Metabolic Dysfunction and Fatty Liver Disease: The Connection and Progression

Metabolic Dysfunction and Fatty Liver Disease: The Connection and Progression

What is Metabolic Dysfunction Associated Fatty Liver Disease (MDAFLD)?

The current definition is independent of other liver diseases and includes evidence of fat buildup on the liver, and one of the following: obesity, presence of Type 2 diabetes, or evidence of metabolic dysfunction¹. But what is metabolic dysfunction? This means that the body’s metabolism is not working properly and is unbalanced at turning our food into energy to fuel our bodies. This can cause our bodies to hold onto more fat, which then deposits onto our liver ². MDAFLD affects about a quarter of the world’s population and is considered the most common cause of chronic liver disease worldwide¹. The increased rate of occurrence has been explained by a rise in inactive lifestyles and high-calorie and unhealthy diets¹. Testing for this includes a biopsy to confirm and assess liver damage. Imaging like an ultrasound or MRI can be used to visualize fat accumulation and blood tests can be used to evaluate liver function¹. Additionally, until recently there were no approved pharmacotherapy options so treatment focused mostly on lifestyle changes ². However, recommendations are changing with new research coming out. Understanding the connection between these two health conditions, and how they can progress to more serious issues is essential in prevention and treatment.

The Connection and Impact on Health

The liver is an important organ with several functions including regulating the production and usage of sugar (glucose) as well as the breakdown of fat (fatty acids or lipids). When there is liver damage and imbalances in hormones such as insulin and glucagon, the regulation of these functions is impaired. This can cause an increase in lipogenesis where the fatty acids are converted into fats for storage, and fat builds up. These imbalances are also linked to insulin resistance and increased inflammation and stress on the liver, which can impact other responses and cause more permanent damage. There is a strong correlation between obesity and diabetes with MDAFLD. Progression then can not only become more permanent but also more serious if steps are not taken early on including lifestyle changes, pharmacological interventions, and monitoring. Without the proper care, damage and cirrhosis or scarring takes over healthy tissues, decreasing liver function which is much more difficult to treat. Further damage may even lead to possible cancer of the liver¹. Additionally, unaddressed metabolic dysfunction can proceed to further metabolic disorders and complications including cardiovascular disease, diabetes, and greater liver damage¹. The more it progresses, the worse the disease becomes and the harder it is to reverse and treat the damage. That is why treating and preventing the progression of MDAFLD is really a multi-step process and should focus on the many factors playing a role in this disease.

Treatment

Lifestyle Changes

The literature focuses on lifestyle changes to help reduce the burden and progression of MDAFLD. The Mediterranean diet has the most supporting data showing that even without weight loss, this diet can reduce fat buildup on the liver ³. Furthermore, this diet can also improve insulin sensitivity in insulin resistance and has shown better efficacy than other caloric restriction diets³. However, data also shows that weight loss has the strongest ability to improve disease, with a direct correlation between the amount lost and the outcomes⁴. Many recommendations for diet include caloric restrictions with a goal to lose 0.5- 1 kg a week. Diet should resemble 50-60% of calories from carbohydrates and around 20-25% fat where less than 10% of total fat intake is saturated fats⁴. Although many recommendations focus on low calories with percentages of nutrients, many very low-calorie diets have not shown long-term benefits due to the low likelihood of being continuously followed⁷. Overall the low glycemic index Mediterranean diet showed fast improvement in a short amount of time, and may be more beneficial than just restrictive diets ⁷. It emphasizes fruits, vegetables, whole grains, lean proteins, and healthy fats, and can decrease severity, progression, and complications working as primary prevention of Type 2 diabetes and cardiovascular disease⁷. Also, snacking should be avoided as it can increase fat in our bodies independent of our calorie content and weight gain⁷.

Regular exercise has a positive impact on weight loss, but also overall health, and exercise independent of weight loss has shown benefits on both liver and heart health⁸. The American Association for the Study of Liver Diseases recommends regular moderate exercise at least 5 times a week for a total of 150 minutes a week⁸. Moderate physical activity would be like brisk walking or resistance training where you are sweating but not out of breath so you can still hold a conversation. However, if this is not tolerated, increasing activity by over an hour a week can prevent and improve disease⁸. Therefore, diet and exercise should be tailored to each patient with the guidance of your physician but the benefit of each is directly related to the intensity, so it is encouraged to exercise and follow a diet as much as possible⁸. Furthermore, alcohol should be avoided due to its damaging effects on our bodies and specifically our liver.

Pharmacotherapy

Many of the medications studied for MDALFD have not shown a significant benefit, like metformin, or have shown some benefit in fat-build up and inflammation, like pioglitazone, but no significant disease-specific benefit⁴. Supplementation with Vitamin E showed improvement in fatty liver build-up, however, further research should be done to see how great disease-specific benefits are and in what patient populations they should be utilized⁴. Another medication class used in the management of diabetes and weight is Glucagon-Like Peptide-1 Receptor Agonists (GLP-1s). This class of medication has drastically changed the treatment of diabetes, working its way into the guidelines and acquiring strong recommendations in obesity and diabetes management. Research is evaluating the use of these medications in MDAFLD and some have shown benefits in obesity, type II diabetes, and reversal of fatty liver. Additionally, data is showing reduced cardiovascular risk, decreased scarring, and other complications.⁹

In March of 2024, the FDA approved resmetirom (Rezdiffra) for the treatment of MDAFLD⁵. However, notably, this medication does not replace lifestyle changes but rather should be used in combination with diet, exercise, and avoidance of alcohol for best outcomes. The data for this medication has shown improvements and even complete resolution of liver scarring and fat build-up⁵. It works to reactivate liver cells that have become inactive due to the disease, leading to a reduction of fat on the liver ⁶. This also improves liver scarring by 1.5-2 times and reduces disease progression by 2-3 times⁶.

Conclusion

With all of this information it is clear more research is required and with that new therapies and recommendations are going to emerge. However, no matter what new therapies come out it is clear that the one of the best things you can do for your health and disease progression is lifestyle modifications. If you need help working on the basics of lifestyle modification or don’t know where to start, you can access our free Foundations of Wellness course here.

Written by Abigail LaGreca, PharmD
Edited by Lindsey Dalton, PharmD

References

1. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of Hepatology. 2020;73(1):202-209. doi:10.1016/j.jhep.2020.03.039 
2. What is metabolic dysfunction-associated steatotic liver disease? Cleveland Clinic. May 1, 2024. 
3. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, O’Dea K, Desmond PV, Johnson NA, Wilson AM. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol. 2013 Jul;59(1):138-43. doi: 10.1016/j.jhep.2013.02.012. Epub 2013 Feb 26. PMID: 23485520. 
4. Godoy-Matos AF, Silva Júnior WS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr. 2020;12:60. Published 2020 Jul 14. doi:10.1186/s13098-020-00570-y 
5. Commissioner O of the. FDA approves first treatment for patients with liver scarring due to fatty liver disease. U.S. Food and Drug Administration. March 2024. 6. About: RezdiffraTM (resmetirom). Rezdiffra. October 2024. 
6. Misciagna G, Del Pilar Díaz M, Caramia DV, Bonfiglio C, Franco I, Noviello MR, Chiloiro M, Abbrescia DI, Mirizzi A, Tanzi M, Caruso MG, Correale M, Reddavide R, Inguaggiato R, Cisternino AM, Osella AR. Effect of a Low Glycemic Index Mediterranean Diet on Non-Alcoholic Fatty Liver Disease. A Randomized Controlled Clinici Trial. J Nutr Health Aging. 2017;21(4):404-412. doi: 10.1007/s12603-016-0809-8. PMID: 28346567. 
7. Rinella, Mary E.1; Neuschwander-Tetri, Brent A.2; Siddiqui, Mohammad Shadab3; Abdelmalek, Manal F.4; Caldwell, Stephen5; Barb, Diana6; Kleiner, David E.7; Loomba, Rohit8. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77(5):p 1797-1835, May 2023. DOI: 10.1097/HEP.0000000000000323 
8. The emerging role of glucagon-like peptide-1 receptor agonists for the treatment of metabolic dysfunction-associated steatohepatitis – sciencedirect. Accessed December 1, 2024. https://www.sciencedirect.com/science/article/pii/S1542356524001605.