Familial chylomicronemia syndrome: an under‐recognized cause of severe hypertriglyceridaemia

Abstract

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder of chylomicron metabolism causing severe elevation of triglyceride (TG) levels (>10 mmol L−1). This condition is associated with a significant risk of recurrent acute pancreatitis (AP). AP caused by hypertriglyceridaemia (HTG) has been associated with a worse prognosis and higher mortality rates compared to pancreatitis of other aetiology. Despite its association with poor quality of life and increased lifelong risk of HTG‐AP, few healthcare providers are familiar with FCS. Because this condition is under‐recognized, the majority of FCS patients are diagnosed after age 20 often after consulting several physicians. Although other forms of severe HTG such as multifactorial chylomicronemia have been associated with high atherosclerotic cardiovascular disease (ASCVD) risk and metabolic abnormalities, ASCVD and metabolic syndrome are not usually observed in FCS patients. Because FCS is a genetic condition, the optimal diagnosis strategy remains genetic testing. The presence of bi‐allelic pathogenic mutations in LPL, APOC2, GPIHBP1, APOA5 or LMF1 genes confirms the diagnosis. However, some cases of FCS caused by autoantibodies against LPL or GPIHBP1 proteins have also been reported. Furthermore, a clinical score for the diagnosis of FCS has been proposed but needs further validation. Available treatment options to lower triglycerides such as fibrates or omega‐3 fatty acids are not efficacious in FCS patients. Currently, the cornerstone of treatment remains a lifelong very low‐fat diet, which prevents the formation of chylomicrons. Finally, inhibitors of apo C‐III and ANGPTL3 are in development and may eventually constitute additional treatment options for FCS patients.

Genetics of Hypertriglyceridemia

“…A very small subset of severely hypertriglyceridemic patients has autosomal recessive chylomicronemia, i.e., FCS (16). The primary lipoprotein disturbance in FCS is accumulation of chylomicrons (17), while VLDL, remnants, and other lipoprotein species are scarce, due to the severe lipolytic blockade that compromises conversion of large TG-carrying particles into smaller lipoprotein species (18). One consequence is that plasma levels of apo B-100-the defining protein of both VLDL and low-density lipoprotein (LDL)-are depressed in FCS (19), reflecting paucity of downstream lipoprotein species in FCS.…”

“…The clinical features in MCM include those related to chylomicronemia, such as lipemia retinalis, hepatosplenomegaly, eruptive xanthomas, nausea, vomiting, and abdominal pain (15). Pancreatitis occurs less commonly in MCM than in FCS; some estimates are ∼10-20% over a lifetime (15), while rates in FCS have been estimated at ∼60-80% (17). Also, because adults primarily express MCM, such pediatric features as failure to thrive are not typical.…”

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

“…In particular, homozygous or compound heterozygous mutations in genes that alter lipoprotein lipase (LPL) activity, like LPL itself, APOC2, LMF1 (lipase maturation factor 1), GPIHBP1 (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1), APOA5, and GPD1 (encoding glycerol-3-phosphate dehydrogenase 1) are associated with high TG, although both severe forms of hypertriglyceridemia and moderate-to-mild hyperglycemia are usually of polygenic origin (10,11). Bi-allelic pathogenic mutations in LPL, APOC2, GPIHBP1, APOA5, or LMF1, that lead to reduced LPL action, are used to confirm familial chylomicronemia syndrome, a rare autosomal recessive disorder characterized by severe elevation of TG levels, eruptive cutaneous xanthomas and acute pancreatitis (12). Furthermore, in some patients with chylomicronemia, autoantibodies against GPIHBP1 have been identified.…”

“…Thus, although the association between hypertriglyceridemia and CVD risk in humans is strong, causal evidence is so far scarce. In fact, subjects with familial chylomicronemia syndrome, which is due to pathogenic mutations in genes controlling LPL itself or LPL activity, do not usually exhibit an elevated risk of atherosclerotic CVD despite the very high levels of TGs ( 12 , 24 ). However, Mendelian randomization analyses indicate that TG-lowering LPL variants and LDL-C-lowering LDLR variants are associated with a similarly lower risk of coronary heart disease per unit difference in APOB ( 25 ).…”

“…The complex relationship between elevated TGs and atherosclerosis may be explained by a model in which increased atherosclerosis (and CVD) is not caused by the high TG content/lipoprotein particle, but to the presence of RLPs (chylomicron and VLDL lipolysis products), which are smaller than chylomicrons and VLDL and can more effectively exert pro-atherogenic effects in the artery wall ( 12 ). As described above, these RLPs are generated as LPL hydrolyzes TGs in the core of chylomicrons and VLDL, resulting in progressively smaller and TG-depleted particles with an increased ratio of cholesterol to TG.…”