Familial chylomicronemia syndrome (FCS)

FCS is a genetic form of severe hypertriglyceridemia (sHTG) caused by mutations in the gene encoding lipoprotein lipase (LPL) or by mutations in genes encoding proteins necessary for LPL function. This condition manifests in physical complications such as lipemia retinalis, eruptive xanthomas, and an increased risk of potentially life-threatening acute pancreatitis (AP). Read about identifying, diagnosing, and managing FCS.^1,2

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About FCS

Familial chylomicronemia syndrome (FCS) is an underdiagnosed genetic form of severe hypertriglyceridemia (sHTG)³

Patients with FCS have triglyceride levels that are 10 to 100 times the normal value^1,4

FCS is caused by complete or partial deficiency of LPL activity due to mutations in the gene encoding LPL or by mutations in genes encoding proteins necessary for LPL function, leading to the accumulation of very low-density lipoproteins (VLDL) and chylomicrons, leaving individuals with severely elevated triglyceride levels and an increased risk of pancreatitis.^1,4

The resulting overabundance of chylomicrons contributes to morbidity

Acute pancreatitis (AP) prevalence as high as 75% has been reported^5*

Recurrent pancreatitis rates as high as 48% have been reported^6†

Mortality rate for recurrent AP reported to be 6%^7‡

Increased risk of organ failure, pancreatic necrosis, and type 3c pancreatogenic diabetes due to chronic pancreatitis^8,9

A retrospective review of patients with triglyceride levels >1000 mg/dL with or without a history of acute pancreatitis (N=32) over a median of 44 months. Estimated overall incidence rate of   acute pancreatitis of 42 per 1000 person-years in FCS and 13 per 1000 person-years in multifactorial chylomicronemia syndrome (MCS).⁵

^†

A retrospective study comparing the clinical and biochemical characteristics of patients with genetically confirmed FCS (n=25) or MCS (n=36).⁶

^‡

Survey of lipidologists on the incidence and outcomes of recurrent acute pancreatitis in patients with FCS (N=251).⁷

apoB-48=apolipoprotein B-48; apoC-III=apolipoprotein C-III; LPL=lipoprotein lipase.

Identifying FCS

The rarity of FCS and overlapping features with MCS—another form of genetic sHTG—often make it difficult to diagnose.¹¹

Comparison of FCS and MCS clinical and genetic features
Clinical/genetic feature	FCS	MCS
Triglyceride levels	Persistently ≥880 mg/dL²	Intermittently ≥880 mg/dL²
Response to pharmacologic treatment	Minimal to no effect (fibrates, niacin, omega-3 fatty acid supplements, and statins)¹²	Variable response (omega-3 fatty acid supplements and niacin)¹²
Genetic basis	Can be monogenic¹³	Polygenic⁶
Age of onset	Often younger (childhood/adolescence)^3,5	Often older (mostly adulthood)⁵
Body weight	Often within normal body mass index (BMI) range⁶	Often overweight (BMI between 28 and 30 kg/m²)⁶
Secondary factors	Less likely (except pregnancy/hormonal birth control)²	Likely (metabolic syndrome)²
Population frequency	1-13 per 1 million people^10,13	Up to 4000 per 1 million people⁶

Diagnosing FCS

Key clinical features that suggest familial chylomicronemia syndrome (FCS)

Generally, the following should prompt the use of established diagnostic scoring criteria and genetic testing to diagnose FCS²

Fasting triglyceride levels  ≥880 mg/dL that are refractory to standard triglyceride-lowering therapies

No known secondary causes for their severe hypertriglyceridemia* (eg, certain conditions or medications)

Recurrent abdominal pain or history of acute pancreatitis

Hypertriglyceridemia can be caused by medications such as glucocorticoids, ethinylestradiol, and neuroleptics, or conditions such as uncontrolled diabetes, hypothyroidism, and pregnancy.²

Diagnostic considerations may include²:

Eruptive xanthomas^†

Lipemic blood

Lipemia retinalis^‡

^†

^‡

Photograph republished from Lai CC, Chang CH. Taiwan J Ophthalmol. 2021;11(4):405-407 under terms of Creative Commons 4.0 License.

Diagnostic scoring tools

Diagnostic scoring tool for familial chylomicronemia syndrome (FCS)

Using the NAFCS scoring criteria to confer a clinical diagnosis

In 2024, the North American FCS (NAFCS) criteria published by Hegele et al were developed and validated specifically for patients in the United States and Canada. This tool uses key clinical features of FCS to generate a score that can help facilitate a diagnosis of FCS.¹¹

This calculator should be used in patients ≥1 year old with hypertriglyceridemia (≥440 mg/dL). In patients ≥10 years old, the calculator is intended for patients who are not responsive to fibrates and high-dose omega-3 fatty acids even when the patient is adherent to therapy (ie, triglycerides do not decrease by 20% or more from these treatments and do not remain reduced).¹¹

Characteristic

Category score

Interpreting results

≥60 strongly indicates definite FCS
≥45 suggests likely FCS rather than MCS
≥30-44 suggests patient may have FCS and genetic testing should be considered^§
<30 deemed unlikely to be FCS, but genetic testing may still be needed

The NAFCS Score does not provide a value for pregnant patients.¹¹

^†

Calculator cannot be used for patients <1 year old. If infant presents with no secondary factors that may contribute to hypertriglyceridemia, consider a diagnosis of FCS. If infant presents with ≥1 secondary factor that may contribute to hypertriglyceridemia, but with 2 triglyceride readings >880 mg/dL and unexplained failure to thrive, consider a diagnosis of FCS.¹¹

^‡

See the secondary factors table below.¹¹

^§

Further research is needed to determine the validity of a score from 30-44.¹¹

BMI, body mass index; MCS=multifactorial chylomicronemia syndrome.

Secondary causes of hypertriglyceridemia

	Adolescents/adults¹⁵	Children¹⁵	Infants¹⁵
Lifestyle	High alcohol intake Reduced physical activity High fat or sugar intake Ultraprocessed (NOVA4) food diet	High fat or sugar intake Ultraprocessed (NOVA4) food diet
Clinical conditions	Autoimmune chylomicronemia (eg, systemic lupus erythematosus, anti-lipoprotein lipase antibodies) Uncontrolled diabetes type 1 or 2 (non-pancreatitis induced) Endocrine causes (eg, Cushing syndrome, polycystic ovarian syndrome, growth hormone deficiency, acromegaly) Human immunodeficiency virus (HIV) Hypothyroidism Metabolic syndrome Rare genetic disorders (eg, glycogen storage disorders) Lipodystrophies Renal causes (eg, chronic renal failure, nephrotic syndrome) Glycerol kinase deficiency Autoantibodies against GPI-HDL binding protein 1	Cancer Congenital nephrotic syndrome Glycogen storage disease type 1 Hypothyroidism Protein-losing enteropathy Lipodystrophies Glycerol kinase deficiency	Cancer Congenital nephrotic syndrome Hypothyroidism Protein-losing enteropathy Glycerol kinase deficiency
Medications	Androgen deprivation therapy Antidepressants (eg, sertraline) Antiretrovirals (eg, protease inhibitors) Atypical antipsychotics Beta-adrenergic blocking agents Bile acid binding resins Diuretics Estrogen, estrogen receptor agonists, estrogen receptor modulators, oral contraceptives Glucocorticoids (eg, corticosteroids) Immunosuppressants (eg, cyclosporine) L-asparaginase Propofol Retinoids, retinoid X receptor agonists Total parenteral nutrition	Total parenteral nutrition Glucocorticoids (eg, corticosteroids) Chemotherapy Antiretrovirals (eg, protease inhibitors) Immunosuppressants (eg, cyclosporine) Propofol For older children: Antidepressants (eg, sertraline) Atypical antipsychotics	Total parenteral nutrition Glucocorticoids (eg, corticosteroids) Chemotherapy

Adapted from Hegele RA, Ahmad Z, Ashraf A, et al. Development and validation of clinical criteria to identify familial chylomicronemia syndrome (FCS) in North America. J Clin Lipidol. 2025;19(1)(online-only supplementary material):83-94.¹⁵
GPI-HDL=glycosylphosphatidylinositol-anchored high-density lipoprotein.

Genetic testing

Diagnosing familial chylomicronemia syndrome (FCS) with clinical scoring tools and no-cost FCS genetic testing

While clinical scoring tools are available, genetic testing continues to be an important option to support FCS diagnosis, and some payers may require genetic test results.

Because genetic testing can be expensive and may not be available for every patient, Ionis has partnered with PreventionGenetics to provide no-cost testing for eligible patients who:

Have severe refractory hypertriglyceridemia, defined by a minimum of 2 consecutive fasting triglyceride levels ≥880 mg/dL or 10 mmol/L
Lack secondary causes or medical conditions known to cause severe hypertriglyceridemia
Are residents of the United States

Learn more about no-cost FCS genetic testing

FCS patient case

Identifying familial chylomicronemia syndrome (FCS) in your patients

Consider the diagnostic journey and clinical presentation of this hypothetical case study and decide how you would proceed

"It's an awful disease, draining and awful. I'm just so tired of being in the hospital. It takes you away from everything."

Not an actual patient. Actor portrayal.

Timothy, 25

Severe hypertriglyceridemia (sHTG) and was diagnosed with FCS

Timothy was first diagnosed with acute pancreatitis (AP) at 19 years of age
A second episode of AP in his early 20s prompted a deeper assessment by a lipidologist
A genetic test for common mutations in patients with FCS was indeterminate. However, a clinical diagnosis was conferred based on the North American FCS scoring criteria

See diagnostic scoring tool for FCS

"It's an awful disease, draining and awful. I'm just so tired of being in the hospital. It takes you away from everything."

Not an actual patient. Actor portrayal.

Timothy was first diagnosed with acute pancreatitis (AP) at 19 years of age
A second episode of AP in his early 20s prompted a deeper assessment by a lipidologist
A genetic test for common mutations in patients with FCS was indeterminate. However, a clinical diagnosis was conferred based on the North American FCS scoring criteria

See diagnostic scoring tool for FCS

Timothy's clinical presentation

Drastic triglyceride fluctuations, ranging from 2850 mg/dL (fasting) to 5000 mg/dL (postprandial)

Refractory to fibrates, EPA, and statins

Lipemic blood reported during first episode of acute pancreatitis at age 19

Recurrent acute pancreatitis

EPA=eicosapentaenoic acid.

Managing FCS

Managing familial chylomicronemia syndrome (FCS):  Now there is more than just the mainstay low-fat diet¹⁶

FCS treatment has evolved

An FDA-approved prescription medicine is available for adult patients with FCS¹⁶

Regardless of treatment, patients must continue to adhere to the recommended FCS diet of <20 grams of fat per day.¹⁷ As a reminder, traditional lipid-lowering treatments are insufficient for reducing triglyceride levels in patients with FCS due to these patients’ lack of lipoprotein lipase activity.^14,18

Learn more about a treatment for adults with FCS

References

Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society. Eur Heart J. 2021;42(47):4791-4806.
Moulin P, Dufour R, Averna M, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an "FCS score". Atherosclerosis. 2018;275:265-272.
Davidson M, Stevenson M, Hsieh A, et al. The burden of familial chylomicronemia syndrome: results from the global IN-FOCUS study. J Clin Lipidol. 2018;12(4):898-907.e2.
Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200-2206.
D’Erasmo L, Di Costanzo A, Cassandra F, et al. Spectrum of mutations and long-term clinical outcomes in genetic chylomicronemia syndromes. Arterioscler Thromb Vasc Biol. 2019;39(12):2531-2541.
Paquette M, Bernard S. The evolving story of multifactorial chylomicronemia syndrome. Front Cardiovasc Med. 2022;9:886266.
Gaudet D, Blom D, Bruckert E, et al. Acute pancreatitis is highly prevalent and complications can be fatal in patients with familial chylomicronemia: results from a survey of lipidologist. J Clin Lipidol. 2016;10(3):680-681. National Lipid Association 2016 Scientific Sessions abstract 136.
Nawaz H, Koutroumpakis E, Easler J, et al. Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis. Am J Gastroenterol. 2015;110(10):1497-1503.
Shemesh E, Zafrir B. Hypertriglyceridemia-related pancreatitis in patients with type 2 diabetes: links and risks. Diabetes Metab Syndr Obes. 2019;12:2041-2052.
O'Dea LSL, MacDougall J, Alexander VJ, et al. Differentiating familial chylomicronemia syndrome from multifactorial severe hypertriglyceridemia by clinical profiles. J Endocr Soc. 2019;3(12):2397-2410.
Hegele RA, Ahmad Z, Ashraf A, et al. Development and validation of clinical criteria to identify familial chylomicronemia syndrome (FCS) in North America. J Clin Lipidol. 2025;19(1):83-94.
Brahm AJ, Hegele RA. Chylomicronaemia—current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352-362.
Pallazola VA, Sajja A, Derenbecker R, et al. Prevalence of familial chylomicronemia syndrome in a quaternary care center. Eur J Prev Cardiol. 2020;27(19):2276-2278.
Chyzhyk V, Brown AS. Familial chylomicronemia syndrome: a rare but devastating autosomal recessive disorder characterized by refractory hypertriglyceridemia and recurrent pancreatitis. Trends Cardiovasc Med. 2020;30(2):80-85.
Hegele RA, Ahmad Z, Ashraf A, et al. Development and validation of clinical criteria to identify familial chylomicronemia syndrome (FCS) in North America. J Clin Lipidol. 2025;19(1)(online-only supplementary material):83-94.
Olezarsen. Prescribing information. Ionis Pharmaceuticals.
Williams L, Rhodes KS, Karmally W, et al. Familial chylomicronemia syndrome: bringing to life dietary recommendations throughout the life span. J Clin Lipidol. 2018;12(4):908-919.
Baass A, Paquette M, Bernard S, Hegele RA. Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia. J Intern Med. 2020;287(4):340-348.

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