Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive genetic disorder (ORPHA:444490) of chylomicron metabolism 1 that results in severe hypertriglyceridemia (sHTG) and recurrent episodes of acute pancreatitis attacks 2, due to very low or even absent lipoprotein lipase (LPL) activity 3. FCS-related genes are the LPL gene per se, and those affecting the correct folding and migration/location of LPL, such as the lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), respectively. Other genes involved in FCS are those encoding for the LPL activator proteins apolipoprotein C2 (APOC2) and apolipoprotein A5 (APOA5) 4. FCS is present in only 1% of subjects with severe HTG 5. Alternatively to FCS, the Multifactorial Chylomicronemia Syndrome (MCS) is another type of chylomicron metabolism disorder (oligogenic or polygenic), exacerbated by the presence of secondary factors such as a diet rich in fats and simple sugars, obesity, alcohol intake and uncontrolled diabetes 1. Althought the clinical features in MCS and FCS patients overlap, the prevalence of abdominal pain and pancreatitis are greater in FCS patients, whereas the prevalence of patients with 2 or more metabolic abnormalities are higher in MCS patients 1.

The method used by our group to measure LPL activity is a complex test involving a liquid-liquid extraction of the released fatty acids (FA) from a commercial emulsion (Intralipid) spiked with tritium-labelled triolein 6. The tedious procedure may result in high variation coefficients. There are no biological variation data or total allowable error calculations available for this method which could help us to reliably interpret the LPL activity data. The interpretation of the data is also difficult in cases with pathogenic variants in APOC2 or APOA5, where the LPL activity deficiency is masked due to the addition of LPL activators to the reaction mixture 6. Consequently, measurement of LPL activity is seldom used nowadays for diagnosing FCS. In addition, post-heparin LPL activity is not able to identify subjects with polygenic hypertriglyceridemia 7.

Because the method to assay LPL activity is not standardised, it is difficult to consider a specific cut-off point to define LPL activity deficiency. In the APPROACH study, the authors considered a cut-off point of 20% of the mean LPL activity of a normal population 8. In another recent study, the authors considered 10% of that mean as a cut-off point 9. In a study carried out by our group, we considered an initial cut-off point of 24.2 mU/mL based on a 99.7% C.I. of the mean LPL activity of a reference FCS population 10.

In Spain, the antisense oligonucleotide that binds ApoC-III mRNA (Volanesorsen) has been approved for prescription to genetically diagnosed patients and for those with LPL activity deficiency in case of an inconclusive genetic test 11. Although the genetic strategy is widely used nowadays, it also has its limitations: (a) when novel variants are found, the pathogenicity must be confirmed by measurements of LPL activity (b) there are cases showing a clear FCS phenotype but no biallelic pathogenic variants are identified 8,10. In these cases, LPL activity measurements are needed to support the FCS diagnosis.

Taking these considerations into account, the aim of this study was to establish a valid LPL activity cut-off for the method we use, and a well-defined FCS diagnostic workflow, including LPL activity measurements, according to our current laboratory procedures.