostic Criteria
Historically, the diagnosis of NAFLD required steatosis in at least 5% of hepatocytes with no other causes of hepatic fat accumulation, including significant alcohol intake (defined as 20 g/day for women and 30 g/day for men), researchers wrote in Hepatology. Diagnostic criteria for MASLD includes hepatic steatosis but adds markers of metabolic dysfunction.
“Patients must have at least one of five cardiometabolic risk factors, which include BMI, waist circumference, hypertension, dyslipidemia and diabetes,” Terrault said. “There are specific criteria for each of them, but they are the same five we have been using to assess cardiovascular risk over many years, we are now just applying them to liver disease.”
According to AASLD, cardiometabolic criteria for adult patients include:
- BMI of 25 kg/m2 or greater (23 kg/m2 among Asian patients) or a waist circumference greater than 94 cm for men and 80 cm for women;
- fasting serum glucose level of 5.6 mmol/L or greater or 2-hour post-load glucose levels of 7.8 mmol/L or greater or HbA1c of 5.7% or greater or type 2 diabetes or treatment for type 2 diabetes;
- blood pressure of 130/85 mmHg or greater or specific antihypertensive drug treatment;
- plasma triglycerides of 1.7 mmol/L or greater or lipid lowering treatment; and
- plasma HDL-cholesterol of 1 mmol/L or less among men and 1.3 mmol/L or less among women or lipid lowering treatment.
“These certain cutoffs were selected because they are consistent with cutoffs that have been validated in conditions that are similar,” Kanwal said. “They are broad, and this was purposeful because we did not want any patient who has this condition to be left behind just because of the criteria.”
Once determined that a patient meets at least one of these criteria, and there are no other causes of steatosis, a diagnosis of MASLD can be made. However, for those with other causes of steatosis, the Delphi panel introduced metabolic alcohol-related liver disease (Met-ALD) which describes those with MASLD who consume more alcohol per week (140-350 g/week for women; 210-420 g/week for men).
“I am quite excited about the introduction of this Met-ALD group, because we always had this question of whether we are defining the right amount of alcohol and cutoffs,” Mazen Noureddin, MD, MHSc, professor of medicine and hepatologist at Houston Methodist Hospital and vice chair of AASLD’s NAFLD special interest group, told Healio Gastroenterology. “A lot of patients were excluded in this group because they supposedly drink more than the previously established amounts.”
He continued, “In addition, this new nomenclature has the potential to bring about a new area of research and therapeutic agents among this group who have otherwise been excluded from clinical trials.”
Those who do not meet any one of the cardiometabolic criteria and who have no other causes of steatosis, including alcoholic liver disease, drug-induced liver injury or monogenic disease, may be diagnosed with cryptogenic SLD.
Data derived from Rinella ME, et al. Hepatology. 2023;doi:10.1097/HEP.0000000000000520.
MASLD vs. NAFLD
Though new research is still underway, both Noureddin and Kanwal noted early data have shown the old and new definitions are “overlapping between 98% and 99%” and, in most instances, will not invalidate prior research.
“There was a lot of thoughtfulness about how MASLD was described and ensuring that it would encompass what we had studied before, especially from the point of view of drug development,” Terrault said. “There are drugs that are in phase 2 and even phase 3 development, and we did not want those drugs to end up with an approval that then does not relate to the disease that we currently are naming.”
She continued: “We can feel confident that MASLD and NAFLD are very tight in terms of what they represent and are going to be applicable moving forward.”
According to a Chinese study of 30,633 participants published in the Journal of Clinical and Translational Hepatology, most patients with existing and new cases met the diagnostic criteria for MASLD (at the time, metabolic dysfunction-associated fatty liver disease [MAFLD]) and NAFLD, accounting for 78.84% and 82.88%, respectively. This indicated that NAFLD “is actually a metabolic disease,” researchers wrote.
Additional data has also shown that the new nomenclature is “superior” in identifying patients at risk for clinical disease progression, researchers wrote in Clinical and Molecular Hepatology. Data from their review demonstrated that patients with MAFLD had statistically significant increases in alanine transferase (23.96 vs. 22.31), NAFLD fibrosis score (–2.05 vs. –2.18) and fibrosis-4 scores (1.06 vs. 1.01) compared with NAFLD, indicating that “MAFLD more specifically selects patients with worse liver function and noninvasive scores.”
“There have been FDA workshops already where MASH has been used in place of NASH and MASLD in place of NAFLD, which shows you it can be a smooth transition,” Noureddin said. “In addition, there have been efforts made by the noninvasive testing consortium to confirm this overlap, as well as the efficacy of noninvasive scores.”
Although the name has changed, Terrault noted it is important to note the approach to managing this patient population has not, and additional noninvasive testing is needed for risk stratification.
“We are looking for individuals who have more of an inflammatory fibrotic phenotype and need a more aggressive approach to their management,” she said. “That is the group usually being referred for specialized liver care and the target for clinical trials.”
Terrault continued: “These patients are also the ones we would potentially think about for interventions with medications that are currently available but are not necessarily approved; they could still make some difference.”
For further guidance on disease management, she noted the most recent practice statement from AASLD on the clinical assessment and management for NAFLD is “directly applicable” to MASLD.
Impact on Patient Care, Universal Disease Understanding
Additional results from the Delphi consensus statement showed 56% felt that a change in nomenclature would positively affect disease awareness with a “super-majority” reporting it would help patients (72%) and health care professionals (80%) alike to better understand the disease.
For patients, Kanwal noted an advantage of this nomenclature change is that they can feel empowered in understanding the underlying cause of their condition. For providers, this rectifies a “missed opportunity” where, in the past, patients with more than one etiology went without an affirmative diagnosis.
“These patients were a missed opportunity both for clinical care and research,” Kanwal said. “We do not have many research studies that speak to that patient population because we did not know how to define them.
“There was a big need to go in the direction where we can at least classify and include these patients in studying their disease course and potential treatments because it is an unmet need.”
According to Kenneth Cusi, MD, FACP, FACE, professor of medicine in the division of endocrinology, diabetes and metabolism at the University of Florida, another advantage is that the disease may now be “more strongly linked” with insulin resistance and metabolic dysfunction, “as cardiometabolic risk factors are often promoted by insulin resistance, instead as liver disease just being defined by a negative, for example, NAFLD.”
He further noted a lack of cardiometabolic risk factors, especially among younger adults, does not mean they are immune to genetic and environmental factors which cause insulin resistance and MASLD.
“All should be encouraged to follow a healthy lifestyle and see their doctors on a regular basis,” Cusi advised.
Remaining Challenges, Potential for Further Investigation
Although the new MASLD nomenclature has the potential to positively affect patient care and improve disease understanding, experts agree that challenges remain.
“There is a great deal of debate about the cardiometabolic risks and how they are going to impact liver disease,” Younossi said. “For example, there are questions about whether diabetes is the same as hypertension in terms of its impact. Or, what about patients who are at risk for this disease but do not have overt cardiometabolic risks?”
Cusi also noted that the new nomenclature lacks clarity regarding what having one vs. two cardiometabolic risk factors may mean for disease severity.
“The good thing is this change highlights the role of metabolic abnormalities, particularly insulin resistance, in the pathophysiology of the disease,” Cusi said. “But again, I think there is some risk that some people with NAFLD will not be considered as having the disease and that would be a missed opportunity to promote dietary and lifestyle changes. It may create a little bit of discordance with prior epidemiological studies.” Another challenge providers may encounter is unlearning the widely known terms “fatty liver” and “nonalcoholic fatty liver.”
“It may be a little bit more complex for a busy primary care physician to remember all the cardiometabolic risks, to know what MASLD is and the difference between MASLD vs. NAFLD,” Younossi said. “It probably would create confusion though I am not sure how impactful this confusion may be.”
He continued: “My recommendation is to broaden the definition of MASLD to include those patients who do not have metabolic risks, because it is important to include those patients diagnosed with the NAFLD definition. I agree there is a huge overlap, but they are not exactly the same patients. We need to generate new evidence for MASLD that was generated from NAFLD.”
Cusi added that educational efforts brought about by scientific societies will be essential for combatting any confusion that may arise.
“This may also be beneficial for bringing more attention to the role of insulin resistance in the development of the disease, integrating the liver into current care practices of primary care providers and improving awareness in terms of the need for screening as proposed by liver and endocrine societies,” he said.
Raising Awareness About Liver Health
These long-awaited changes to liver disease nomenclature not only shed light on this highly underrecognized and stigmatized condition but also underscore the importance of liver health in general.
“Do not worry about the name change,” Cusi advised. “Use it to your benefit if it helps you become more aware of the condition, and continue focusing on the patient and the importance of screening and early referral. Insulin resistance is not only at the core of diabetes or cardiovascular disease, but also of liver health.”
“We need to move toward acknowledging these are not just conditions individuals have, but they are important conditions that can lead to cirrhosis, liver cancer and liver-related death,” Terrault said. “We need global awareness around it in the sense that we should all know about the health of our livers and seek out help in an effort to know if our livers are healthy.”
For specialized providers, Noureddin acknowledged that this change may be difficult, but it is one that must be accepted to continue advancing patients care at both the specialty and primary care level.
Going forward, Kanwal noted, the responsibility of all liver specialists will be one of a teacher passing along this new information and raising awareness.
“This is a highly underrecognized condition and, with this change, we will be able to improve the number of people who are currently diagnosed and correctly linked with treatment,” she said. “Disease awareness impacts the clinician and the patients equally. I am hoping with the attention that is garnered this will accelerate the pace of existing research and that we will see better and new treatments coming down the pipeline soon.”
- References:
- Fouad Y. World J Hepatol. 2023;doi:10.4254/wjh.v15.i2.123.
- Gofton C, et al. Clin Mol Hepatol. 2022;doi:10.3350/cmh.2022.0367.
- New NAFLD nomenclature. https://www.aasld.org/new-nafld-nomenclature.
- Rinella ME, et al. Hepatology. 2023;doi:10.1097/HEP.0000000000000323.
- Rinella ME, et al. Hepatology. 2023;doi:10.1097/HEP.0000000000000520.
- Yu C, et al. J Clin Transl Hepatol. 2022;doi:10.14218/JCTH.2021.00089.
- For more information:
- Kenneth Cusi, MD, FACP, FACE, is chief of the division of endocrinology, diabetes and metabolism in the department of medicine at the University of Florida and can be reached at kenneth.cusi@medicine.ufl.edu.
- Fasiha Kanwal, MD, MSHS, is professor and section chief of gastroenterology at Baylor College of Medicine and can be reached at kanwal@bcm.edu.
- Mazen Noureddin, MD, MHSc, is professor of medicine and a hepatologist at Houston Methodist Hospital and vice chair of AASLD’s NAFLD special interest group and can be reached at mnoureddin@houstonmethodist.org.
- Norah Terrault, MD, MPH, FAASLD, is chief of gastroenterology and hepatology at Keck Medical Center at USC and president of AASLD and can be reached at norah.terrault@med.usc.edu.
- Zobair M. Younossi, MD, MPH, is professor and chairman of the department of medicine at Inova Fairfax Medical Campus and chairman of the Global NASH Council, and can be reached at zobair.younossi@cldq.org.
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