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MASH Pathogenesis
Recent Updates in MASH Pathogenesis

Released: December 04, 2023

Expiration: December 04, 2024

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Key Takeaways
  • Nonalcoholic fatty liver disease (NAFLD) was changed to metabolic dysfunction-associated steatotic liver disease (MASLD) and nonalcoholic steatohepatitis (NASH) was changed to metabolic dysfunction-associated steatohepatitis (MASH).
  • Genetics, epigenetics, and environment are all important modifiers in the development of MASLD and MASH.
  • Patients with MASH will be empowered to make lifestyle modifications if they have a good understanding of pathophysiology.

Name Change
At the European Association for the Study of Liver Disease (EASL) Congress 2023, leaders from multinational liver societies announced that steatotic liver disease would be the overarching term to describe various forms of steatosis. The term nonalcoholic fatty liver disease (NAFLD) was changed to metabolic dysfunction-associated steatotic liver disease (MASLD) and nonalcoholic steatohepatitis (NASH) was changed to metabolic dysfunction-associated steatohepatitis (MASH). The new nomenclature is thought to be an affirmative change that is nonstigmatizing.

What Is MASH?
MASLD includes steatotic liver disease that is due to an infiltration of lipid in hepatocytes. MASH is lipotoxicity from a large presence of fat and hepatocyte damage from inflammation, which can affect 3% to 5% of the population worldwide. MASH can be difficult to distinguish from hepatitis caused by alcohol, therefore, alcohol use must be ruled out to diagnose correctly. Patients with MASH can be asymptomatic, and a liver biopsy often is needed to determine MASH vs a simple steatosis. The risk of MASH increases if the patient has obesity, dyslipidemia, glucose intolerance, or hypertension. Genetics, epigenetics, and environment are all important modifiers in the development of MASLD and MASH.

Pathophysiology and Patient Education
Pathophysiology includes steatosis from hepatic triglyceride accumulation, inflammation, and fibrosis. Proposed mechanisms of steatosis include a reduced production of very low-density lipoprotein and decreased fatty acid oxidation with increased free fatty acids directed to the liver. Lipid peroxidative damage to cell membranes may cause inflammation. All of these changes are thought to lead to fibrosis as hepatic stellate cells are stimulated. Cirrhosis and portal hypertension can develop as MASH advances and are conditions providers and patients will want to avoid.

Patients with MASH will be empowered to make lifestyle modifications if they have a good understanding of pathophysiology. Patients often need education to realize how much added sugar is in their diet and how their liver is turning that into fat. Physicians can help encourage patients to lose 10% of their body weight by explaining the positive impact it will have on their liver.

To explain MASH to a patient, I have them think of a liver that is overtaxed from the delivery of too much metabolic substrate, that is, fat and carbohydrates. This can help the patient understand the relationship among MASH, obesity, and diabetes, and why they occur together so often.

It Begins With Adipose Tissue
Adipose tissue plays an important role in MASH. Adipose tissue stores extra energy in the form of triglycerides, but it has limited storage capacity. When the adipose tissue is maxed out, the tissue becomes stressed and fatty acids leak out. The liver then is responsible for managing the excess fatty acids in the blood.

In MASH, the relationship between adipose tissue and the liver varies among different patients. Some patients will get MASH without much adipose tissue where lipodystrophies play a role. These patients have limited adipose tissue storage, due to genetics or medications, and even without having a high body mass index, the liver must handle the fatty acids that cannot be stored as triglycerides in the adipose tissue.

Obesity Connection
Obesity is common in patients with MASH. When a patient loses 10% of their body weight, the liver, among other organs, benefits. The benefit is still seen even if the patient remains obese after the 10% weight loss. The mechanism is most likely due to the adipose tissue’s capacity for excess energy storage in the form of triglycerides. The 10% weight loss relieves the stress on the adipose tissue, which in turn is no longer sending excess fatty acids to the liver that lead to MASH.

Diabetes and Fat
In a world where the prevalence of diabetes is on the rise, it is important for patients to understand that diabetes is another manifestation of adipose tissue not having the capacity to safely store fat. Dysregulated lipid metabolism can be caused by insulin resistance from lipotoxicity.

Some report diabetes is caused by a disease of lipid metabolism that produces a dysregulation of blood glucose levels. Diabetes management has always been heavily focused on glycemic control. However, the inadequate storage of lipids can lead to increased cardiovascular risk if glucose is not controlled correctly. Patients need to be aware that cardiovascular disease is a major cause of mortality in patients with diabetes, especially those with comorbid MASH.

Patients with type 2 diabetes do very well on sodium glucose co-transporter 2 inhibitors and glucagon-like-peptide-1 receptor agonists that help eliminate glucose from the body and improve metabolism, sometimes even promoting weight loss. The drawback for patients is the cost and accessibility of these newer medications.

MASH Treatment
It is thought that as patients understand the pathophysiology and connection to other metabolic conditions such as obesity and diabetes, adherence to lifestyle modifications and therapy options for MASH will improve morbidity and mortality. My colleague, Dr Jesudian, and I will be discussing the management of MASH and future therapeutic options that are in the pipeline. Be sure to watch for future commentaries.

Your Thoughts
How do you talk to your patients about the complex pathogenesis of MASH? Join the conversation by answering the polling question or providing a comment below.

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