Highlights

• Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia and a high risk of recurrent acute pancreatitis.
• Diagnosis of FCS requires clinical suspicion, severe persistent hypertriglyceridemia, and genetic testing for pathogenic variants in LPL and related genes.
• Strict dietary fat restriction (<10%-15% of daily caloric intake) remains the cornerstone of FCS management, with APOC3 inhibitors—such as the recent FDA-approved olezarsan—showing promise in reducing triglyceride levels and pancreatitis risk.
• Pregnant patients with FCS are at high risk for severe hypertriglyceridemia-induced pancreatitis, requiring close monitoring, aggressive dietary management, and potential therapeutic plasma exchange (TPE).
• A multidisciplinary approach, including lipidologists, dietitians, and genetic counselors, is essential for optimizing care and improving patient outcomes.

Abstract

Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprotein lipase (LPL) activity. This expert opinion statement synthesizes current knowledge on the definition, pathophysiology, genetics, prevalence, diagnosis, and management of FCS. FCS typically manifests at a young age with persistent severe hypertriglyceridemia—defined as ≥10 mmol/L (≥885 mg/dL), or ≥1000 mg/dL (≥11.2 mmol/L) depending on region and whether Systeme International (SI) units are utilized—in the absence of secondary factors, resistance to conventional lipid-lowering therapies, and a high lifetime risk of acute pancreatitis. It is caused by biallelic pathogenic variants in the LPL gene encoding LPL, or 1 of 4 other related genes that encode proteins that interact with LPL. Affected individuals require a strict, lifelong very low-fat diet with <15% of energy from fat. Emerging therapies inhibiting apolipoprotein C-III show promise in reducing serum triglycerides and pancreatitis risk in patients with FCS. A multidisciplinary approach, encompassing dietary management, pharmacotherapy, and patient education, is pivotal in mitigating the significant morbidity associated with FCS.