Familial Chylomicronemia Syndrome (FCS)
Familial Chylomicronemia Syndrome (FCS) is estimated to occur 1 in 1 to 2 million people (Burnett and Hegele, 1999; Pouwels et al. 2008). FCS can be diagnosed at any age and affects gender, race, and ethnicity equally (Brunzell 1999). FCS has been called different names. Some commonly used synonyms for FCS include:
- Lipoprotein lipase deficiency (LPLD)
- Type 1 hyperlipoproteinemia
- Endogenous hypertriglyceridemia
- Familial fat-induced hypertriglyceridemia
- Familial hyperchylomicronemia
- Familial LPL deficiency
- Hyperlipidemia Type I (Fredrickson)
- Hyperlipoproteinemia Type IA
- Lipase D deficiency
- Chylomicronemia syndrome
- Chylomicronemia, familial
- Familial chylomicronemia
- Hyperchylomicronemia familial
- Hyperlipemia idiopathic Burger-Grutz type
- Lipase D deficiency
- Burger-Grutz syndrome
Living with FCS imposes a significant burden on all aspects of patient’s lives and the lives of their families and caregivers. People with FCS report a reduced quality of life due to both the symptoms of FCS and needing to follow an extremely restricted low-fat diet (Davidson et al. 2017). Together, people with FCS report the disease affects their ability to concentrate in school, limits employment opportunities due to frequent absences and inability to travel, and participate in social activities with peers and family (Davidson et al. 2017). Family members and caregivers may feel burdened trying to accommodate the restricted low-fat diet.
FCS is caused by insufficient or impaired function of the enzyme, lipoprotein lipase (LPL), which is responsible for breaking down (metabolizing) triglycerides. Decreased lipoprotein lipase function results from either mutations in the gene encoding lipoprotein lipase, or mutations in genes that code for other proteins needed for lipoprotein lipase to function properly.
Without lipoprotein lipase, triglycerides accumulate in the blood. Triglycerides are primarily carried in dietary lipids called chylomicrons. The chylomicrons remain intact and accumulate in the plasma of patients with FCS (Johansen et al. 2011). The accumulation of chylomicrons can reduce blood flow through the pancreas, leading to acute pancreatitis (Valdivielso et al. 2014). Acute pancreatitis can lead to pancreatic damage or be fatal, in addition to other symptoms and complications.
While severe abdominal pain is the most common symptom of FCS, the symptoms of FCS can be clinical, emotional, and cognitive and may include (Brahm and Hegele, 2015; Davidson et al. 2017):
- abdominal pain (daily low-level to debilitating)
- physical weakness
- acute pancreatitis
- impaired memory
- difficulty concentrating and problem solving
- “brain fog”
- anxiety/fear/worry about health
- eruptive xanthomas (pink bumps that appear on your body, arms, and legs)
- lipaemia retinalis (milky appearance of blood vessels in the eye)
- socially isolation due to diet
FCS is diagnosed based on fasting triglyceride levels above or 750 mg/dL (8.5 mmol/L), which do not respond to standard lipid-lowering therapy (Brahm and Hegele 2015), a history of recurrent abdominal pain and/or pancreatitis, and a family history of high plasma triglyceride levels (Brunzell 1993). Fasting triglyceride levels are measured from a blood sample. When blood is drawn the plasma may have a milky appearance due to excessive lipids.
The diagnosis of FCS can be confirmed through genetic testing for mutations in the gene that encodes lipoprotein lipase (LPL), or mutations in genes that code for other proteins needed for lipoprotein lipase (LPL) to function properly. The most common mutations are LPL, apolipoprotein C2 (APOC2), lipase maturation factor 1 (LMF1), apolipoprotein A5 (APOA5), and glycosylphosphotidylinositol-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1) (Brahm and Hegele 2015, Ahmad et al. 2017, Stroes et al. 2017).
There are currently no FDA-approved treatments for FCS. Traditional treatments to reduce lipid levels such as statins, fibrates and niacin are not effective in people with FCS because the effectiveness of these medications depends, at least in part, on a functional lipoprotein lipase enzyme.
Dietary Management of FCS
Management of high serum triglyceride levels is by eating an extremely restrictive low-fat diet (<20g fat/day), which is 10 to 15% of total caloric intake. People with FCS may eat vegetables, fruits, whole grains, egg whites, legumes, fat-free dairy products, seafood, and lean poultry. People with FCS can obtain essential fatty acids with supplements that include fat-soluble vitamins (vitamins A, D, E, K), minerals, and medium-chain triglycerides, as needed. Eating small, frequent meals that contain fat-free or low-fat protein is suggested. Additional recommendations for managing diet restrictions in patients with FCS are available for infants, children, and adolescents (Williams and Wilson, 2016).
The strict diet avoids fat, simple carbohydrates, products high in sugars (desserts, fruit juices), alcohol, and drugs known to increase triglyceride levels such as diuretics, steroids, estrogens, high blood pressure medications, medications that suppress the immune system, antidepressants, some heart medications, and fish oil supplements (Brunzell, 2011). Even following the strict diet, triglyceride levels may remain elevated and patients with FCS may experience episodes of abdominal pain and recurrent pancreatitis. People with FCS report low satisfaction with this diet (Davidson et al. 2017). Eating away from home is difficult, especially in restaurants. Purchasing fat-free foods can be expensive and preparing fat-free meals can be time-consuming. People with FCS are monitored regularly to ensure proper nutritional intake.
Quality of Life
FCS affects the quality of life of patients and their caregivers. The symptoms of FCS place a psychosocial and clinical burden on patients and their families and/or caregivers. The psychosocial burden is associated with the restricted diet, anxiety and stress and unpredictability of when FCS symptoms may appear. The clinical burden of FCS includes chronic abdominal pain and pancreatitis. Acute pancreatitis causes debilitating pain, anxiety, loss of employment, and hospitalizations. People with FCS report fatigue, weakness, fear, worry, cognitive impairment such as impaired memory and difficulty concentrating. These symptoms can have a significant impact on one’s day-to-day quality of life and may impair one’s ability to work (Davidson et al. 2017).
Risks of FCS
Repeated episodes of acute pancreatitis can lead to chronic pancreatitis (Yang et al. 2009; Berglund et al. 2012) and signs of exocrine or endocrine pancreatic insufficiency, including pancreatic (type 3c) diabetes (Gaudet et al. 2013). Patients with extremely high levels of triglycerides may have a more severe course of pancreatitis, leading to worse outcomes including longer hospital stays, a higher rate of pancreatic necrosis, more frequent persistent organ failure, and higher rates of mortality (Nawaz et al. 2015). This risk may be lowered by treatment with a healthcare team that understands all aspects of the disease and may include a lipidologist, pancreatologist, gastroenterologist, primary care physician, registered dietitian, psychologist, and/or social worker.
Videos on FCS
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- Ahmad Z, Halter R, Stevenson M. Building a better understanding of the burden of disease in familial chylomicronemia syndrome, Expert Review of Clinical Pharmacology, 2017; 10:1,1-3, DOI: 10.1080/17512433.2017.1251839
- Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine society clinical practice guideline. J of Clinical Endocrinology & Metabolism 2012; 97: 2969-2989.
- Brahm, A. J. & Hegele, R. A. Chylomicronaemia–current diagnosis and future therapies. Rev. Endocrinol. 2015;11, 352–362; published online 3 March 2015; doi:10.1038/nrendo.2015.26
- Burnett JR HA, Hegele RA. Familial Lipoprotein Lipase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. (University of Washington, Seattle, 1999 Oct 12 [Updated 2017 Jun 22])
- Davidson M, Stevenson M, Hsieh A, Ahmad Z, Witzum JL. The burden of familial chylomicronemia syndrome: interim results from the In-Focus study. Journal of 2017.
- Gaudet D, Méthot T, Déry S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: An open-label trial. Gene Therapy 2013; 20: 361-369.
- Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. Journal of lipid research, 52(2), 189-206 (2011).
- Pouwels ED, Blom DJ, Firth JC, Henderson HE, Marais AD. Severe hypertriglyceridaemia as a result of familial chylomicronaemia: the Cape Town experience. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 98(2), 105-108 (2008).
- Stroes E, Moulin P, Parhofer KG, Rebours V, Löhr J-M, M. Diagnostic algorithm for familial chylomicronemia syndrome. Atherosclerosis Supplements 2017; 23: 1–7.
- Valdivielso P, Ramirez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Internal Med. 2014;25:689-94.
- Williams L, Wilson DP. Editorial commentary: Dietary management of familial chylomicronemia syndrome. J Clin Lipidol. 2016;10:462-465.
- Yang F, Wang Y, Sternfeld L, et al. The role of free fatty acids, pancreatic lipase and Ca2+ signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiologica 2009; 195: 13-28.