This young woman had multiple features strongly suggestive of FCS: extreme TG level elevation (>1000 mg/dL) without secondary causes (glucose, thyroid, and LFT values within the reference ranges; no TG level–raising medications; no alcohol use; low-fat diet), recurrent pancreatitis from early adulthood, family history of pancreatitis, severe hyperlipidemia at a young age, and milky plasma on repeated testing.
FCS is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations in lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1), or lipase maturation factor 1 (LMF1)—all of which are essential for normal lipoprotein lipase (LPL)–mediated lipolysis of chylomicrons. Unlike polygenic or multifactorial HTG, FCS does not respond to conventional fibrate or omega-3 therapy, and distinction matters because novel RNA-targeted therapies (e.g., olezarsen, plozasiran) are available and appropriate referral is critical.
Empiric fibrate and omega-3 initiation without a definitive diagnosis delays appropriate workup in a patient with a strong FCS phenotype. Standard lipid-lowering medications are largely ineffective in FCS because LPL activity is absent or severely impaired; treating without confirming the diagnosis risks repeated hospitalizations.
A secondary-cause screen is important and was appropriately conducted in this patient (her laboratory study results already showed TSH level, glucose level, and LFT values within the reference ranges, and there was an absence of contributing medications); her results effectively excluded secondary causes. Diagnosing a patient with polygenic HTG without pursuing genetic confirmation in the setting of a compelling FCS phenotype is inadequate; genetic testing does not influence management in typical polygenic HTG but is decisive in suspected monogenic disorders.
A very-low-fat diet (<15 g/day in FCS; sometimes <5 g/day during acute flares) is a cornerstone of management in confirmed FCS, and appropriate dietary counseling should be initiated promptly. However, referring for bariatric surgery would not be appropriate for her; she did not have obesity and FCS is not a disease of caloric excess or insulin resistance. Surgical intervention would not address the underlying enzymatic defect.
This patient case quiz is part of the larger Hypertriglyceridemia (HTG) and Cardiovascular (CV) Health: Recognizing Risks and Tackling Management initiative, supported by Ionis Pharmaceuticals. To visit the HTG and CV Health grant page and access additional educational activities on this topic, click here.
References
- Saadatagah S, Larouche M, Naderian M, et al. Recognition and management of persistent chylomicronemia: a joint expert clinical consensus by the National Lipid Association and the American Society for Preventive Cardiology. J Clin Lipidol. 2025;19(4):723-736. doi:10.1016/j.jacl.2025.03.012
- Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200-2206. doi:10.1056/NEJMoa1400284
- Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(9):2969-2989. doi:10.1210/jc.2011-3213
- Stroes E, Moulin P, Parhofer KG, Rebours V, Löhr JM, Averna M. Diagnostic algorithm for familial chylomicronemia syndrome. Atheroscler Suppl. 2017;23:1-7. doi:10.1016/j.atherosclerosissup.2016.10.002
