Familial chylomicronemia syndrome (FCS)

Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive disorder of chylomicron metabolism characterized by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridemia (HTG [TG levels >10 mmol/L] (>885 mg/dL)) and the abnormal persistence of chylomicrons in fasting plasma.^1–3

FCS nomenclature

Chylomicronemia is the accumulation in the bloodstream of chylomicrons.¹ The “chylomicronemia syndrome” refers to the presence of at least one clinical feature accompanying primary chylomicronemia, such as eruptive xanthomas, lipemia retinalis, pancreatitis, or hepatosplenomegaly.³

What are chylomicrons?

Chylomicrons are large, TG-rich lipoprotein particles produced after a meal. Under physiological conditions, chylomicrons are rapidly cleared from plasma by the action of lipoprotein lipase (LPL), an enzyme located on the endothelial surface of adipose and muscle tissues, which hydrolyzes TG into fatty acids and glycerol. In FCS, a lack of LPL functionality, mostly due to pathogenic variants in the set of genes involved in LPL function, markedly impairs the clearance of chylomicrons from the plasma.¹

About FCS

FCS is a monogenic chylomicronemia that results from loss-of-function mutations within the genes that encode key checkpoint molecules in lipolysis.³

Onset of FCS is typically in childhood or early adulthood, usually presenting with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. It is often associated with failure to thrive, together with relatively low levels of all other classes of lipoprotein fractions.^3,5 Approximately 25% of affected children develop symptoms before the age of one and the majority develop symptoms before 10 years of age. Males and females are affected equally.⁵

LPL is secreted by adipocytes and myocytes and mediates lipolysis of triglycerides from chylomicrons. The liberated free fatty acids are internalized to be used for energy or stored. FCS is caused by mutations in genes that encode key molecules in the lipolytic cascade. Loss of LPL activity is associated with a massive accumulation of chylomicrons in the plasma.^2,6  

FCS genetic mutations 

FCS follows an autosomal recessive pattern of inheritance and results predominantly from biallelic mutations in the LPL gene encoding LPL. The remainder are caused by rarer biallelic mutations in 4 additional genes involved in supporting or enabling LPL function, namely APOC2, APOA5, LMF1, and GPIHBP1, which encode, respectively, apolipoprotein (apo) C-II and A-V, lipase maturation factor 1 (LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1).^3,7,8 

The majority of individuals with chylomicronemia and plasma TG concentration >2000 mg/dL do not have FCS; rather, they have one of the more common genetic disorders of triglyceride metabolism.⁵ The majority of patients with severe HTG do not have recessive LPL deficiency or FCS at the DNA level. Approximately 3% of patients with chylomicronemia (TG >1000 mg/dL) have mutations on 2 alleles of genes encoding either LPL or one of its interacting proteins.⁹  

LPL mutations 

Mutations in the LPL gene account for more than 80% of FCS cases reported in the literature, and more than 180 mutations have been identified, including frameshift, missense, and nonsense mutations; however, no single mutation in LPL predominates.^3,6 

Non-LPL genetic mutations 

Mutations in APOC2 are the second most frequently reported cause of monogenic chylomicronemia. Other mutations include those in APOA5 (encoding the LPL cofactor apoA‑V), LMF1 (encoding the LPL chaperone LMF1), and GPIHBP1 (encoding GPIHBP1). apoA‑V, LMF1, and GPIHBP1 are enhancers or modifiers of chylomicron hydrolysis; carriers of recessive mutations in the genes encoding these proteins tend to present later and with less severe phenotypes than individuals with deficiencies in LPL and apoC-II.³ 

Immunogenic causes of FCS 

A rare subset of FCS is immunologic rather than monogenic in nature. A patient with autoantibodies against LPL was reported in 1989, with a few other cases reported subsequently.²  

The hallmark of FCS includes severe fasting chylomicronemia, the abnormal persistence of circulating chylomicrons following a fasting period of 12–14 hours, with plasma TG >1000 mg/dL.⁷ 

The presence of chylomicrons in a fasting plasma sample is easily observable. A key characteristic of FCS is a “creamy” or “milky” appearance of fasting blood samples, indicating the presence of chylomicrons and/or other large TG-rich lipoproteins. After resting blood samples overnight or following centrifugation, a white chylomicron layer floats above the other plasma components.^2,3  

The manifestations associated with FCS are quite heterogeneous and nonspecific.² Patients with FCS may experience physical complications including abdominal pain, which can range in intensity from mild to incapacitating.¹ Acute pancreatitis (AP) is the most serious physical manifestation, which not only may lead to chronic pancreatic functional impairment after a single attack, but may also be life-threatening.^4,8 

The risk of AP increases as TG levels increase; studies have highlighted a significant relationship between TG level and pancreatitis, with a 4% increased risk of AP for every 100 mg/dL or ~1.1 mmol/L increase in TG levels.^4,8 

Recurrent AP occurs in ≥50% of FCS patients; the overall associated mortality rate is 5–6%, but it increases to 30% in subgroups of markedly hypertriglyceridemic patients who experience pancreatic necrosis following an infected pancreatic abscess or persistent multiple organ failure.⁸ AP may lead to chronic pancreatitis, permanent damage to pancreatic tissue, pancreatic insufficiency, and type 2 diabetes.⁴ 

Pathogenesis of AP caused by HTG is not fully understood, but is believed to be a result of impaired blood flow in the pancreatic capillaries due to lipoprotein accumulation. Impaired blood flow in the pancreas can cause hypoxic conditions, the release of pancreatic lipase into capillaries, pancreatic lipase-mediated triglyceride hydrolysis, and release of free fatty acids, leading to activation of inflammatory pathways, ischemia, and thrombosis.¹⁰ 

Other clinical symptoms include transient eruptive xanthomas, small yellow papules often appearing on the trunk and extremities, which affect <50% of individuals with FCS, and lipemia retinalis, a milky appearance of the retinal vessels.^1,5 The high levels of circulating chylomicrons can accumulate in specific body locations, such as the skin, producing eruptive xanthomas, or in the retinal blood vessel, manifesting as lipemia retinalis.⁶  

Hepatosplenomegaly may also result from TG uptake by macrophages. Neurological symptoms, such as irritability, memory problems, dementia, and depression, have also been documented. Patients with FCS tend to have a lower body weight because of restrictions in food intake owing to abdominal pain.¹

FCS is a rare disease, with an estimated worldwide prevalence of approximately one individual per million. It has been described in all ethnicities, although a higher prevalence has been observed in some geographical areas such as Quebec, due to a founder effect.^1,3 

The recognition and correct diagnosis of FCS is challenging due to its rarity, and the lack of specificity of signs and symptoms. Lipid experts, endocrinologists, gastroenterologists, pancreatologists, and general practitioners may encounter patients who potentially have the disease. Therefore, cooperation between experts and improved knowledge of FCS is essential in improving diagnosis.⁶ 

FCS should be suspected in patients with fasting severe HTG, ie, TG ≥ 885mg/dL, in the absence of secondary causes such as obesity, alcohol, insulin resistance, specific medications, diabetes, or other diseases. FCS represents ~1–2% of all patients referred to lipid clinics with TG levels this high; it is important to exclude all concomitant agents and activities that may contribute to HTG.^2,6 Fasting TG levels remain extremely elevated at different time points; finding of severe HTG in 3 consecutive samplings should raise the suspicion of a genetic disease.⁶ 

FCS patients show very poor or absent response to therapy with traditional lipid-lowering agents. A 3-month trial of fibrates and omega-3 is a pragmatic method to confirm the suspicion of a genetic disorder.⁶ 

Although AP is the most serious clinical manifestation of FCS, it is known that not all patients suffer from pancreatitis events and the absence of a history of pancreatitis should not exclude its suspicion if other signs or symptoms are indicative.⁶ 

The presence of a pathogenic biallelic mutation in LPL, APOC2, GPIHBP1, APOA5 or LMF1 genes is required to establish the genetic diagnosis. Full gene sequencing of LPL and the 4 additional genes is advised and represents the gold standard to precisely determine which mutated protein forms the basis of the metabolic disorder.^2,6 

Proposed scoring system for FCS 

Because FCS is a rare condition, the diagnosis might be missed in some patients. In this score, weighting is given to each clinical variable; fasting TG values, the presence of secondary factors, previous history of pancreatitis, unexplained recurrent abdominal pain, history of combined hyperlipidemia, response to lipid lowering therapy, and the age at onset of symptoms in order to determine whether the patient has “very likely FCS”, “unlikely FCS” or “very unlikely FCS”.^1,2  

Differentiating FCS and MCS 

High levels of TGs are more often due to multifactorial chylomicronemia syndrome (MCS) than FCS and there is a large overlap in the two phenotypes. Patients with MCS may have a combination of a heterozygous loss of function mutation and/or likely pathogenic frequent variants in TG-raising genes, thus producing (oligogenic/polygenic) severe HTG. However, in such cases, hyperchylomicronemia is often transient and low LPL activity is inconstant. Therefore, in order to establish a FCS diagnosis, TG levels over time, clinical signs, and history must be all be considered.¹ 

Reproducible increases of plasma TG >10 mmol/L (885 mg/dL) over several weeks or months is a relevant criterion supporting diagnosis of FCS. Plasma TG levels in MCS have more variability and are much more sensitive to dietary and/or fibrate treatment, whereas in FCS, TG concentration is minimally improved with these measures. Some clinical features also support the diagnosis of FCS, rather than MCS. FCS occurs in younger patients, mostly without secondary factors, whereas MCS typically occurs in overweight adult patients with metabolic syndrome. Moreover, the occurrence of AP is more frequent in FCS than in MCS due to the partial response to a low-fat diet and higher plasma TG concentrations.¹ 

Patients with FCS experience significant clinical and psychosocial burdens that reduce their quality of life and limit employment and social interactions. In one study, only 22% of FCS patients reported being fully employed, and 75% attributed FCS as a major factor responsible for their unemployment status.¹⁰ 

Because patients with FCS cannot metabolize TGs and fats, current medical nutrition therapy is a very low-fat diet consisting of total fat intake <10–15% daily calories (ie, <15–20 g of fat per day) with limited simple, refined carbohydrates, and avoidance of alcohol. Strict dietary adherence is critical for FCS patients of all ages, but is difficult to maintain and a source of a significant burden.¹¹ In one study, 80% of patients indicated that compliance with the low-fat diet was difficult or very difficult and 90% of the patients agreed or strongly agreed that they still have symptoms of FCS while adhering to the low-fat diet.⁴ Managing the lifestyle events involved with such a restricted fat intake is draining and time-consuming for almost all patients and can be associated with fear, anxiety, helplessness, and guilt when dietary fat limits are exceeded. Patients often experience a lower quality of life than people without FCS.⁸ 

The emotional burden on patients is related to their uncertainty about the next attack of pain or AP, need for a highly restrictive diet, and search for a knowledgeable and empathetic physician. Anxiety related to AP attacks and long-term health was reported by most patients. Patients reported the lifestyle and behavioral adaptations associated with FCS, such as following a restrictive very low-fat diet, as contributing to their low mental well-being.^8,10 

Nearly two-thirds of patients stated that FCS interfered significantly with their self-worth, emotional well-being, sleep, and mental functioning. In addition, a large majority of patients were not optimistic about the future and were worried about their condition worsening, long-term health effects, potential job loss, and ability to live a normal life.⁸