Severe hypertriglyceridemia may has a genetic cause
FCS is a monogenic disease with different pattern of inheritance
Secondary and primary causes of hypertriglyceridemia
Read moreIn 80-90% of patients with FCS, low activity of lipoprotein lipase (LPL) is caused by mutations in the gene that encodes this enzyme. Low LPL activity can also be caused by mutations in one or more regulators of its function, including:1,2
LMF1
Lipase maturation factor 1
(1-2%)
ApoA5
Apolipoprotein A5
(2-5%)
ApoC2
Apolipoprotein C2
(2-5%)
CREB3L3
Cyclic AMP-responsive element-binding protein 3-like protein 3
(Rare)
GPD1
glycerol-3-phosphate dehydrogenase-1
(Rare)
GCKR
Glucokinase-Regulatory-Protein
(Rare)
GPIHBP1
Glycosylphosphatidylinositol-anchored HDL-binding protein 1
(5-10%)
Low LPL activity leads to a diminished triglyceride breakdown in the chylomicrons that pass through the capillaries, resulting in chylomicron accumulation and fasting plasma triglyceride levels that exceed normal values by 10- to 100-fold.1,3
Bashir 2020
Genetic causes of HTG4,5,6,7
Adapted from Moulin 20184
*Monogenetic: The genetic load is high enough to cause a constant HTG, regardless of other factors such as additional mutations or lifestyle factors.
**Polygenetic: A single mutation is not sufficient to cause a clinical phenotype. The severity of HTG is is determined by cumulative/interactive effects of several genetic risk variants.***
***These risk variants include both heterozygous rare variants with major metabolic effects and frequent variants (polymorphisms) with minor effects. These mutations occur in combination with TG-increasing SNPs. A large number of SNPs with an effect on TG can also lead to polygenic HTG on its own.
+ Secondary factors include alcohol, diabetes, metabolic syndrome, hypothyroidism, corticotherapy and additional drugs
† SNPs = single nucleotide polymorphism = susceptibility variants = polymorphisms
Additional diagnostic considerations: Phenotypic differentiation of FCS and MCS
Accumulation of chylomicrons in the microcirculation reduces pancreatic capillary blood flow, which results in pancreatic ischaemia, recurrent acute pancreatitis, and severe abdominal pain.8
The exact mechanism by which this chylomicron-rich, hyperviscous blood triggers ischaemia selectively in the pancreas is still under investigation.
References
- Bashir B, et al. Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome— Causes, Clinical Presentation, and Therapeutic Options. Metabolites. 2023; 13(5):621.
- Hegele et al. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement Lancet Diabetes Endocrinol 2020; 8: 50–67
- Gaudet, et al. Targeting APOC3 in the Familial Chylomicronemia Syndrome. N Engl J Med. 2014;371 :2200–6.
- Moulin P, 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.
- Brahm, A. J. & Hegele, R. A. Nat. Rev. Endocrinol. 11, 352–362 (2015)
- Gotoda T, et al. Diagnosis and management of type I and type V hyperlipoproteinemia J Atheroscler Thromb. 19: 1–12 (2012).
- Dron JS, Hegele RA. Genetics of Hypertriglyceridemia. Front Endocrinol (Lausanne). 24:11:455 (2020).
- Gan SI, et al. Hypertriglyceridemia-induced pancreatitis: A case-based review World J Gastroenterol 2006 November 28; 12(44): 7197-7202
Key facts
Familial chylomicronemia syndrome (FCS) is a rare genetic disorder of lipid metabolism which leads to severely raised triglyceride levels and chylomicrons (chylomicronemia).
Diagnosis
FCS diagnosis is based on a three-step approach:
- High triglyceride evaluation
- Identification of candidates for FCS genetic testing
- Genetic test of possible affected genes
Causes and Pathophysiology
FCS is a monogenic disease with different pattern of inheritance. In 80-90% of patients with FCS, low activity of lipoprotein lipase (LPL) is caused by mutations in the gene that encodes this enzyme.