Familial chylomicronemia syndrome (FCS)

This genetic form of severe hypertriglyceridemia (sHTG) is 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 sHTG3

Patients with FCS have triglyceride levels that are 10 to 100 times the normal value1,4

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

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 reported5*

Recurrent pancreatitis rates as high as 48% have been reported6†

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 pancreatitis8,9

*

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

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Because of their persistently elevated triglyceride levels, patients with FCS are at greater risk of acute pancreatitis than those with sHTG due to other causes.10

Identifying FCS

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

Clinical/genetic feature
FCS
(also known as Fredrickson type 1 hyperlipoproteinemia and lipoprotein lipase deficiency)12
MCS
(formerly known as Fredrickson type V hyperlipoproteinemia)6
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)13 Variable response (omega-3 fatty acid supplements and niacin)13
Genetic basis
 Can be monogenic14 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 people10,14 Up to 4000 per 1 million people6
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Accurate diagnosis is essential for proper management of FCS in your adult patients.15

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

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

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

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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:

picture of eruptive xanthomas

Eruptive xanthomas†

picture of a vial of lipemic blood

Lipemic blood

picture of lipemia retinalis

Lipemia retinalis‡

† Reprinted with permission from: Abdelghany M, Massoud S. Eruptive xanthoma. Cleve Clin J Med.
2015;82(4)209-210. Copyright © 2024 Cleveland Clinic Foundation. All rights reserved.
‡ Photograph republished from Lai CC, Chang CH. Taiwan J Ophthalmol. 2021;11(4):405-407 under terms of Creative Commons 4.0 License.
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Consider using established scoring criteria to aid in diagnosis or to support a diagnosis of FCS with either indeterminate or positive genetic test results.

Please note that not all genetic variants associated with FCS have been identified. So, genetic testing can be supportive of a clinical FCS diagnosis, even with indeterminate results.2,11

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
i

Current age (years)

Age range indicator Age range indicator
Hypertriglyceridemia onset (years) Only asked of patients ≥10
Plus Icon
i

Body mass index (percentile for children/adolescents)

Plus Icon
i

History of pancreatitis

Plus Icon
i

Presence of secondary factors that may contribute to hypertriglyceridemia‡

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i

Laboratory values (select if true)

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i

Additional points added:

Equal Icon
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
Result
0

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):83-94.

* 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

Secondary causes of hypertriglyceridemia

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

portrait of FCS patient model named Timothy with quote: It's an awful disease, draining and awful. I'm just so tired of being in the hospital. It takes you away from everything.
“It's an awful disease, draining and awful. I'm just so tired of being in the hospital. It takes you away from everything.”
Actor portrayal. Not an actual patient.

Timothy, 25

Severe hypertriglyceridemia (sHTG) and was diagnosed with familial chylomicronemia syndrome (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 arrow icon
“It's an awful disease, draining and awful. I'm just so tired of being in the hospital. It takes you away from everything.”
Actor portrayal. Not an actual patient.
  • 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 arrow icon

Timothy's clinical presentation

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

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Refractory to fibrates, EPA, and statins

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

red icon of person experiencing pain

Recurrent acute pancreatitis

red icon of magnifying glass and dna strand
Please note that not all genetic variants associated with FCS have been identified. So, genetic testing can be supportive of a clinical FCS diagnosis, even with indeterminate results.2

Managing FCS

Managing familial chylomicronemia syndrome (FCS):
Now there is more than just the mainstay low-fat diet17

FCS treatment has evolved

An FDA-approved prescription medicine is available for adult patients with FCS17

Regardless of treatment, patients must continue to adhere to the recommended FCS diet of <20 grams of fat per day.18 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.15,19

Learn more about a treatment for adults with FCS
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Patients diagnosed with FCS should consult with a registered dietitian nutritionist to develop a specialized, low-fat diet.18

References

  1. 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.
  2. 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.
  3. 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.
  4. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200-2206.
  5. 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.
  6. Paquette M, Bernard S. The evolving story of multifactorial chylomicronemia syndrome. Front Cardiovasc Med. 2022;9:886266.
  7. 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.
  8. 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.
  9. Shemesh E, Zafrir B. Hypertriglyceridemia-related pancreatitis in patients with type 2 diabetes: links and risks. Diabetes Metab Syndr Obes. 2019;12:2041-2052.
  10. 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.
  11. 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.
  12. Chait A, Eckel RH. The chylomicronemia syndrome is most often multifactorial: a narrative review of causes and treatment. Ann Intern Med. 2019;170(9):626-634.
  13. Brahm AJ, Hegele RA. Chylomicronaemia—current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352-362.
  14. 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.
  15. 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.
  16. 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.
  17. Olezarsen. Prescribing information. Ionis Pharmaceuticals; 2025.
  18. 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.
  19. 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.