One major contributor to the rise in liver disease is metabolic dysfunction-associated steatohepatitis (MASH), a severe condition linked to poor diet and obesity. A recent study, published in Hepatology, has provided new insights into the pathology of MASH, focusing on the role of T lymphocytes in the disease progression.
Researchers, led by Burtis and colleagues, investigated the characteristics and functions of T cells in individuals with liver cirrhosis and an animal model of MASH. They discovered that T cells, particularly CD8+ T cells, accumulate in the liver during MASH, multiplying and altering their function in response to harmful substances associated with poor diet. This accumulation is similar to what occurs during infections like Hepatitis C, suggesting a potential role for antigen-activated CD8+ T cells in MASH pathogenesis.
The study highlights that antigenic stimulation likely drives T-cell accumulation and chronic exhaustion in MASH. Understanding this process may help identify the specific substances that trigger T cell activation and growth in the liver, paving the way for developing a biomarker test. Such a test could enable doctors to track and treat the disease’s progression before it reaches a late stage, potentially preventing the need for liver transplants.
MASH is a slow-progressing disease, often taking decades to fully develop. Despite its gradual progression, it is rapidly becoming the most prevalent liver disease worldwide. According to a study by Harrison et. al, in the United States, approximately 40% of adults are obese, and around 14% of asymptomatic middle-aged individuals have biopsy-proven MASH. The increasing prevalence of MASH underscores the urgent need for better understanding and earlier diagnosis.
CD8+ T cells, or cytotoxic T lymphocytes, play a significant role in the pathogenesis of metabolic-associated steatotic hepatitis (MASH), which is often linked to obesity and metabolic syndrome. These T cells are activated in response to liver injury and inflammation, contributing to the immune response against stressed or damaged hepatocytes due to fat accumulation and metabolic disturbances. Their cytotoxic activity can directly kill hepatocytes through the release of perforin and granzymes, leading to apoptosis and exacerbating liver inflammation. Additionally, CD8+ T cells produce pro-inflammatory cytokines, such as IFN-γ and TNF-α, which further stimulate inflammatory pathways in the liver and increase liver injury and fibrosis. They also interact with other immune cells, amplifying the inflammatory response, and their chronic activation can lead to the development of fibrosis by promoting hepatic stellate cell activation and extracellular matrix deposition. Furthermore, CD8+ T cells may be influenced by immune checkpoint pathways, which can modulate their activity and impact the progression of MASH. Overall, CD8+ T cells contribute to both the immune response and the worsening of liver pathology in MASH, making them important targets for therapeutic interventions aimed at reducing liver inflammation and preventing disease progression.
Burtis and his team discovered that during MASH, T cells multiply and alter their function in response to harmful substances linked to poor diet. The study revealed that clonally expanded CD8+ T cells accumulate in the livers of both humans and mice with MASH, similar to the response seen in infections such as Hepatitis C. This finding suggests that antigen-activated CD8+ T cells play a crucial role in the disease’s progression. The researchers stress the need for further studies to comprehend the timing and persistence of antigen-driven T-cell responses in the liver and their role in disease progression and resolution.
The global rate of liver transplantation is on the rise, driven by an increasing number of individuals developing liver disease due to poor diet and alcohol consumption. As the burden of liver disease grows, the demand for liver transplants has surged. In 2021, there were 34,694 liver transplants performed worldwide, marking a 6.5% increase from 2020 and a 20% increase from 2015, involving both living and deceased donors. However, access to transplants varies significantly across different regions. Overall, the findings from the study suggest that advancing knowledge of MASH pathophysiology can lead to earlier interventions and improved therapeutic strategies, ultimately reducing the reliance on liver transplantation as a treatment option for advanced liver disease.
References
- Burtis AEC, DeNicola DMC, Ferguson ME, Santos RG, Pinilla C, Kriss MS, et al. Ag-driven CD8+ T cell clonal expansion is a prominent feature of MASH in humans and mice. Hepatology. :10.1097/HEP.0000000000000971.
- Terrault NA, Francoz C, Berenguer M, Charlton M, Heimbach J. Liver Transplantation 2023: Status Report, Current and Future Challenges. Clinical Gastroenterology and Hepatology. 2023 Jul;21(8):2150–66.
- Harrison SA, Gawrieh S, Roberts K, Lisanti CJ, Schwope RB, Cebe KM, et al. Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort. Journal of Hepatology. 2021 Aug 1;75(2):284–91.