Untreated MASH Can Be a Driver of Liver Disease

Modern gasoline engines are things of wonder. Precise amounts of air and fuel enter a compression chamber, are smashed into a tiny space, and then combust with the help of a spark igniting at the exact right time. The precision of the engine has a little wiggle room; you can often add extra air to the process and get a boost of power, but adding more fuel doesn’t work like that. Too much gas floods the engine, and instead of exploding, the fuel sits unburnt in the cylinders and clogs everything up. An occasionally flooded engine isn’t great, but repeated flooding can damage spark plugs, rods, pistons, and ultimately lead to the degradation and destruction of the entire engine.

This process is strikingly similar to what happens with fatty liver disease, properly termed metabolic dysfunction–associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis, or MASH (formerly known as non-alcoholic steatohepatitis, NASH). At its most basic level, MASLD is a chronic liver disease in which there is too much fat buildup in the liver, causing inflammation and damage.^[1,2]

Around 1 in 4 people worldwide have MASLD, making it the most common liver disease and a leading cause of liver cancer and cirrhosis.^[2,3,4] Between 12% and 40% of people with MASLD progress to MASH, and the numbers of both have increased precipitously over the past 35 years.^[2,3] Risks of developing or exacerbating MASLD and MASH include:^[4]

• genes involved with the metabolism of fats and sugars in the liver, 
• environmental factors like low exercise, high-sugar diets, and alcohol
• and medical issues like being obese, type 2 diabetes, high blood pressure, high cholesterol, and cardiovascular disease.

Many people with MASLD and MASH have no symptoms, but some experience abdominal pain, fatigue, and/or weakness. Untreated MASH can be a driver of cirrhosis, liver cancer, diabetes, chronic kidney disease, and muscle loss.^[2]

So why is the liver so important anyway? A lot of cardiologists think the heart is the engine of the body, but the liver is where the power is really made. The liver is the metabolic center of the body; it determines how to convert the fats, sugars, and proteins we eat into the energy we use and store.^[1] Food we eat is broken down, then takes a direct road to the liver, which incorporates signals from the intestines and the body’s fat cells to process, package, and deliver processed (metabolized) food remnants to other parts of the body.^[1] Normally the liver absorbs and makes some fats, but with MASLD and MASH, the mixture is too rich. When more than 5% (by weight) of the liver is made of fatty triglycerides, you have MASLD.^[1] When that fat starts causing inflammation, cell damage, and scarring fibrosis, you have MASH.^[1] 

Now, let’s change gears and examine what goes wrong with the liver to transition from MASLD to MASH. Beyond the risk factors, the first shift to a degraded liver is diet. A diet high in sugar, high fructose corn syrup, and saturated fats creates an excess of energy in the intestines; a gut glut, if you will. Some of the extra sugars ferment into alcohol, and all of it travels to the liver.^[1,5] In the liver, sugars are converted to fats, excess fats damage mitochondria (the powerhouses of the cells), and extra sugar lowers the liver’s sensitivity to insulin (this is exacerbated by diabetes).^[1,4,6] Extra fats, both absorbed and created in the liver from sugar, cause liver cells to grow and release inflammatory molecules.^[4] Normal liver cells are edged out by hepatic stellate cells, which have less mitochondrial function and which try to “fix” the liver by building scar tissue in a process called fibrosis.^[4] With time, the machinery of the liver gets degraded: mitochondria are damaged, the liver can’t metabolize food as well, liver cells are distorted and replaced, and inflammation runs rampant. Luckily, even at this stage, it isn’t too late to shift into reverse and get out of MASH.

The most obvious route, if one of the hardest, is lifestyle modification. Cutting body weight by 5-10% may help, especially when achieved through a combination of diet and exercise. A doctor may also recommend obesity medications - though only one is FDA approved for MASH - or bariatric surgery.^[1] Diabetes medications, also occasionally prescribed off-label, may help increase insulin sensitivity and help the liver process food more effectively.^[1] Currently, the only two FDA-approved medications for MASH are resmetirom, marketed as Rezdiffra, and semaglutide, marketed as Wegovy.^[1] Resmetirom, which underwent clinical trials and was approved in 2024, increases the ability of the liver to process fats and is thought to improve mitochondrial function, tuning up the liver.^[1] Semaglutide, just approved in 2025, is a GLP-1 inhibitor originally targeted for diabetes, then weight loss, and now also MASH.^[7] More clinical trials are on the horizon, including ones that mimic FGF21, a hormone that helps regulate metabolism.^[8] Scientists think this hormone evolved to help protect the liver from times when early humans found abundant sources of food and gorged themselves.^[8] It seems to help relieve some of the stress on the liver from excess sugars and fats, helps balance intake levels, redirects energy away from the liver, and may reduce fibrosis due to MASH.^[8] Whether the medications that mimic FGF21 can achieve the same effects remains to be seen in clinical trials. Luckily, trials that target MASH are revving up and ready to bring us across the finish line to healthier livers!

Creative Director Benton Lowey-Ball, BS, BFA

References:

[1] Steinberg, G. R., Valvano, C. M., De Nardo, W., & Watt, M. J. (2025). Integrative metabolism in MASLD and MASH: pathophysiology and emerging mechanisms. Journal of Hepatology, 83(2), 584-595. https://www.sciencedirect.com/science/article/pii/S0168827825001424

[2] Younossi, Z. M., Kalligeros, M., & Henry, L. (2024). Epidemiology of metabolic dysfunction-associated steatotic liver disease. Clinical and molecular hepatology, 31(Suppl), S32. https://pmc.ncbi.nlm.nih.gov/articles/PMC11925440/

[3] Younossi, Z. M., Golabi, P., Paik, J. M., Henry, A., Van Dongen, C., & Henry, L. (2023). The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology, 77(4), 1335-1347. https://journals.lww.com/hep/fulltext/2023/04000/the_global_epidemiology_of_nonalcoholic_fatty.27.aspx

[4] Allen, A. M., Younossi, Z. M., Diehl, A. M., Charlton, M. R., & Lazarus, J. V. (2024). Envisioning how to advance the MASH field. Nature Reviews Gastroenterology & Hepatology, 21(10), 726-738. https://www.nature.com/articles/s41575-024-00938-9

[5] Elshaghabee, F. M., Bockelmann, W., Meske, D., De Vrese, M., Walte, H. G., Schrezenmeir, J., & Heller, K. J. (2016). Ethanol production by selected intestinal microorganisms and lactic acid bacteria growing under different nutritional conditions. Frontiers in microbiology, 7, 47.

[6] Bauer, D. C., & McPhee, S. J. (2013). Pathophysiology of Disease: An Introduction to Clinical Medicine.  P412-413

[7] U.S. Food and Drug Administration. (2025, August 15). FDA approves treatment for serious liver disease known as “MASH”. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash