SAT-261 - Dual Genetic Drivers of Severe Hypertriglyceridemia and Recurrent Pancreatitis: A Case Highlighting APOA5 and PRSS1 Variants

Background
Familial hypertriglyceridemia (FHTG) is clinically heterogeneous and frequently complicated by acute pancreatitis. Conventional phenotype-based classification often fails to identify patients with combined genetic susceptibility to dyslipidemia and pancreatic injury.

Case

A 55-year-old woman with type 2 diabetes mellitus, obesity (BMI 30.45 kg/m²), and mixed dyslipidemia presented with recurrent acute pancreatitis and persistently lipemic serum. Despite adherence to insulin therapy, metformin, high-intensity statin therapy, saroglitazar, and dietary fat restriction, triglyceride levels remained markedly elevated with poor therapeutic response. She required repeated gastroenterology admissions and pancreatic enzyme supplementation.

Evaluation

Given refractory hypertriglyceridemia and recurrent pancreatitis, whole-exome sequencing was performed. A homozygous APOA5 variant (c.333G>T; p.Met111Ile; VUS) was identified, a gene implicated in triglyceride-rich lipoprotein metabolism and late-onset hyperchylomicronemia. In addition, heterozygous PRSS1 variants were detected, including p.Asn29Ile (pathogenic) and p.Leu14Val (VUS), consistent with hereditary pancreatitis susceptibility. The PRSS1 pathogenic variant has established functional effects on trypsinogen activation, predisposing to recurrent pancreatic inflammation.

Management and Outcome

Management was intensified with strict dietary fat restriction, optimized insulin therapy, planned initiation of icosapent ethyl, and genetic counselling. Recognition of a dual genetic etiology explained disease severity, therapeutic resistance, and recurrence risk.

Conclusion

This case illustrates a dual-hit model in which genetically mediated hypertriglyceridemia (APOA5) coexists with inherited pancreatic susceptibility (PRSS1), resulting in severe, recurrent pancreatitis. Early genomic evaluation should be considered in patients with refractory hypertriglyceridemia and pancreatitis to enable precision management and risk stratification.

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