Non-alcoholic steatohepatitis (NASH) is a severe and increasingly common form of liver disease characterized by fat accumulation, inflammation, and liver cell damage. With few effective treatments, the medical community is researching new strategies. One of the most promising involves the naturally occurring hormone Fibroblast Growth Factor 21 (FGF21), a protein notable for its potential to address the multiple facets of liver damage seen in NASH.
Understanding Non-alcoholic Steatohepatitis (NASH)
Non-alcoholic fatty liver disease (NAFLD) is caused by fat buildup in the liver. While simple fatty liver may not cause problems, NASH is a dangerous progression defined by liver inflammation and cellular injury in addition to the excess fat. This inflammation is a response to the stress from fat accumulation and can lead to cellular damage.
The primary risk factors for NASH are linked to metabolic disorders, often called metabolic syndrome. These include:
- Obesity
- Type 2 diabetes
- High blood pressure
- Abnormal levels of fats in the blood
These conditions promote fat storage in the liver, increasing the likelihood of inflammation.
The danger of NASH is its potential to advance to more severe liver conditions. The chronic inflammation and cell death trigger the formation of scar tissue, a process called fibrosis. Over time, extensive scarring can lead to cirrhosis, where the liver is permanently damaged. Cirrhosis increases the risk of liver failure and a type of liver cancer called hepatocellular carcinoma.
The Natural Role of Fibroblast Growth Factor 21 (FGF21)
Fibroblast Growth Factor 21 is a hormone-like protein produced mainly by the liver that regulates metabolism. Its production is stimulated by metabolic stresses like prolonged fasting or high-fat diets. Once released, FGF21 travels to different tissues to exert its effects.
The primary functions of FGF21 are centered on maintaining metabolic balance. It helps increase glucose uptake by cells, which can lower blood sugar. The hormone also influences lipid metabolism by promoting the breakdown of fats and reducing triglyceride production in the liver.
These actions help the body efficiently use and store energy, preventing the harmful accumulation of fats. By promoting energy expenditure and insulin sensitivity, FGF21 helps coordinate the body’s response to nutrient availability and maintain a healthy metabolic state.
The Therapeutic Mechanism of FGF21 in NASH
The therapeutic potential of FGF21 for NASH comes from its ability to target multiple aspects of the disease. One action is reducing liver fat, an anti-steatotic effect. FGF21 enhances the liver’s ability to burn fatty acids for energy, which helps clear the excess fat that accumulates in liver cells.
FGF21 also has anti-inflammatory properties. Since chronic inflammation in NASH drives liver cell injury, FGF21’s ability to suppress these inflammatory pathways is beneficial. This action helps protect liver cells from further damage and death.
Another therapeutic action of FGF21 is its anti-fibrotic effect. FGF21 directly interferes with the activation of hepatic stellate cells, the primary cells responsible for producing scar tissue in the liver. By inhibiting these cells, FGF21 can slow or even reverse the progression of fibrosis.
FGF21 Analogs in Clinical Trials
Natural FGF21 has beneficial effects, but its short half-life limits its therapeutic use. Researchers developed FGF21 analogs, which are modified versions of the hormone designed to last longer in the bloodstream. These engineered proteins retain the therapeutic actions of FGF21 but allow for less frequent dosing, like once-weekly injections.
Several FGF21 analogs, including pegozafermin and efruxifermin, have been evaluated in clinical trials for NASH. Studies focus on endpoints defined by regulatory agencies for approval. These include “NASH resolution without worsening of fibrosis” and “improvement in fibrosis by at least one stage without worsening of NASH.”
Results from these trials show that a significant percentage of patients treated with FGF21 analogs have improved liver fat content and fibrosis. For example, some studies found that treatment for 24 to 48 weeks led to a statistically significant number of patients achieving at least a one-stage improvement in liver fibrosis.
Current Status and Future Outlook
FGF21 analogs are a promising class of drugs for NASH, with several candidates in late-stage clinical development. Some are under review by regulatory bodies like the U.S. Food and Drug Administration (FDA) for potential approval. This progress is important due to the limited treatment options for NASH.
Despite promising efficacy, FGF21 analogs are associated with certain side effects. The most commonly reported adverse events are gastrointestinal, including nausea, diarrhea, and vomiting. These side effects are generally mild to moderate but can impact patient tolerability.
The development of FGF21 analogs is a significant step for NASH therapies. By targeting the underlying metabolic, inflammatory, and fibrotic consequences of the disease, these drugs have the potential to become a foundational treatment. The ability of these agents to improve liver fibrosis is important, as fibrosis progression is a strong predictor of adverse clinical outcomes in patients with NASH.