Non-alcoholic steatohepatitis (NASH) is a serious liver condition. It is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in the liver not caused by heavy alcohol use. As NAFLD, and subsequently NASH, become more widespread, interest in effective treatments, particularly medications, is growing.
Understanding NASH
NASH is defined by the presence of fat in the liver, accompanied by inflammation and liver cell damage, with or without scarring (fibrosis). This condition progresses from simple fatty liver, where only fat accumulates, to the more severe NASH, involving inflammation and potential injury to liver cells. Over time, persistent inflammation can lead to fibrosis, which is the formation of scar tissue in the liver. If fibrosis continues to worsen, it can advance to cirrhosis, a severe scarring of the liver that can impair its function and potentially lead to liver failure or liver cancer.
Several factors increase the likelihood of developing NASH, often related to metabolic health. Obesity, type 2 diabetes, and metabolic syndrome are commonly associated with the condition. Metabolic syndrome is a cluster of conditions including a large waist size, high blood pressure, high blood sugar, and abnormal cholesterol or triglyceride levels. Individuals with these risk factors are more susceptible to fat accumulation in the liver, which can then progress to inflammation and damage characteristic of NASH.
Approved Medication for NASH
Resmetirom, marketed as Rezdiffra, is the first and only medication approved by the U.S. Food and Drug Administration (FDA) for NASH. This oral, once-daily medication is approved for adults with non-cirrhotic NASH who have moderate to advanced liver scarring (fibrosis stages F2 to F3). Its approval marks a major advancement, as lifestyle changes were previously the only recommended approach.
Resmetirom functions as a thyroid hormone receptor-beta (THR-β) agonist, primarily targeting receptors in the liver. By selectively activating THR-β, the medication helps reduce fat in the liver by stimulating lipid breakdown and clearance. This action alleviates fat accumulation within liver cells, a hallmark of NASH. Clinical trials showed Resmetirom led to NASH resolution and improved liver fibrosis. Common side effects include diarrhea, nausea, and abdominal pain.
Emerging Medications for NASH
Numerous medications are in various stages of clinical development for NASH treatment. These emerging therapies target different pathways involved in the disease’s progression, including metabolism, inflammation, and fibrosis. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, are being investigated for their ability to reduce liver fat and improve liver histology. These medications, already used for diabetes and weight management, may also impact NASH by improving insulin sensitivity and promoting weight loss.
Farnesoid X receptor (FXR) agonists, like obeticholic acid, represent another class under investigation. FXR agonists work by modulating bile acid pathways, which play a role in liver metabolism, inflammation, and fibrosis. While obeticholic acid has shown promise in improving liver histology, its development has encountered regulatory hurdles. Fibroblast growth factor 21 (FGF21) analogs are also being explored. These analogs, such as pegozafermin, aim to regulate glucose and lipid metabolism, potentially reducing steatosis and lipotoxicity in the liver.
Acetyl-CoA carboxylase (ACC) inhibitors, exemplified by firsocostat, target an enzyme involved in fatty acid synthesis. By inhibiting ACC, these drugs reduce the production of new fats in the liver. The development of these and other mechanisms, including pan-peroxisome proliferator-activated receptor (PPAR) agonists like lanifibranor, reflects the multifaceted approach to address NASH. Many of these emerging therapies are being studied in advanced clinical trials, with the hope of providing additional treatment options.
Lifestyle and Supportive Therapies
Lifestyle modifications are a primary approach for managing NASH. Gradual weight loss through diet and exercise is highly recommended. Losing even 3% to 5% of body weight can begin to reduce fat in the liver, while a loss of 10% or more can lead to significant improvements in liver health, including NASH resolution and fibrosis improvement.
Dietary adjustments involve reducing the intake of sugars, particularly fructose from sweetened beverages, and limiting saturated fats found in high-fat meats, cheese, and processed foods. Adopting a balanced diet rich in fruits, vegetables, and whole grains, similar to a Mediterranean-style diet, is beneficial. Regular physical activity, such as 150 minutes of moderate-intensity exercise per week, can also help reduce liver fat and improve metabolic health, even without substantial weight loss.
Managing co-existing conditions, such as type 2 diabetes, high cholesterol, and hypertension, is another important aspect of NASH care. Effective control of these metabolic disorders can lessen the burden on the liver and slow disease progression. Avoiding alcohol and being mindful of certain medications that may worsen liver health are important supportive measures to protect the liver from further damage. These non-pharmacological strategies are an integral part of NASH management.