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Context Severe hypertriglyceridemia (fasting triglycerides (TG) concentration ≥ 10 mmol/L) can be caused by multifactorial chylomicronemia syndrome (MCS) or familial chylomicronemia syndrome (FCS). Both conditions are associated with an increased risk of acute pancreatitis. The clinical differences between MCS patients with or without a rare variant in TG-related genes have never been studied. Objectives To compare the clinical and biochemical characteristics of FCS, positive-MCS patients and negative-MCS patients, as well as to investigate the predictors of acute pancreatitis in MCS patients. Methods All patients referred at the clinic for severe hypertriglyceridemia underwent genetic testing for the 5 canonical genes involved in TG metabolism (LPL, APOC2, GPIHBP1, APOA5, and LMF1) using next-generation sequencing. Results A total of 53 variant negative-MCS, 22 variant positive-MCS and 28 FCS subjects were included in this retrospective cross-sectional study. A significant difference was observed in the prevalence of pancreatitis (9%, 41% and 61%) and multiple pancreatitis (6%, 23% and 46%) in the negative-MCS, the positive-MCS and the FCS groups, respectively (P<0.0001). Predictors of pancreatitis among MCS subjects included the presence of a rare variant, lower apolipoprotein B, as well as a higher GGT, maximal TG value and fructose consumption. Conclusion We observed that the MCS individuals who carried a rare variant have an intermediate phenotype between FCS and negative-MCS subjects. Since novel molecules such as the antisense oligonucleotide against APOC3 mRNA showed high efficacy in reducing TG levels in patients with multifactorial chylomicronemia, identification of higher-risk MCS patients that would benefit from additional treatment is primordial.

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