Metabolic dysfunction-associated steatotic liver disease or MASLD (previously known as non-alcoholic fatty liver disease or NAFLD) occurs when there is excessive accumulation of fat in the liver, in the presence of cardiometabolic risk factors and without a history of high alcohol intake.
Recent estimates suggest MASLD affects 32–38% of adults worldwide.1 Worryingly, the high prevalence of MASLD in adults is mirrored in children (5–11% in the general paediatric population, 30–50% in children with obesity).2 Insulin resistance, elevated free fatty acid delivery to the liver (from dietary sources and peripheral lipolysis), and increased intrahepatic de novo lipogenesis play key roles in the pathogenesis of MASLD, with significant contributions from genetic and environmental factors.
UNDERSTANDING MASLD
MASLD ranges from liver steatosis (MASL), to liver steatosis with inflammation and hepatocyte ballooning (metabolic dysfunction-associated steatohepatitis, MASH), through to fibrosis (F1–F3) and cirrhosis (F4). All stages of MASLD are associated with increased morbidity and mortality. However, the strongest associations exist between fibrosis stage and all-cause mortality, with clinically significant fibrosis (i.e. ≥F2) associated with more than double the risk of dying compared with MASLD without fibrosis.3
‘As the awareness of MASLD increases … endocrinologists need to be involved in developing care pathways and delivering care to patients with MASLD.’
Varying fibrosis progression rates (18–41%) and regression rates (13–37%) have been reported, with higher rates of progression occurring as the severity of fibrosis increases.4 On average, progression from one stage to the next occurs over 10 years.4 If progression of MASLD is not halted or reversed, the potential future consequences for society in terms of poor patient outcomes and high healthcare utilisation are significant. For instance, MASH cirrhosis has become one of the leading causes of liver failure requiring transplantation.5
The main causes of mortality in patients with MASLD are cardiovascular events and extra-hepatic cancer, with liver failure and/or hepatocellular cancer accounting for the minority of deaths.6 Therefore, addressing cardiovascular, metabolic and/or hepatic risk factors (i.e. weight reduction in people with overweight/obesity, smoking cessation, optimisation of blood pressure and hyperlipidaemia, dietary modification, alcohol intake reduction) have been the mainstay of the management of MASLD. However, there is now an emerging pipeline of disease-modifying agents.
ITS RELEVANCE TO ENDOCRINOLOGISTS
Amongst people with type 2 diabetes or obesity, ~70% have MASLD and ~35% have MASH. Both type 2 diabetes and obesity are associated with increased likelihood of progression to advanced fibrosis.7,8 Patients with other endocrine conditions (polycystic ovary syndrome, male hypogonadism, Turner syndrome, growth hormone deficiency) and postmenopausal women may have elevated risks of developing MASLD and/or MASH fibrosis.9 Therefore, endocrinologists are likely to manage many patients who have MASLD as a co-morbidity.
Due to the central role of insulin resistance in the pathophysiology of MASLD, as well as the novel endocrine treatments for MASLD that are being developed, endocrinologists are well-placed to take leading roles in the management of this condition.
Resmetirom (a liver-directed thyroid hormone receptor-β agonist) is the first agent to be licensed specifically for the management of MASH fibrosis. It leads to MASH resolution and fibrosis regression, and lowers low-density lipoprotein cholesterol.10 In addition to causing weight loss, semaglutide (a glucagon-like peptide-1 (GLP-1) receptor agonist), tirzepatide (a GLP-1–glucagon receptor co-agonist), retratrutide (a GLP-1–glucagon–glucose-dependent insulinotropic polypeptide receptor tri-agonist) have been demonstrated to have beneficial effects on steatosis, MASH and/or fibrosis. Multiple randomised control trials are underway to investigate the activity of other gut hormone mono- and co-agonists in MASLD. Non-gut hormone treatments (e.g. fibroblast growth factor-21 analogues) are also being assessed, with phase 3 studies in progress.
PATIENT CARE AND IMPROVING OUTCOMES
Due to the high prevalence of MASLD in the population, most patients will be managed in primary care. International guidelines suggest risk stratification to identify patients with MASLD who require specialist review. Patients with more advanced disease are currently managed in secondary care, predominantly by hepatologists. However, practice is evolving, with some patients being managed in specialist joint hepatology–endocrinology clinics, including input from dietitians and other healthcare professionals. This approach provides more holistic care, which may lead to better outcomes for patients.
As the awareness of MASLD increases, and evidence for the efficacy of different management options emerges (with subsequent licensing of medications for MASLD), endocrinologists need to be involved in developing care pathways and delivering care to patients with MASLD. Alongside the ever-increasing plethora of medications for the management of obesity and type 2 diabetes, the diverse emerging pipeline of drugs for MASLD, and the opportunity for management of multi-morbidity with single agents, there is a need for high-quality prospective studies and expertise in endocrinology to guide selection of agents tailored to patients with different co-morbidity profiles.
CHIOMA IZZI-ENGBEAYA
Imperial College Healthcare NHS Trust, London
REFERENCES
1. Riazi K et al. 2022 Lancet Gastroenterology & Hepatology https://doi.org/10.1016/S2468-1253(22)00165-0.
2. Panganiban J et al. 2025 Obesity Pillars https://doi.org/10.1016/j.obpill.2025.100164.
3. Ng CH et al. 2023 Clinical Gastroenterology & Hepatology https://doi.org/10.1016/j.cgh.2022.04.014.
4. Le P et al. 2023 Clinical Gastroenterology & Hepatology https://doi.org/10.1016/j.cgh.2022.07.033.
5. Wang S et al. 2020 PLoS One https://doi.org/10.1371/journal.pone.0239393.
6. Younossi ZM et al. 2023 Hepatology https://doi.org/10.1097/HEP.0000000000000004.
7. Doffoel M et al. 2025 PLoS One https://doi.org/10.1371/journal.pone.0316158.
8. van Kleef LA et al. 2025 Liver International https://doi.org/10.1111/liv.16169.
9. Hutchinson AL et al. 2023 Journal of Hepatology https://doi.org/10.1016/j.hep.2023.08.030.
10. Harrison SA et al. 2024 New England Journal of Medicine https://doi.org/10.1056/NEJMoa2309000.
