Hypertriglyceridemic acute pancreatitis (HTG-AP) is a unique form of pancreatitis characterized by extremely high triglyceride levels in the blood, often exceeding 1000 mg/dL. This type of pancreatitis has become more prevalent due to the global rise in obesity, diabetes, and metabolic syndrome, and it now ranks as the third leading cause of pancreatitis. Epidemiological studies show that HTG-AP accounts for a significant portion of all pancreatitis cases, particularly in Eastern populations, where it can reach nearly 30% in some Asian cohorts. Research has also revealed a higher incidence and mortality rate in Eastern countries compared to Western populations.
HTG-AP tends to affect younger individuals, with men being disproportionately affected. Patients often have metabolic risk factors such as obesity, diabetes, excessive alcohol consumption, or familial hyperlipidemia. Clinically, HTG-AP presents similarly to other forms of pancreatitis, with persistent epigastric pain, nausea, vomiting, and elevated pancreatic enzymes. However, it is often more severe, with rapid onset, extensive pancreatic necrosis, and a heightened systemic inflammatory response, leading to respiratory failure, acute kidney injury, and circulatory collapse more frequently. Studies report that severe cases can reach 30-40%, with an overall mortality rate of 5-15%, significantly higher than biliary or alcoholic pancreatitis.
The serum triglyceride concentration at admission is closely linked to the extent of pancreatic necrosis, systemic inflammation, and clinical outcome. When triglyceride levels exceed 2000 mg/dL, the risk of severe pancreatitis and organ failure increases markedly. Consequently, HTG-AP presents a significant challenge in managing severe pancreatitis. Patients with HTG-AP often experience impaired metabolic recovery and incomplete restoration of pancreatic function. Follow-up studies show that approximately 20-30% of patients develop pancreatic exocrine insufficiency within six months, leading to steatorrhea, weight loss, and malnutrition. Some patients also develop impaired glucose tolerance, secondary diabetes mellitus, and pancreatic cancer, with a markedly increased risk of recurrent pancreatitis. Additionally, 15-25% of patients progress to pancreatogenic diabetes due to sustained β-cell dysfunction and persistent insulin resistance. The incidence of chronic pancreatitis is also elevated, with structural changes and pancreatic fibrosis occurring within one to three years after the initial episode in a subset of patients.
Recent advancements have highlighted the role of ferroptosis, a novel type of controlled cell death characterized by iron-dependent lipid peroxidation, as a key element in the pathogenesis of HTG-AP. This review explores the underlying mechanisms of ferroptosis in HTG-AP, focusing on lipid peroxidation, iron catalysis, and their synergistic effects on pancreatic injury related to hypertriglyceridemia. By doing so, it sheds light on the emerging links between metabolic disorders and cell death pathways.
In terms of treatment, this review discusses current therapeutic approaches and their limitations, emphasizing the potential of ferroptosis inhibitors as promising therapeutic agents that could fundamentally alter the treatment landscape. However, challenges such as treatment specificity and adverse effects remain significant barriers. This paper aims to synthesize existing research findings and propose future directions for HTG-AP research, recognizing the potential of ferroptosis as a therapeutic target to enhance our understanding of clinical treatment strategies for HTG-AP.
