番茄社区app

In 2023, an independent committee of experts published a Delphi consensus statement, updating the nomenclature of fatty liver disease.¹ The experts selected the umbrella term steatotic liver disease (SLD) to describe the various causes of steatosis, as well as the term metabolic dysfunction-associated SLD (MASLD) to replace nonalcoholic fatty liver disease (NAFLD) and the term metabolic dysfunction-associated steatohepatitis (MASH) to replace nonalcoholic steatohepatitis (NASH). SLD, including MASLD and MASH, affects over 25% of the population worldwide and is considered by the scientific community, overall, to be a global health crisis.²

番茄社区app interviewed Christos S. Mantzoros, MD, DSc, PhD h.c. mult., about the current state of SLD. Dr. Mantzoros is senior author of a comprehensive review on SLD published in a recent issue of Pharmacological Reviews.² The article provides updated information on SLD pathophysiology-based nomenclature, diagnosis, and MASLD/MASH pharmacotherapeutics, along with their mechanisms of action, based on the latest progress in clinical research and guidelines.²

Dr. Mantzoros currently serves as Professor of Medicine at Harvard Medical School and at Boston University鈥檚 Chobanian and Avedisian School of Medicine. He also is Chief of Endocrinology, Diabetes and Metabolism at the VA Boston Healthcare System; Director of Human Nutrition at the Division of Endocrinology Diabetes and Metabolism at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and Editor-in-Chief of the journal Metabolism鈥� Clinical and Experimental. The interview was lightly edited.

番茄社区app: What fueled the proposed changes in nomenclature from NAFLD/NASH to MASLD/MASH and the use of the term SLD?

Dr. Mantzoros: Progress in science has illuminated and continues to illuminate our understanding of what the very nature of the disease actually is. This has led to a progression from a completely agnostic term, i.e., cryptogenic (from the Greek words cryptos and genesis, indicating that the pathogenesis of the disease remained elusive to us up until several years ago) to a negative term later on, i.e., NAFLD (describing what the disease is not, i.e., not due to excess alcohol intake) to a more positive description indicating our current understanding that this disease, as the 鈥渘ew kid on the cardiometabolic block.鈥� It is related to ectopic fat deposition and resultant metabolic abnormalities. A number of colleagues and patients then thought that the word fat is associated with stigma and proposed that the word steatotic be used instead. Steatotic means fatty in Greek but apparently is not thought of being associated with stigma in the minds of most people.

How do you think the most recent SLD nomenclature can be improved upon?

Beyond these changes, I personally believe that, earlier or later, we will have to follow science and subclassify SLD into its major components: SLD due to obesity itself (too much energy stored in fat exceeds the storage capacity of the subcutaneous tissue and leads to ectopic deposition to the liver and other organs), lipodystrophy (in rare cases, there is destruction of subcutaneous adipose tissue and thus elimination of normal storage space, leading to ectopic fat deposition), or sarcopenia (the problem originates mainly through loss of muscle mass as we grow older), and/or a combination of obesity with sarcopenia. 

In other words, I see SLD as an umbrella diagnosis similar to diabetes or hyperthyroidism. Similar to diabetes having subclassifications with important therapeutic consequences, SLD appears to also have the subgroups I just mentioned, which will need to be diagnosed and treated differently in the future as we develop medications appropriate for each one of these subclasses of SLD.

What are the key steps in the modified SLD diagnostic approach that you and your team have proposed?

We and others have proposed to first exclude, on the basis of their distinct etiology, other disease states, such as hormonal abnormalities (hypothyroidism or Cushing鈥檚 syndrome, etc.) or specific liver problems (hepatitides, etc.) that could be confused with SLD, then classify alcohol-related SLD separately, leaving room for another group where alcohol-related and SLD would overlap. Within SLD, we have proposed that we need to distinguish among the 4 subclassifications that I just described, which will eventually dictate different and more specific treatments in the context of a more personalized approach.

Can you give clinicians a general sense of the current state of clinical research on potential agents for the treatment of MASLD/MASH?

There are 2 major areas of research I can see in this rapidly evolving field.

The first one is to narrow down the best non-invasive diagnostic approaches, allowing us to avoid using liver biopsies that are costly, not widely available, and carry a small morbidity and mortality risk at the individual level, but which, if applied to the large segment of the population that has excess fat in their liver (approximately 30%), could translate to more than 15,000 deaths and hundreds of thousands of hospitalizations in North America alone. Efforts towards devoting imaging tools (more expensive) or 鈥渓iquid biopsies鈥� using artificial intelligence (more accessible and apparently less expensive) are currently competing for the sweet spot of the future preferred diagnostic modality to be applied widely.

The second major area of research is exploring what medications we can use in addition to optimizing diet, exercise, and behavioral modification which I consider as the platform on which each intervention with medications will have to be based upon. Classes of medications under development could be divided into those that decrease influx of fat into the liver, those that would help the liver burn more fat and thus get rid of it, or medications that act downstream and limit inflammation and/or fibrosis. 

In the first class, one could see medications that decrease obesity (especially but not exclusively incretin analogues), medications that may increase muscle mass, and/or medications that would otherwise improve metabolism and insulin resistance. In the second class, we have medications being developed to increase the function of mitochondria (i.e., make the energy factory of our body to burn more calories) and/or improve cardiometabolic profile (such as a recently provisionally approved thyroid receptor beta analogue).

What are some key challenges in clinical research that need to be resolved to further the development of these agents?

More accurate diagnosis and understanding of the very nature of the disease, as I mention, are key for the development of the most appropriate lifestyle modification and the development of the most accurate and precise therapeutic approach in a personalized medicine context.

Do you have a final point you'd like to convey to clinicians?

I believe that, as we understand the nature of the disease better and as we develop more accurate diagnostic and therapeutic approaches, we do need to think about SLD much more frequently. For example, up to 70% of persons with diabetes coming to our clinics have SLD but most of us still do not think about SLD and do not test for it. A change of minds and clinical practice will take some time but, as our diagnostic and therapeutic tools improve, continuous education efforts will certainly change the way we practice medicine and will certainly improve outcomes and allow our patients to live longer and healthier lives.

Published: May 15, 2024