Familial Chylomicronaemia Syndrome (LPL, APOC2, APOA5, GPIHBP1, LMF1)

Recessive hyperlipoproteinaemia caused by failure of intravascular chylomicron lipolysis, with extreme, persistent hypertriglyceridaemia, recurrent acute pancreatitis, and lifelong dependence on a very low-fat diet; it must be distinguished from the far more common multifactorial chylomicronaemia.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

The following table summarises the differences among the five genetic forms, with the proportions within FCS according to three sources from different periods and ancestries.

Table sources: [1, 2, 17, 18, 28, 29]. Abbreviations: VLDL, very-low-density lipoproteins; HDL, high-density lipoproteins; ANGPTL, angiopoietin-like protein; NLA, National Lipid Association.

1. Introduction

1.1. Initial clinical description and identification of the enzymatic defect

The first description attributed to the disease is that of Bürger and Grütz in 1932: an 11-year-old boy, the son of first cousins, with cutaneous xanthomas, hepatosplenomegaly, and creamy-appearing fasting plasma [30, 31]. In 1939, Holt and colleagues described two siblings with marked hyperlipaemia, one of whom had severe attacks of abdominal pain; this patient was later followed by Knittle and Ahrens, and the work of Fredrickson and colleagues demonstrated deficient lipoprotein lipase activity in his postheparin plasma [31]. In 1960, Havel and Gordon studied three siblings with fasting hyperchylomicronaemia and located the defect in the heparin-released lipolytic activity, establishing the model of disease caused by failure of intravascular chylomicron clearance [31, 32].

In 1978, Breckenridge and colleagues described hypertriglyceridaemia associated with absence of apolipoprotein C-II: the patient lacked effective lipolytic activity, TG fell after a blood transfusion given for anaemia, and the plasma contained no apoC-II, identifying the cofactor as a second cause of the same phenotype [31, 33]. In 1986, Baggio and colleagues corrected the hypertriglyceridaemia of two siblings with apoC-II deficiency by infusing normal plasma and a synthetic fragment of the protein [34].

1.2. Molecular milestones

Cloning of the LPL gene and identification of founder variants defined the molecular basis of the most common form. In 1991, Ma and colleagues showed that a single substitution in exon 5 of LPL, historically designated P207L (= NM_000237.3:c.701C>T p.(Pro234Leu)), was the most common cause of familial chylomicronaemia among French Canadians in Quebec [35]. In 2007, Beigneux and colleagues showed that the endothelial protein GPIHBP1 is essential for lipolytic processing of chylomicrons, and in the same year Wang and Hegele described two siblings homozygous for a GPIHBP1 variant with fasting chylomicronaemia [36, 37]. Also in 2007, Péterfy and colleagues identified LMF1 from the cld (combined lipase deficiency) mouse and confirmed combined lipase deficiency in a homozygous patient [10, 38]. Biallelic apoA-V deficiency was described in consanguineous families in 2006 and 2008 (Calandra and colleagues; Dorfmeister and colleagues, cited in the Saudubray textbook) [29].

Treatment has gone through three phases. Until 2012, a very low-fat diet was the only intervention with a consistent effect [31]. On 25 October 2012, the European Commission granted alipogene tiparvovec (Glybera®), an adeno-associated virus serotype 1 vector carrying the gain-of-function variant LPL S447X (historical numbering, = NM_000237.3:c.1421C>G p.(Ser474Ter)), the first marketing authorisation for a gene therapy in the Western world, under exceptional circumstances; the authorisation expired on 28 October 2017, after the holder decided not to seek renewal because of lack of demand [24, 29, 39]. The third phase is pharmacological inhibition of apoC-III: volanesorsen received conditional marketing authorisation in the European Union (EU) on 3 May 2019, after a complete response letter from the Food and Drug Administration (FDA) in August 2018; olezarsen was approved by the FDA on 19 December 2024, and in the EU on 17 September 2025; plozasiran was approved by the FDA on 18 November 2025, and in the EU on 19 June 2026 [7, 40–43].

1.3. Nomenclature and reclassification

The Fredrickson classification, based on the electrophoretic pattern and the appearance of refrigerated plasma, designated isolated accumulation of chylomicrons as type I and combined accumulation of chylomicrons and VLDL as type V [31]. The term “familial chylomicronaemia syndrome” was recommended by the 2018 European panel to cover all monogenic forms, regardless of the gene [18]. The adjective “familial” is debatable, because the disease is recessive and a typical family history is often absent [5].

The definitions used throughout this article are as follows. Severe hypertriglyceridaemia (sHTG) denotes TG ≥10 mmol/L (≥885 mg/dL) in some European and Canadian sources, and ≥500 mg/dL (5.65 mmol/L) in the US indication for olezarsen and in the classification of the NLA and the American Society for Preventive Cardiology (ASPC), which adds a category of extreme hypertriglyceridaemia (≥1000 mg/dL) [1, 5, 19]. “Classic” or genetic FCS requires biallelic variants in one of the five canonical genes [4]. “Functional” or “clinical” FCS denotes the full phenotype without genetic testing or with inconclusive testing, and the NLA recommends evaluating and treating it as the genetically confirmed form [1, 4]. Multifactorial chylomicronaemia syndrome (MCS), formerly type V hyperlipoproteinaemia, results from the sum of genetic susceptibility (rare heterozygous variants or polygenic risk) and secondary factors [1, 2]. “Persistent chylomicronaemia” (PC) is the phenotypic category proposed by the 2025 NLA/ASPC consensus: TG ≥1000 mg/dL in more than half of measurements, regardless of genotype [5]. Refractory MCS, with TG persistently >10 mmol/L despite conventional treatment, accounts for about 8% of MCS in a Canadian cohort [44].

Familial hypertriglyceridaemia (formerly type IV, ORPHA:413), which has a polygenic basis and TG usually between 3 and 10 mmol/L, is a distinct entity considered in the differential diagnosis [39, 45]. Familial hypercholesterolaemia is not addressed, and hereditary pancreatitis due to PRSS1 appears only as a differential diagnosis of recurrent pancreatitis [46].

2. Molecular Genetics and Pathophysiology

2.1. The machinery of intravascular lipolysis

Chylomicrons are large TG-rich particles formed in the enterocyte after ingestion of long-chain fat; they are normally cleared within 3 to 4 hours and become undetectable after an overnight fast [1, 2]. Their clearance depends on a multiprotein complex on the luminal surface of the capillary endothelium of extrahepatic tissues: LPL, synthesised in adipose tissue and in cardiac and skeletal muscle, is folded and assembled in the endoplasmic reticulum by LMF1, transported to the capillary lumen and anchored by GPIHBP1, activated by apoC-II present on TG-rich lipoproteins, and enhanced by apoA-V [1, 2, 9, 10]. ApoC-III acts in the opposite direction, inhibiting LPL-mediated hydrolysis and hepatic uptake of remnants, and the proteins ANGPTL3, ANGPTL4, and ANGPTL8 are physiological LPL inhibitors [1, 5, 47].

Loss of any obligatory element of the pathway produces the same biochemical phenotype: a primary excess of fasting chylomicrons, with a relative deficiency of the other lipoprotein classes. Because few remnants are formed, VLDL are low or normal, low-density lipoproteins (LDL) are low, and HDL are low, owing to a paucity of particles and to exchange mediated by cholesteryl ester transfer protein (CETP) [1]. In MCS, by contrast, excess VLDL saturates a partially impaired lipolysis, with accumulation of VLDL, chylomicrons, and remnants [1]. This difference explains two markers used in diagnosis: the high TG/total cholesterol ratio and the low apoB in FCS, because each chylomicron carries a single apoB-48 molecule and a large amount of TG [18, 44].

The proposed mechanism of pancreatitis combines rheological and toxic factors: chylomicrons would impair pancreatic capillary flow, causing ischaemia and acidosis, and released pancreatic lipase would hydrolyse TG locally, generating free fatty acids and radicals toxic to acinar cells [1]. The proposed explanation for the absence of accelerated atherosclerosis in biallelic FCS is particle size, which prevents the particles from penetrating the arterial intima [1, 29].

2.2. LPL

The LPL gene is located at 8p21.3 (8p22 in historical sources, according to the original mapping), has 10 exons spanning about 30 kb, and encodes a glycoprotein of 448 amino acids in its mature form, preceded by a 27-amino-acid signal peptide [2, 11, 31]. The enzyme functions as a homodimer of 60-kDa subunits; the larger N-terminal domain contains the catalytic site, and the C-terminal domain, connected by a short linker, determines substrate specificity and heparin binding [2, 31]. LPL hydrolyses the glycerol ester bonds of circulating TG, is inhibited by protamine, and also serves as a bridge for receptor-mediated lipoprotein uptake; its messenger RNA is expressed in muscle, kidney, adrenal gland, intestine, and neonatal liver, but not in adult liver [6, 31].

The mechanism of pathogenic variants is loss of function. Most are missense variants with markedly reduced or absent activity, clustered in exons 4, 5, and 6, which encode the regions of homology among lipases; in a compilation cited by Nyhan's Atlas, 75% clustered in exons 5 and 6 [31]. Many patients have immunoreactive protein (CRM+, cross-reacting material); the first CRM− case combined a 6-kb deletion (exons 3 to 5) on one allele and a 2-kb deletion in exon 6 on the other, with no messenger RNA in adipose tissue [31]. More than 300 pathogenic or likely pathogenic variants have been described, and more than 1500 people with biallelic LPL variants have been identified [1, 2, 48]. In the Japanese population, a complex Alu-mediated deletion–insertion that removes exon 2 has been described [31].

2.3. APOC2

APOC2 is located at 19q13.32, near APOE, has 4 exons spanning 3.3 kb, and encodes the activating cofactor of LPL [7, 31]. In apoC-II deficiency the enzyme is normal but does not function; the protein is absent or nonfunctional, with undetectable or markedly reduced immunologic concentrations (0.12–0.13 mg/dL in Baggio's index siblings) [7, 34, 49]. The classic alleles were named after cities (Padova, Paris, Hamburg, Nijmegen, Toronto, St Michael) and include nonsense variants, one initiation codon variant, one splice-donor variant in intron 2, and four frameshift variants; most reported patients are homozygous and from consanguineous families [31]. A patient homozygous for the variant historically designated Y63X had encephalopathy with lipid deposits on magnetic resonance imaging, neurological deficit, and developmental delay [31]. The sources consulted do not provide HGVS notation for these historical alleles, so they are not converted to current nomenclature. The variant NM_000483.5:c.55+1G>C, classified as pathogenic in ClinVar, was identified in three infants from consanguineous families [7, 50, 51].

2.4. APOA5

APOA5 is located at 11q23.3, in the APOA1/APOC3/APOA4/APOA5 cluster; the MANE Select transcript is NM_001371904.1, not the NM_001166598 cited in some databases [8, 11]. ApoA-V is a minor apolipoprotein of HDL, VLDL, and chylomicrons that stimulates apoC-II–dependent hydrolysis and inhibits hepatic production of VLDL-TG without altering production of VLDL-apoB [8]. Because it is a coactivator rather than an enzyme, the disease tends to begin later and to have more variable severity than LPL deficiency; postheparin LPL activity is normal, and no clinical apoA-V assay exists [8]. OMIM lists two relationships: late-onset hyperchylomicronaemia (144650, recessive) and susceptibility to hypertriglyceridaemia (145750); in GenCC, APOA5-related hypertriglyceridaemia is classified as dominant or semidominant by different submitters, and ClinGen has no validity or actionability assertions for the gene [8]. The common allele NM_001371904.1:c.56C>G p.(Ser19Trp) and the APOA5*2 and *3 haplotypes are risk factors for MCS, with no isolated causal effect [18, 50].

2.5. GPIHBP1

GPIHBP1 is located at 8q24.3 and encodes a glycosylphosphatidylinositol-anchored endothelial protein of the Ly6 family that transports LPL from the subendothelial space to the luminal surface, anchors it, stabilises it against ANGPTL4-mediated unfolding, and binds chylomicrons and apoA-V–containing particles [9, 36]. In GPIHBP1 deficiency, LPL is present but is neither positioned nor stabilised, and LPL mass in postheparin plasma is reduced in some patients [9]. The variant p.(Gly56Arg), described in 2007 in two siblings with chylomicronaemia, is now classified as of uncertain significance in ClinVar, whereas p.(Gln115Pro) is classified as pathogenic [37, 50]. Neutralising anti-GPIHBP1 autoantibodies reproduce the phenotype in acquired form (section 6) [1, 4].

2.6. LMF1

LMF1 is located at 16p13.3 and encodes a transmembrane endoplasmic reticulum chaperone that folds and assembles newly synthesised homodimeric lipases; each molecule handles at least 50 LPL molecules [10]. It is required by all three vascular lipases (LPL, hepatic lipase, and endothelial lipase), so its deficiency produces a combined deficiency: in a patient with the p.(Trp464Ter) variant (in ClinVar, NM_022773.4:c.1391G>A p.(Trp464Ter), VCV000143993, pathogenic) [50], postheparin phospholipase activity (endothelial lipase) was reduced by more than 95% [10, 52]. Low LPL activity with normal hepatic lipase makes an LMF1 cause unlikely [10]. The classic description includes recurrent pancreatitis, tuberous xanthomas, and lipodystrophy, with variable penetrance and usual onset in late adulthood; by 2026, 14 biallelic cases presenting between ages 23 and 65 years had been published, before the first infant was described [2, 10, 17]. A quantitative cell-based assay of LMF1 function in a cld cell line exists and is used in research to classify variants of uncertain significance [10].

2.7. Inheritance pattern, digenic inheritance, and heterozygotes

FCS is autosomal recessive: homozygosity, compound heterozygosity in the same gene or, more rarely, a digenic combination of variants in two genes of the pathway [1, 21]. In the UK registry, 1.7% of genetic FCS cases were digenic, and in Larouche's pregnancy series 4 of the 20 women with FCS had digenic combinations [28, 53].

LPL heterozygotes have about 50% of normal LPL activity in adipose tissue, but this reduction is not always demonstrable in postheparin plasma [31]. The phenotype ranges from normal to severely elevated TG, depending on secondary factors, and varies in the same individual over time [1, 2, 54]. In the extended pedigree of a proband homozygous for the variant historically designated G188E (= NM_000237.3:c.644G>A p.(Gly215Glu)), heterozygotes had higher TG, VLDL cholesterol, and apoB and lower LDL and HDL, but could be distinguished from noncarriers only after age 40 years [31, 55]. About 10% of people with MCS are heterozygous for a pathogenic LPL variant, and 15–20% carry a rare heterozygous variant in any of the canonical genes [1, 2]. In families with FCS, elevated TG do not cosegregate reliably with heterozygosity, because hypertriglyceridaemia from other causes is common in adults [1, 31]. An isolated heterozygous variant should not be presented in the report as a sufficient explanation for severe hypertriglyceridaemia [9].

2.8. Variant spectrum and nomenclature

Historical LPL nomenclature numbers the mature protein, without the 27 amino acids of the signal peptide, so historical numbers are 27 lower than those of current HGVS nomenclature. The following correspondences were confirmed in VariantValidator and ClinVar, not by manual conversion.

Sources: [11, 31, 50, 56, 57].

In other genes, the variants cited in the article have the following notation: APOC3 “R19X” corresponds to NM_000040.3:c.55C>T p.(Arg19Ter), already in precursor numbering; the APOE ε2 allele, historically Arg158Cys, corresponds to NM_000041.4:c.526C>T p.(Arg176Cys); GPIHBP1 p.(Gly56Arg) is NM_178172.6:c.166G>C and p.(Gln115Pro) is c.344A>C; LMF1 p.(Arg233Ter) is NM_022773.4:c.697C>T (VCV001677881, pathogenic/likely pathogenic) [11, 50]. The LMF1 variant designated Y460X (c.1380C>G) has no ClinVar record found by name [17, 50].

2.9. Genotype–phenotype correlations and penetrance

Most LPL variants have been described in isolated cases or small series, which hampers systematic correlations. In the analysis by Zhang and colleagues, complete loss of activity was associated with earlier onset, and residual activity of 6–7% with later onset and milder symptoms [2, 58]. Clinical severity correlates with the degree of chylomicronaemia, which depends on fat intake [2]. The European panel assigned each gene a grade of expression variability and treatment resistance:

Source: Table 1 of Moulin 2018 [18].

The biochemical penetrance of biallelic FCS is high, but clinical penetrance depends on diet, age, and factors such as pregnancy and alcohol. The LMF1 form has variable penetrance according to GeneReviews [2].

2.10. Allelic disorders, candidate genes, and modifiers

The common LPL variant p.(Asn318Ser) has a modest effect on lipids and coronary risk and is associated with hypertriglyceridaemia when it coexists with the APOE ε2 allele, diabetes, familial combined hyperlipidaemia, hepatic lipase deficiency, or glycogen storage disease Ib; on its own, it is not enough to cause severe hypertriglyceridaemia [2]. LPL has a second OMIM relationship, familial combined hyperlipidaemia 3 (144250), with dominant inheritance, recorded in the sources only as an identifier [6].

APOC3 loss-of-function variants produce the opposite phenotype: among the Lancaster Amish, about 5% are heterozygous for p.(Arg19Ter), with apoC-III reduced by half, lower TG, and less coronary calcification [59]; in the NHLBI Exome Sequencing Project, about 1 in 150 people carries one of four loss-of-function variants, with 39% lower TG and a 40% lower risk of coronary disease (odds ratio 0.60; 95% confidence interval [CI] 0.47–0.75) [60]; among 75,725 Danes, heterozygosity was associated with 44% lower nonfasting TG and a 41% lower risk of ischaemic vascular disease [61]. Null homozygotes in a consanguineous Pakistani cohort were healthy and had a blunted postprandial rise in TG [62]. These genetic data underpin therapeutic inhibition of apoC-III.

CREB3L3 has been proposed as a sixth gene but does not meet causality criteria for FCS, because no biallelic homozygotes have been described; exome and genome data suggest that there may be no additional causal genes, and targeted methods may miss noncoding or deep intronic variants [1, 44]. The Balance trial included GPD1 among the eligible genes, and the 2018 European panel also mentioned it, but GPD1 deficiency is now a distinct entity, transient infantile hypertriglyceridaemia with hepatic steatosis (section 6) [18, 21, 63]. The APOE ε2 allele is overrepresented in MCS [18].

3. Clinical Spectrum and Manifestations by System

3.1. Biochemical profile and appearance of the plasma

In untreated FCS, TG are usually between 1000 and 4000 mg/dL and may reach 15,000 mg/dL; TG make up 80–95% of chylomicron mass, and cholesterol is normal or moderately elevated, rising only when TG are very high, so the cholesterol/TG ratio is below 0.2 and often below 0.1 [31]. The NLA places the typical range at 20–40 mmol/L (1770–3540 mg/dL), rarely below 10 mmol/L and never below 2 mmol/L [1]. The blood has been described as looking like “cream of tomato soup”, and refrigerated plasma forms a creamy layer over a clear infranatant [31]. Chylomicronaemia may be evident from the second day of life [31]. Removing fat from the diet clears the chylomicrons within a few days, with TG falling to 200–400 mg/dL, a response that supports the diagnosis; on a low-fat, high-carbohydrate diet, LDL rise to normal, VLDL increase, and HDL remain low [31].

In adults with FCS, the Fredrickson pattern is more often type V than type I; type I is insensitive but highly specific in adults and more common in children, possibly because of efficient VLDL hydrolysis by hepatic lipase [18, 31].

3.2. Digestive system and pancreatitis

Recurrent abdominal pain occurs in almost all patients [2, 31]. It ranges from mild to disabling, is usually epigastric with radiation to the back, and may be diffuse and mimic an acute abdomen, with fever, leukocytosis, guarding, and rigidity, which has led to exploratory laparotomies that found only milky peritoneal exudate and pale viscera [2, 31]. It is accompanied by anorexia, bloating, vomiting, and diarrhoea, and opioid dependence has been described [31]. In many episodes it probably represents subclinical pancreatitis due to chylomicronaemia [2]. Reported triggers are dietary indiscretion, resumption of a normal diet after a period of restriction, intercurrent infections, alcohol, pregnancy, and oral contraceptives [31].

Acute pancreatitis is the most serious complication. The NLA estimates a lifetime risk of 65–90% in FCS and 20–40% in MCS, with one event every 3 to 5 years; the text of the same document gives 60–90% and 6–30%, an internal discrepancy presented here as published [1]. Risk increases with TG >10 mmol/L (>885 mg/dL), rises abruptly above 20 mmol/L (>1770 mg/dL), and increases by about 4% for every 100 mg/dL of TG [1, 18]. Older sources placed attacks above 1000 mg/dL and morbidity and mortality mainly above 2000 mg/dL [31]. Severe hypertriglyceridaemia is the third leading cause of acute pancreatitis, after gallstones and alcohol, with death in 1–5% of cases and a worse course than other etiologies; after the first episode, recurrences occur at lower TG thresholds [5]. Mortality from pancreatitis in FCS is estimated at 5–6% [39, 64]. Severe forms feature pancreatic necrosis, pseudocysts, abscesses, mesenteric fat necrosis, and adhesions; total pancreatic necrosis and death are rare [1, 2, 31]. Chronic pancreatitis, exocrine pancreatic insufficiency with steatorrhea, and type 3c diabetes result from repeated episodes, are uncommon, and rarely appear before middle age [1, 2]. One patient followed for 31 years, with 22 episodes of pancreatitis, retained preserved endocrine function, without pseudocysts or calcification [31].

Serum amylase may be normal in patients with pancreatitis confirmed at laparotomy, because turbid plasma interferes with the assay; the interference can be overcome by serial dilution, by measuring urinary amylase, or by the amylase/creatinine clearance ratio, and because lipase may also be falsely affected by lipaemia or fail to rise, confirmation relies on clinical findings and imaging [1, 8, 31]. In a 37-day-old infant with apoC-II deficiency and pancreatitis, amylase was low and of no diagnostic use [7].

3.3. Skin, eye, liver, and spleen

Eruptive xanthomas appear in about half of patients: yellow papules of 1 to 5 mm, sometimes with an erythematous halo, on the buttocks, proximal limbs, extensor surfaces, trunk, face, and mucous membranes (palate, tonsils) [2, 31]. They result from extravascular phagocytosis of chylomicrons by macrophages, appear days after TG exceed 2000 mg/dL, are painless and nonpruritic (except at sites of abrasion), and regress over weeks to months as TG fall; persistence or recurrence indicates inadequate treatment [2, 31]. FCS does not cause tendon, tuberous, or plane xanthomas or xanthelasma, with the exception of the tuberous xanthomas described in LMF1 deficiency [10, 31]. The European panel places the frequency of transient xanthomas below 50% [18].

Lipaemia retinalis appears with TG >4000 mg/dL: a salmon-coloured fundus and milky-white retinal vessels caused by light scattering; it is reversible, without vision loss, and is rarely accompanied by lipid deposits, microaneurysms, or haemorrhages [2, 31].

Hepatosplenomegaly is common, more prominent in infants and children, and results from TG uptake by macrophages (foam cells in the spleen and Kupffer cells); it regresses within 24 to 48 hours on a fat-free diet and may normalise within a week, although some enlargement persists in the long term [2, 31]. Splenic pain may occur [31]. Hepatic steatosis is common in FCS and MCS, and the risk of steatohepatitis or cirrhosis is uncertain; isolated reports of hepatic and splenic vein thrombosis have not been confirmed in series or registries [1].

3.4. Haematologic and neurological systems and quality of life

Some patients have anaemia, mild to moderate haemolysis, and, in one case, thrombocytopenia and leukopenia; in apoC-II deficiency, about half of reported patients had anaemia [31]. Variability in platelet count is part of the natural history of some patients, which matters when interpreting the platelet toxicity of oligonucleotides [21]. Seizures, transient paralysis, and gastrointestinal bleeding have been attributed to fat embolism, and intermittent scrotal swelling with milky effusion in the tunica vaginalis has been described in 5 patients [31]. Hyperviscosity is reported as a rare manifestation [29].

FCS is associated with emotional, cognitive, and psychosocial symptoms (“brain fog”, memory problems, irritability, depression) that affect quality of life and may be reversible [2, 18, 65]. In the global IN-FOCUS survey (166 patients from 10 countries, 62% from the USA), the median age at diagnosis was 9 years, patients had seen an average of 5 physicians before diagnosis, 40% had been hospitalised in the past year, the 40% with pancreatitis reported an average of 13 lifetime episodes, more than 90% had difficulty managing dietary fat, and 53% remained symptomatic despite diet; 94% reported an impact on employment [66]. The NLA cites a median of 34 lifetime episodes of pancreatitis and 30 workdays lost per year, figures that do not match those of IN-FOCUS and whose primary source could not be identified [1].

3.5. Cardiovascular system

The sources diverge, and the divergence mainly reflects population differences. In biallelic FCS, Nyhan's Atlas found no appreciable atherosclerosis at autopsy in patients aged 24 to 42 years, and the NLA states that FCS does not by itself increase the risk of atherosclerotic cardiovascular disease (ASCVD), with an ASCVD prevalence of 0% in FCS and 17% in MCS in one report [1, 31]. Benlian and colleagues described premature atherosclerosis in patients with chylomicronaemia due to LPL variants, and GeneReviews attributes to heterozygotes an increased risk of premature ASCVD with mildly or moderately elevated TG [2, 67]. In Table S3 of the NLA document, which compiles 14 adults with genetically confirmed LPL deficiency (aged 33 to 73 years), 4 had documented coronary disease or coronary stenoses, most of them smokers or diabetic [1]. In the UK registry, ASCVD was more prevalent in MCS, but the difference was no longer significant after adjustment for age, sex, and body mass index (BMI) [68]. The NLA/ASPC consensus acknowledges that some patients with FCS and risk factors accumulate atherogenic remnants and have events [5]. GPIHBP1 deficiency was associated with early coronary disease in a table of the Saudubray textbook [29]. In the synthesis of the genetic architecture of coronary disease in the textbook Clinical Cardiogenetics, rare coding variants in APOA5, identified by exome sequencing in affected families, are among those of large effect, with near-monogenic transmission, and LPL and APOA5 are also among the more than 160 common-variant loci of small effect identified by genome-wide association studies [69].

3.6. Presentation by age

In infancy, presentation includes irritability, colic, vomiting, failure to thrive, hepatosplenomegaly, pallor, and lower gastrointestinal bleeding. In a series of 14 infants with onset before age 1 year, 7 had irritability, 4 pallor or anaemia, 2 lower intestinal bleeding, and 1 splenomegaly; another was identified through family history and another incidentally; all had lactescent plasma, and the bleeding stopped on a low-fat diet [31]. A newborn with TG of 38,000 mg/dL and congestive heart failure had normalisation of cardiac function after plasmapheresis [31]. Many cases are recognised incidentally from lactescent blood drawn for another reason, as in the case described in section 10 [17, 31].

In childhood and adolescence, recurrent abdominal pain, pancreatitis, and xanthomas predominate; about 25% of patients with LPL deficiency have symptoms before age 1 year and most before age 10 years [2]. The median age at diagnosis is between 9 and 24 years, and 20–30% of patients are diagnosed only in adulthood; some girls have their first pancreatitis at puberty [1]. In adulthood, the disease may become apparent for the first time during pregnancy, with oestrogen use, or with alcohol [2, 31]. A 70-year-old man homozygous for LPL c.844G>T p.(Glu282Ter) was diagnosed late [56].

3.7. Comparison with multifactorial chylomicronaemia in cohorts

At the Lipid Genetics Clinic in London (Ontario, Canada), 193 adults with TG ≥10 mmol/L followed between 1997 and 2021 (2 to 23 years of follow-up, 3 to 45 measurements) were genotyped with a five-gene panel and a 16-polymorphism polygenic score; 11 had biallelic FCS and 182 MCS [44]. The FCS genotypes were 6 LPL (3 homozygous and 3 compound heterozygous), 4 homozygous APOC2, 1 homozygous APOA5, and 1 compound heterozygous LMF1, a total of 12 that the article does not explain; 80 of the 182 MCS patients had a polygenic score above the 90th percentile [44].

Source: Table 1 of Spagnuolo 2025 [44]. Abbreviations: TC, total cholesterol; HDL-C, HDL cholesterol; NS, not significant.

In multivariable regression, TG/TC ratio >3.52, BMI, age, and minimum TG >10 mmol/L were independently associated with FCS [44]. In the UK national registry (154 patients: 74 FCS and 80 MCS), FCS was more common in people of non-European ancestry and with parental consanguinity; pancreatitis occurred in 84% of FCS and 60% of MCS patients, unexplained abdominal pain in 84% and 52%, and the median age at symptom onset was 15.0 years (interquartile range 5.5–26.5) versus 34.0 years; the first pancreatitis occurred at 24.0 and 33.5 years, respectively, and heterozygotes with MCS had an intermediate phenotype [68].

3.8. Gene-specific features

LPL deficiency is the earliest-onset and most common form. ApoC-II deficiency generally has post-adolescent onset, with abdominal pain and pancreatitis, splenomegaly in some patients, and anaemia in about half; none of the patients in the classic series had xanthomas or hepatomegaly, although Saudubray describes xanthomas and hepatosplenomegaly in adults and severe cases in infancy [29, 31]. GeneReviews gives an onset range of 13 to 60 years, but neonatal presentations occur: three infants from consanguineous families with TG of 3228 to 5802 mg/dL, vomiting, lactescent serum, and eruptive xanthomas [2, 7, 51]. ApoC-II deficiency may be associated with chronic pancreatic insufficiency with steatorrhea and insulin-dependent diabetes [2]. In APOA5, GPIHBP1, and LMF1 deficiencies, GeneReviews describes chylomicronaemia in late adulthood, whereas Saudubray describes abdominal pain, xanthomas, hepatosplenomegaly, and failure to thrive in childhood with APOA5 and relapsing pancreatitis in late childhood and adulthood with GPIHBP1; the variation reflects the small number of published cases [2, 29]. In a Spanish series of 8 children with severe hypertriglyceridaemia, 5 had FCS (2 GPIHBP1, 1 APOA5, 1 APOC2, 1 LPL), 1 had autoimmune chylomicronaemia due to anti-GPIHBP1 antibodies, and 2 had secondary causes [70].

3.9. Pregnancy in the natural history

Pregnancy raises TG about 2.5-fold by late gestation, and oestrogens and placental lactogen can reduce LPL activity by up to 85% [53]. In a retrospective study at three lipid clinics (Chicoutimi and Québec, Canada; Lyon, France) including 116 pregnancies in 49 women with chylomicronaemia (20 FCS with 51 pregnancies; 29 MCS with 65), 42% of women with FCS and 10% of those with MCS had at least one episode of pancreatitis during pregnancy (p=0.01), in 17% and 5% of pregnancies; 56% of gestational pancreatitis episodes occurred in primigravidas with FCS [53]. Chylomicronaemia was diagnosed during pregnancy in 25% of FCS and 17% of MCS cases [53]. Preterm birth occurred in 19.6% versus 6.2% (p=0.05; the abstract gives values different from the table), induced delivery in 58.8% versus 26.2%, and birth weight was 2.97 ± 0.67 kg versus 3.29 ± 0.65 kg; there were 2 fetal deaths after pancreatitis [53]. The frequency of pancreatitis in pregnancy was estimated at 30 times (MCS) to 120 times (FCS) that of the general obstetric population [2, 53]. Mortality from gestational pancreatitis in older series was reported at 21% to 37% for the mother and 20% to 60% for the fetus, figures derived from indirect attribution and predating current practice [53, 71].

3.10. Natural history and treated disease

The frequencies of pancreatitis, xanthomas, and hepatosplenomegaly given above derive mainly from patients with inconsistent access to dietary management and without apoC-III inhibitors. With strict diet started early, symptoms can be prevented and growth is normal, but adherence is difficult and symptoms may occur even with early restriction [2, 72]. In the apoC-III inhibitor trials, the incidence of pancreatitis in the placebo groups was 20% to 30% over 12 months, figures that describe patients already on diet and selected for a history of pancreatitis (section 7) [19, 20]. In follow-up exceeding 30 years, the TG threshold that triggers pancreatitis appeared to decrease over time, and the insulin response to glucose declined progressively, without diabetic blood glucose or glycated haemoglobin (HbA1c) values [31].

4. Clinical Recognition and Red Flags

4.1. When to suspect

GeneReviews proposes suspecting FCS, particularly before age 40 years, in the presence of recurrent abdominal pain, recurrent acute pancreatitis, eruptive xanthomas, hepatosplenomegaly, lactescent plasma, or untreated TG >2000 mg/dL regardless of fasting status, with a family history consistent with recessive inheritance (affected siblings, consanguinity); absence of family history does not exclude the diagnosis, and the disease may mimic dominant inheritance when a heterozygous parent has hypertriglyceridaemia sustained by secondary factors [2]. The NLA adds that the first sign is often incidentally detected lipaemic plasma and the first physical sign eruptive xanthomas on the trunk, back, and buttocks, and recommends assessing body fat distribution to exclude lipodystrophy [1].

Among adults with TG ≥10 mmol/L, the probability of FCS increases with symptom onset in childhood, normal or low BMI, absence of secondary factors, TG/TC ratio >3.5 (mmol/L) or >8 (mg/dL), low apoB, TG that never fall below 10 mmol/L, and lack of response to fibrates and omega-3 fatty acids [1, 4, 44]. Only 0.1–1% of patients with chylomicronaemia have FCS [5].

4.2. Emergency signs

Persistent epigastric pain radiating to the back, vomiting, prostration, hypotension, sweating, or shock in a patient with chylomicronaemia require immediate evaluation for acute pancreatitis, even with normal amylase [1, 31]. Abdominal pain is sometimes a sign of progression to pancreatitis [2]. TG >20 mmol/L mark the abrupt rise in risk [1]. In pregnancy, the combination of pancreatitis, hyperviscosity, and preeclampsia and the risk of fetal death justify hospital admission when TG are not controlled [1, 53]. In the newborn, extreme chylomicronaemia may be accompanied by heart failure [31].

4.3. Laboratory pitfalls

Lipaemia interferes with several assays. TG reduce the aqueous fraction of plasma by about 1% for every 0.9 g/dL; with TG of 10,000 mg/dL, a measured sodium of 129 mEq/L may correspond to 145 mEq/L in plasma water, a pseudohyponatraemia that should not be treated [31]. Lipaemia spuriously raises haemoglobin and bilirubin, and amylase may be falsely normal [31]. Glycerol kinase deficiency produces pseudohypertriglyceridaemia, because free glycerol is measured as TG [5].

4.4. Newborn screening

The sources consulted do not describe newborn screening programmes for FCS. Presymptomatic identification comes from screening the siblings of known patients, ideally in infancy, with testing for the familial variants and TG measurement, so that fat restriction can begin before symptoms appear [2].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Sample collection and initial evaluation

The lipid profile should be drawn after a 12- to 14-hour fast, on the usual diet, without unusual weight change in the preceding two weeks and without lipid-altering drugs; in young infants a modified fast is used [31]. With TG >1000 mg/dL, fasting is no longer necessary for follow-up [2]. The NLA recommends as a baseline panel repeated fasting lipid profiles, apoB, thyroid-stimulating hormone (TSH), HbA1c, transaminases, creatinine, and urinalysis (glucose, protein, and/or albumin/creatinine ratio) [1]. TG ≥10 mmol/L or ≥1000 mg/dL indicate the presence of chylomicrons [1].

The refrigerator test consists of leaving plasma for 18 to 24 hours at 4 °C: in type I FCS a creamy layer forms over a clear infranatant; in type V the creamy layer sits over a turbid infranatant [31]. The European panel recommends leaving plasma in the refrigerator overnight when low-speed centrifugation does not show the layer, and considers agarose electrophoresis unreliable, because the largest chylomicrons do not enter the gel [18].

Source: Table 86.1 of Nyhan's Atlas [31]. TG are elevated in types I, III, IV, and V.

5.2. Discriminating biochemical markers

The TG/TC ratio is the most practical single marker: >3.5 in mmol/L or >8 in mg/dL in 70–90% of FCS and 0–10% of MCS according to the NLA; in the Canadian cohort, TG/TC >3.52 occurred in 72.7% of FCS and in no MCS, and the authors propose it as a more practical variable than apoB for a revised score [1, 44]. The European panel uses a cutoff of TG/TC >5 (mg/mg) or >2.2 (mmol/mmol) with apoB <100 mg/dL in the presence of TG >10 mmol/L [18]. ApoB is below 0.7 g/L in 60–80% of FCS and 10–20% of MCS; a cutoff of 0.77 g/L has been proposed, and the NAFCS score uses <1.0 g/L [1, 4]. For conversion, TG in mmol/L × 88.57 = mg/dL, and cholesterol in mmol/L × 38.67 = mg/dL [29].

5.3. Clinical scores

No published consensus clinical criteria exist for LPL deficiency, but there are two scoring systems for FCS, both evaluated against genetic diagnosis, with a negative predictive value above 90% and a positive predictive value between 70% and 80% [2]. The European score was proposed by a panel convened in Amsterdam in July 2017, with support from Akcea, and applies to patients with severe primary hypertriglyceridaemia (fasting TG >10 mmol/L), outside an acute setting [18].

Source: [18]. If the diagnosis is made during pregnancy, reassessment after delivery is required. The maximum sum of the items in the figure is 15, whereas GeneReviews reports 14 [2, 18].

The North American score (NAFCS) was developed by a modified RAND/UCLA Delphi panel (10 physicians from the USA and Canada and 1 patient with FCS; 296 scenarios; May 2023; sponsored by Ionis, with the panel blinded to the sponsor) and assumes a patient not yet on severe fat restriction, without sustained response (reduction <20%) to fibrates and high-dose omega-3 fatty acids, with assessment of the last 3 tests (adults) or 2 (children) [4]. The calculator is available online [1].

Source: [2, 4]. Secondary factors include high alcohol intake, an ultraprocessed diet, diabetes not induced by pancreatitis, human immunodeficiency virus (HIV) infection, antidepressants, and antiretrovirals [4].

Sources: [4, 18, 74]. Abbreviations: AUC, area under the curve; PPV and NPV, positive and negative predictive values.

The scores have known limitations. The NAFCS discriminates poorly between functional FCS and refractory MCS, penalises late onset (one confirmed FCS case scored 32 points, without pancreatitis and with one secondary factor), does not apply to infants or pregnant women, may lack apoB data, and has been validated in only 11 classic FCS cases [4]. A young woman with lupus and anti-GPIHBP1 antibodies had an NAFCS >60, showing that the score does not distinguish autoimmune chylomicronaemia [4]. The European score may perform less well in non-LPL FCS and in European populations without a founder effect [18]. The authors of the European score state that it is diagnostic and should not be a condition for access to new treatments; GeneReviews notes that, in practice, regulators accept either a genetic diagnosis or the clinical score [2, 18]. In Hungary, applying the score to 1,342,124 hospital records identified 26 patients with ≥10 points, an estimate of 19.4 per million without genetic confirmation in all of them [75].

5.4. Classification of persistent chylomicronaemia (NLA/ASPC 2025)

The NLA/ASPC consensus proposes a phenotypic classification to guide treatment regardless of genotype. PC is defined by TG ≥1000 mg/dL in more than half of measurements and, operationally, by 3 measurements ≥1000 mg/dL over 6 to 12 weeks after diet and first-line treatment [5]. Four subtypes are distinguished: (1) genetic FCS; (2) clinical FCS (high score without testing or without biallelic variants); (3) PC with alarm features; (4) PC without alarm features. Alarm features are recurrent TG-induced acute pancreatitis (not gallstone-related or alcoholic), recurrent hospitalisations for severe abdominal pain with no other cause, pancreatitis in childhood, a family history of hypertriglyceridaemia-induced pancreatitis, and postheparin LPL activity <20% of normal. Subtypes 1 to 3 carry very high risk and subtype 4 high risk [5]. These criteria match the clinical inclusion criteria of PALISADE and the selection criteria in the European summary of product characteristics (SmPC) for plozasiran [20, 22].

5.5. Functional tests

LPL activity is measured in plasma drawn after intravenous heparin, in an assay with normal plasma or apoC-II and with exclusion of hepatic lipase (selective inhibition of LPL with protamine or concentrated sodium chloride, anti–hepatic lipase antibody, or chromatographic separation) [2, 31]. Heparin doses and timing vary among sources: 60 U/kg with sampling at 10 minutes (GeneReviews), 60–100 U/kg and 10–15 minutes (Nyhan's Atlas), 50 IU/kg and 10 minutes (European panel); this is a diagnostic procedure and not a therapeutic dose [2, 18, 31]. In LPL deficiency, activity is usually <10% of control and may be absent; the NLA places FCS typically below 20% of normal but stresses that the assay is not commercially available and is variable and poorly reproducible [1, 31]. In MCS, activity at 10 minutes is normal and often reduced at 60 minutes [18]. Activity can also be measured in an adipose tissue needle aspiration biopsy, without interference from hepatic lipase [2, 31].

Functional tests point to the gene. In apoC-II deficiency, mixing the patient's plasma with normal plasma restores lipolysis and TG fall rapidly, which does not happen in LPL deficiency; apoC-II can be measured by immunoassay or by polyacrylamide gel electrophoresis of tetramethylurea-soluble apoproteins [7, 31, 39]. In APOA5 deficiency, postheparin activity is normal [8]. In GPIHBP1 deficiency, postheparin plasma LPL mass is reduced in some patients [9]. In LMF1 deficiency, both LPL and hepatic lipase are decreased [10]. Testing for anti-LPL and anti-GPIHBP1 autoantibodies is available only in a few research laboratories [1].

5.6. Genetic testing

The NLA considers genetic testing the reference standard, with shared decision-making and genetic counselling before and after testing [1]. The diagnosis is established by identifying biallelic pathogenic or likely pathogenic variants (ACMG/AMP classes, American College of Medical Genetics and Genomics/Association for Molecular Pathology, clinically equivalent) [2, 76]. GeneReviews describes two approaches: single-gene testing or a multigene panel (sequencing followed, if 0 or 1 variant is found, by targeted deletion/duplication analysis), or exome or genome sequencing when the phenotype cannot be distinguished from other hyperlipidaemias [2]. The panel should include the five canonical genes and, ideally, lipodystrophy genes (AGPAT2, BSCL2, LMNA, PPARG) and APOE genotyping [1].

In LPL, about 96% of known pathogenic variants are detectable by sequencing and about 4% are deletions or duplications, detectable by quantitative PCR, long-range PCR, MLPA (multiplex ligation-dependent probe amplification), or targeted microarray; exome and genome sequencing detect copy-number variants (CNV) with lower sensitivity [2]. Nyhan's Atlas indicates that sequencing of the coding region detects about 97% of patients with biochemically confirmed LPL deficiency [31]. These proportions describe the distribution of variants by method, not the clinical sensitivity of testing for FCS.

Yield depends on preselection. With NAFCS >45, the probability of a positive genetic result is 75–80% [1]. In the United Kingdom, of 880 patients tested in two national laboratories through December 2023 (mean age 42.5 ± 15.3 years), 114 (12.9%) received a genetic diagnosis of FCS and 100 (11.4%) had MCS with a heterozygous pathogenic or likely pathogenic variant [28]. More than one third of patients with clinical FCS have no known biallelic combinations [5].

A negative test does not exclude FCS: deep intronic, regulatory, or structural variants, exon deletions not covered by sequencing, or genes not yet recognised may go undetected [1, 2]. When the clinical diagnosis is firm and only one variant is found, the second allele may not have been detected or may not have been reported [2]. Apparent homozygosity should raise the possibility of a deletion of one or more exons on the other allele (false homozygosity) or of uniparental isodisomy, which justifies testing the parents [2]. Indeterminate results (one or two variants of uncertain significance [VUS], or a single pathogenic heterozygous variant) neither establish nor exclude the diagnosis [1, 2]. Polygenic risk has no standardised clinical test [1]. Segregation in parents and siblings helps establish variant phase, and research functional assays, such as the LMF1 cell-based assay, may support VUS reclassification [2, 10].

The report should state the gene, the versioned reference transcript (for example, NM_000237.3 for LPL), the HGVS notation at the coding DNA and protein levels, zygosity, phase when known, and the ACMG/AMP class of each variant [11, 76]. For LPL variants described in historical nomenclature, the correspondence with current numbering differs by 27 codons and should be confirmed in resources such as VariantValidator or ClinVar (section 2.8) [11, 50]. Genetic testing takes 6 to 8 weeks or longer; an NAFCS ≥60 may allow an FCS-approved therapy to be started without waiting for the result, in jurisdictions whose labelled indication permits it [4].

5.7. Practical algorithm

The diagnostic pathway, built from the recommendations of the NLA, the NLA/ASPC consensus, and GeneReviews, is organised in six steps [1, 2, 5, 39]:

The NAFCS authors recommend genetic testing of all pregnant women with pancreatitis or very high TG and of infants younger than 1 year with hypertriglyceridaemia, because the scores do not apply to these groups [4].

5.8. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; views on their use differ among professionals and families [2]. The sources consulted do not describe fetal ultrasound markers of FCS.

6. Differential Diagnosis

6.1. Comparison table

Sources: [1, 4–6, 18, 39, 44–46, 63, 77–80]. The sources consulted do not describe hepatic lipase deficiency or glycerol kinase deficiency in detail; they appear only as differentials to be excluded [1, 2, 5].

6.2. Multifactorial chylomicronaemia

MCS is the main differential and is 50 to 100 times more common than FCS: about 1:500 North American adults (range 1:400 to 1:600), and more than 95% of cases of severe hypertriglyceridaemia [1, 44]. It results from genetic susceptibility (a rare heterozygous variant in 15–20%, a high polygenic score in 35–50%) combined with triggers: 70–90% of patients have at least one secondary factor, versus 0–20% in FCS [1]. Nongenetic factors modulate severity in FCS but determine the presence of chylomicronaemia in MCS [5]. The most useful clinical criterion is the response to control of secondary factors: in MCS, TG often fall below 5 and even below 2 mmol/L, and 33% of MCS and no FCS patients had a minimum TG <2 mmol/L in the Canadian cohort [44]. LPL heterozygotes may transiently develop severe hypertriglyceridaemia resembling genuine deficiency, but they respond to control of secondary factors and to fibrates [2].

Refractory MCS (TG never <10 mmol/L; 16 of 182 MCS patients, 8.8%, in the Canadian cohort) approaches FCS: mean BMI 33.1 kg/m², minimum TG 13.6 mmol/L, Moulin >10 in 37.5%, and a pathogenic heterozygous variant in 37.5% (versus 15.7% in the remaining MCS; p=0.04) [44]. The authors conclude that clinical need, rather than genotype, should determine access to apoC-III inhibitors [44]. Genotyping is of no use in most MCS cases [44].

6.3. Dysbetalipoproteinaemia and polygenic familial hyperlipidaemias

Familial dysbetalipoproteinaemia results from defective clearance of VLDL and chylomicron remnants; about 0.5% of the world population is ε2/ε2, but only a minority develop the disease (estimated prevalence 1–2:10,000), which requires concomitant factors such as a hypercaloric diet, alcohol, diabetes, obesity, hypothyroidism, kidney disease, or oestrogen deficiency [39]. Palmar xanthomas are pathognomonic, but their absence does not exclude the diagnosis; TC is usually >8.0 mmol/L (300 mg/dL) and may reach 26 mmol/L, with TG in a similar range; clinical CVD appears at a mean age of 40 years in men and 59 years in women [39]. Biochemical criteria include apoB/TC <0.15 g/mmol or apoB <1.2 g/L with TG >1.5 mmol/L, TG/apoB <10, and TC/apoB >6.2, and absence of ε2/ε2 does not exclude the diagnosis [39]. The distinction has practical consequences: unlike FCS, dysbetalipoproteinaemia carries high atherosclerotic risk and responds to statins; in a European cross-sectional study (305 patients, 7 hospitals, 4 countries), fewer than half were adequately treated [39]. Chylomicronaemia is rare even in ε2/ε2 individuals, and its presence suggests MCS [18].

Familial hypertriglyceridaemia (formerly type IV) is polygenic, with hepatic VLDL overproduction and reduced catabolism of VLDL and chylomicrons; TG are between 3 and 10 mmol/L, with associations with obesity, insulin resistance, hypertension, and hyperuricaemia, and its association with CVD is weak compared with that of LDL cholesterol [39]. It is a diagnosis of exclusion, made after familial combined hyperlipidaemia and dysbetalipoproteinaemia, which carry greater cardiovascular risk, have been ruled out [39]. Familial hypercholesterolaemia is not part of the differential diagnosis of chylomicronaemia.

6.4. Lipodystrophies

In Berardinelli-Seip congenital generalised lipodystrophy, hyperinsulinaemia and elevated TG appear in infancy, with chylomicronaemia, eruptive xanthomas, and acute pancreatitis; associated features include low HDL, diabetes at puberty, hepatomegaly with steatosis and cirrhosis, and hypertrophic cardiomyopathy in 25%; total fat restriction keeps TG normal, and leptin controls the hypertriglyceridaemia and diabetes [77]. Familial partial lipodystrophies due to LMNA or PPARG are the most common monogenic forms and are recognised by absence of subcutaneous fat in the extremities, with prominent muscles and veins [1]. LMNA-related familial partial lipodystrophy type 2 is included in the GeneReviews list of metabolic causes of pancreatitis [46]. Volanesorsen was studied in familial partial lipodystrophy (BROADEN trial), which was terminated early when the accumulated data allowed a decision [81].

6.5. Autoimmune chylomicronaemia

Anti-LPL or anti-GPIHBP1 autoantibodies produce an acquired, sporadic, adult-onset chylomicronaemia with treatment resistance and a type I phenotype [18]. They should be sought when severe hypertriglyceridaemia appears together with an autoimmune disease such as systemic lupus erythematosus [1]. A young woman with lupus and neutralising anti-GPIHBP1 antibodies, with an NAFCS >60, responded to immunomodulation [4], and one of the 8 children in the Spanish series had autoimmune anti-GPIHBP1 chylomicronaemia [70]. The European panel estimated this cause at less than 1% of cases with an FCS phenotype [18].

6.6. Inherited metabolic diseases with hypertriglyceridaemia

In glycogen storage disease type I, there is marked hyperlipidaemia with high VLDL and LDL, sometimes milky plasma, xanthomas on the buttocks, hips, elbows, and knees, and paramacular retinal lesions; pancreatitis appears to be a consequence of the hypertriglyceridaemia, and one patient died of haemorrhagic pancreatitis; hypoglycaemia, lactic acidaemia, and hyperuricaemia point to the diagnosis [78]. A 2026 report describes a child with glycogen storage disease Ia, refractory hypertriglyceridaemia, and pancreatitis in whom an anti–apoC-III antisense oligonucleotide, used off-label, lowered TG from 4951 to 1643 mg/dL [80]. GPD1 deficiency (about 20 patients described) causes transient infantile hypertriglyceridaemia with hepatomegaly and steatosis, and its differential includes glycogen storage diseases I and III, citrin deficiency, lysosomal acid lipase deficiency, and partial lipodystrophy; a hypercaloric, low-fat, high-carbohydrate diet with MCT may improve growth [63, 79]. Lysinuric protein intolerance, organic acidurias, and respiratory chain disorders may present with acute pancreatitis in children, and PLVAP-related protein-losing enteropathy is associated with hypertriglyceridaemia [46, 73].

6.7. Recurrent pancreatitis of nonlipid genetic cause

The term “hereditary pancreatitis” is reserved for highly penetrant heterozygous germline gain-of-function variants in PRSS1, such as NM_002769.5:c.86A>T p.(Asn29Ile) and c.365G>A p.(Arg122His); “familial pancreatitis” denotes two or more relatives up to the second degree with an unknown or complex cause, and CFTR, SPINK1, and CTRC are other susceptibility genes [46]. Risk assessment for chronic pancreatitis begins at the first episode of acute pancreatitis, once common causes, including hypertriglyceridaemia, have been excluded; the yield of genetic testing in pancreatitis ranges from 4.24% to 37% [46]. In practice, measuring TG during and outside the acute phase separates chylomicronaemia-induced pancreatitis from forms due to PRSS1 and related genes, but coexisting causes are possible.

6.8. Secondary causes and drugs

Table S1 of the NLA document and Table 2 of the NLA/ASPC consensus list the secondary factors that should be sought before concluding that a patient has FCS and that also aggravate the genetic disease:

Sources: [1, 5]. Abbreviations: RXR, retinoid X receptor; SSRI, selective serotonin reuptake inhibitor.

7. Treatment and Risk Management Strategies

7.1. Treatment goals and organisation of care

FCS has no cure. The goal is to prevent pancreatitis and abdominal symptoms while maintaining growth, nutritional status, and quality of life. TG targets differ because no trials have validated them: GeneReviews indicates that morbidity and mortality are preventable with TG <2000 mg/dL and that <1000 mg/dL is a good clinical goal; the NLA proposes <10 mmol/L (885 mg/dL), acknowledging that there is no definitive evidence-based target; the European panel proposes TG <10 mmol/L; Nyhan's Atlas records recommendations of <1000 or even <750 mg/dL [1, 2, 18, 31, 82]. Treatment should be initiated and supervised by a specialist in lipids or metabolic diseases, with a dietitian experienced in fat restriction; the NLA/ASPC consensus describes a team including a lipidologist, dietitian, diabetologist, pancreatologist, cardiologist, psychologist, social worker, pharmacist, and patient organisations [2, 5, 29]. Secondary factors should be corrected in all patients, because they also aggravate the monogenic disease [1].

The evaluations recommended by GeneReviews after diagnosis include weight and length or height (growth delay), presence and frequency of abdominal pain (with evaluation for pancreatitis when severe), assessment for hepatosplenomegaly (confirmed by ultrasound), skin examination for xanthomas, assessment of emotional, cognitive, and psychosocial symptoms, genetics consultation, and family and social support [2].

7.2. Very low-fat diet

Fat restriction is the cornerstone of treatment and acts rapidly: it eliminates the hyperchylomicronaemia and its manifestations, and a single fatty meal can raise TG from hundreds to several thousand mg/dL [31]. Quantitative recommendations vary among sources:

The diet is well tolerated in terms of growth: a very restricted diet started before age 1 year had no adverse effect on growth in a series of infants from Quebec [31, 72]. Fat malabsorption is very rare [2]. Adherence is the main obstacle: more than 90% of patients report difficulty managing fat, 55% report food cravings, dry skin, and mood changes, and adherence becomes harder in adolescence [1, 66]. TG should be measured across the day and not only in the fasting state, because a late-afternoon postprandial sample may reveal values far higher than those of an apparently safe fasting sample [18, 31].

In infants, a low-fat, MCT-rich formula is used; skimmed, fortified breast milk requires further research [1]. The composition of the formulas cited by the NLA, per 100 kcal, is as follows:

Source: Table 6 of the NLA document [1].

7.3. Conventional lipid-lowering drugs

Drugs that act through LPL-dependent pathways have minimal or no efficacy in FCS, unlike in MCS [1, 2, 18, 39]. The text of chapter 36 of Saudubray states that LPL and apoC-II deficiencies do not respond to lipid-lowering drugs, but Table 36.2 of the same chapter lists fibrates as “primary therapy” along with pioglitazone; the text, which agrees with the other sources, takes precedence [29]. In the Canadian cohort, 90.9% of FCS patients had used fibrates without reaching TG <2 mmol/L [44].

Glucagon-like peptide 1 (GLP-1) receptor agonists did not increase pancreatitis in large controlled trials, according to the NLA/ASPC consensus [5]. Pemafibrate did not reduce cardiovascular events in the PROMINENT trial (10,497 patients with type 2 diabetes and mild to moderate hypertriglyceridaemia) and increased apoB and LDL cholesterol; STRENGTH (EPA and DHA mixture) was negative and REDUCE-IT (icosapent ethyl) positive, with differences in population, compound, and placebo discussed by the ESC/EAS [83].

7.4. ApoC-III inhibitors: common mechanism

The three authorised drugs reduce hepatic synthesis of apoC-III, removing an inhibitor of lipolysis and of hepatic uptake of TG-rich lipoproteins. In FCS, where LPL is absent or nonfunctional, the effect is explained by LPL-independent mechanisms or by mechanisms dependent on residual activity: increased hepatic clearance of TG-rich lipoproteins, reduced VLDL assembly and secretion, and possibly reduced intestinal absorption [1, 5, 23]. ApoB-48, a marker of chylomicrons, fell by 51% to 75% from baseline in the pivotal trials, whereas LDL cholesterol and total apoB increased, from very low baseline values [19, 20, 23]. The labels do not stratify efficacy by gene, so the benefit in the APOA5, GPIHBP1, APOC2, and LMF1 forms is inferred from the mechanism and from the inclusion of these patients in the trials [8, 21].

7.5. Olezarsen (Tryngolza®)

Olezarsen is an antisense oligonucleotide (ASO) targeting apoC-III messenger RNA, conjugated to N-acetylgalactosamine (GalNAc3) for hepatocyte uptake; it reaches peak concentration in about 2 hours, is more than 99% protein bound, has a terminal half-life of about 4 weeks, and less than 1% is excreted unchanged in urine within 24 hours; it neither inhibits nor induces cytochrome P450 [19].

In the USA, it is indicated as an adjunct to diet to reduce TG in adults with FCS (approval of 19 December 2024) and, since the extension of 24 June 2026, to reduce TG and the risk of acute pancreatitis in adults with severe hypertriglyceridaemia (TG ≥500 mg/dL) [19, 41]. In the EU, the marketing authorisation of 17 September 2025 limits the indication to adults with genetically confirmed FCS, and the EMA data consulted in October 2026 do not include the extension to severe hypertriglyceridaemia [21, 40].

The dosage in FCS is 80 mg SC once monthly, with an autoinjector (USA) or prefilled pen (EU) of 80 mg/0.8 mL; in severe hypertriglyceridaemia (USA), 50 mg monthly, increased to 80 mg if tolerated and if further reduction is needed; the 50-mg dose is not approved for FCS [19, 21]. The injection is given in the abdomen or the front of the thigh, or in the back of the upper arm when administered by a health care professional or caregiver, with the autoinjector removed from the refrigerator 30 minutes beforehand; a missed dose is given as soon as possible, and the monthly interval resumes from that date [19]. The effect on TG can be assessed within 3 months of initiation; the European SmPC acknowledges that some patients may not respond after 6 months and that, in that case, discontinuation should be considered individually [19, 21]. No adjustment is needed for age ≥65 years, mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m²), or mild hepatic impairment; according to the European SmPC it has not been studied in severe renal impairment or moderate to severe hepatic impairment, whereas the FDA label identified no differences up to Child-Pugh B [19, 21]. Safety and efficacy below age 18 years have not been established [19, 21].

The only contraindication is severe hypersensitivity to olezarsen or the excipients (bronchospasm, diffuse erythema, facial oedema, urticaria, chills, myalgias) [19]. In FCS, the most common adverse reactions were injection-site reactions (19% versus 9% with placebo), decreased platelets (12% versus 4%), and arthralgia (9% versus 0%); discontinuation due to adverse events was 7%, mainly for hypersensitivity [19]. Hyperglycaemia in patients without preexisting diabetes occurred in 52% with olezarsen and 35% with placebo, with a mean rise in fasting glucose ≤17 mg/dL and in HbA1c <0.2 points [19]. Platelets fell by a mean of 6% to 10% through week 53, without associated major bleeding; the European SmPC stresses that some patients with FCS have disease-related platelet variability and that data with platelets <100,000/mm³ are limited, and does not rule out thrombocytopenia, hepatotoxicity, and nephrotoxicity as class effects [19, 21]. In severe hypertriglyceridaemia, aminotransferase elevations ≥3× ULN occurred in 7% with 80 mg, 3% with 50 mg, and 3% with placebo, and hepatic fat fraction increased by a mean of 2 percentage points with 50 mg and 4 with 80 mg at 12 months, of uncertain clinical significance; the label recommends considering liver tests before initiation or a dose increase and thereafter when clinically indicated, considering interruption or dose reduction for persistent elevation ≥3× ULN, and discontinuing for liver injury with symptoms, hyperbilirubinaemia, or jaundice [19]. In male mice, the unconjugated ASO increased hepatocellular adenomas and carcinomas and haemangiomas and haemangiosarcomas, a nonclinical finding in the label [19]. Olezarsen may be combined with statins and fibrates [21].

7.6. Plozasiran (Redemplo®)

Plozasiran is a GalNAc-conjugated small interfering RNA (siRNA) targeting apoC-III messenger RNA; it has a plasma half-life of 3 to 4 hours, but a prolonged pharmacodynamic effect that justifies dosing every 3 months; it is 78% protein bound, 16–19% is excreted in urine, and it is not a substrate, inhibitor, or inducer of cytochrome P450 [20]. It was approved by the FDA on 18 November 2025, as an adjunct to diet to reduce TG in adults with FCS, and in the EU on 19 June 2026, with the same indication [22, 40, 42]. The European SmPC accepts diagnosis by genetic testing or by clinical criteria: fasting TG ≥10 mmol/L (≥880 mg/dL) refractory to standard lipid-lowering treatment and at least one of the following: prior acute pancreatitis not caused by alcohol or gallstones, recurrent hospitalisations for severe abdominal pain with no other explanation, pancreatitis in childhood, or a family history of hypertriglyceridaemia-induced pancreatitis [22].

The dosage is 25 mg SC every 3 months, in a 25 mg/0.5 mL prefilled syringe, with a diet of ≤20 g of fat per day; it is injected into the front of the thigh or the abdomen (except within 5 cm of the navel), or into the upper arm when administered by a caregiver, avoiding damaged skin, scars, or stretch marks; a missed dose is given as soon as possible, and the 3-month interval restarts from that date [20, 22]. The 50-mg dose studied in PALISADE is not approved [20]. No adjustment is needed for age ≥65 years, mild to moderate renal impairment, or mild hepatic impairment; it has not been studied with eGFR <30 mL/min/1.73 m² or in moderate to severe hepatic impairment; paediatric safety has not been established [20, 22].

The FDA label lists no contraindications, and the European SmPC lists hypersensitivity [20, 22]. In PALISADE, the most common adverse reactions were hyperglycaemia (20% versus 8% with placebo), headache (16% versus 8%), nausea (14% versus 8%), and injection-site reactions (10% versus 4%); discontinuation due to adverse events was 6.0% (hyperglycaemia and urticaria) [20]. Hyperglycaemia in patients without preexisting diabetes occurred in 40% with 25 mg and 20% with placebo, with HbA1c up to +0.36% and fasting glucose up to +9 mg/dL; the European SmPC recommends clinical and biochemical monitoring in diabetic patients and in those at increased risk [20, 22]. Aminotransferases rose within the normal range in the first 3 months and then stabilised, and platelets did not change [1, 20]. In pooled data from three controlled trials with 25 mg, hyperglycaemia occurred in 12.8%, headache in 6.8%, and nausea and local reactions in 4.7% [22]. Plozasiran was not carcinogenic in RasH2Tg mice [20].

7.7. Volanesorsen (Waylivra®)

Volanesorsen is a second-generation, unconjugated ASO that binds the 3′ untranslated region of APOC3 messenger RNA [23]. It has held conditional marketing authorisation in the EU since 3 May 2019 (CHMP opinion of 28 February 2019), as an orphan medicinal product subject to additional monitoring, with the most recent annual renewal by Commission decision of 11 July 2025; it is not approved in the USA, where the FDA issued a complete response letter on 27 August 2018, because of concerns about platelet safety [7, 40, 43]. It is indicated as an adjunct to diet in adults with genetically confirmed FCS at high risk of pancreatitis, with an inadequate response to diet and lipid-lowering therapy [23].

In adults (safety and efficacy below 18 years not established; no distinct maximum dose defined in the SmPC, which fixes the dose at 285 mg), the starting dose is 285 mg in 1.5 mL SC once weekly for 3 months, then reduced to 285 mg every 2 weeks; the solution contains 200 mg/mL of volanesorsen sodium, equivalent to 190 mg/mL of volanesorsen, so the 300 mg/week cited by the ESC/EAS corresponds to the sodium salt of the same dose [23, 83]. Treatment should be discontinued if, after 3 months of 285 mg weekly, the TG reduction is <25% or TG do not fall below 22.6 mmol/L; after 6 months, weekly dosing may be resumed if the response is inadequate and platelets are normal, reverting to every 2 weeks if there is no significant additional reduction at 9 months [23]. A missed dose is given if noticed within 48 hours; otherwise, it is skipped [23]. Before initiation, secondary causes such as uncontrolled diabetes and hypothyroidism should be corrected [23].

Source: Table 1 of the Waylivra® SmPC [23]. Before initiation, if platelets are <140×10⁹/L, the count is repeated about one week later, and treatment is not started if they remain below that value; chronic or unexplained thrombocytopenia is a contraindication [23]. Patients weighing <70 kg are more prone to thrombocytopenia; antiplatelet agents, nonsteroidal anti-inflammatory drugs, and anticoagulants should be reconsidered with platelets <75×10⁹/L and discontinued with <50×10⁹/L [23].

The SmPC also requires a urine dipstick every 3 months (with creatinine and 24-hour proteinuria if positive), with discontinuation for proteinuria ≥500 mg/24 h, a creatinine increase ≥0.3 mg/dL (26.5 μmol/L) above the ULN, or eGFR ≤30 mL/min/1.73 m²; liver enzymes and bilirubin every 3 months, with discontinuation for ALT or AST >8× ULN, >5× ULN persisting for ≥2 weeks, or smaller elevations with bilirubin >2× ULN or INR >1.5; and erythrocyte sedimentation rate every 3 months [23]. In the FCS studies (N=87), decreased platelets occurred in 29%, thrombocytopenia in 21%, and injection-site reactions in 82%; in APPROACH, confirmed platelets <140×10⁹/L occurred in 75% with volanesorsen and 24% with placebo, and <100×10⁹/L in 47% versus 0%, with 5 discontinuations for platelets (2 with <25×10⁹/L) [23]. In the CS7 open-label extension, 79% had platelets <140 and 50% <100×10⁹/L, with 11 discontinuations for platelet events, no major bleeding, and recovery in all after discontinuation, with or without glucocorticoids [23]. Immune thrombocytopenic purpura, serum sickness–like reaction, diabetes, proteinuria, haematuria, and increased creatinine have been reported; antidrug antibodies developed in 16% to 33% with no apparent effect [23]. The conditional marketing authorisation requires a registry-based post-authorisation safety study (PASS) for thrombocytopenia, bleeding, and adherence to monitoring, due in the fourth quarter of 2028, and educational materials for health care professionals and patients [23]. The NLA anticipates that volanesorsen will be replaced by olezarsen [1].

7.8. Comparative regulatory status

Sources: [7, 19–24, 40–42, 81, 83, 89]. All approved indications are for adults. According to the sponsor, plozasiran has also been approved in Canada, China, and Australia, dates that have not been confirmed in an official regulatory source [89]. The sources consulted contain no data on reimbursement or access in Portugal (INFARMED) or Brazil (ANVISA).

7.9. Pivotal clinical trials

Sources: [5, 19–21, 23, 89–94].

Interpretation of these trials has limitations. The populations are not comparable: APPROACH and Balance required FCS defined genetically or by enzyme activity, PALISADE included 42% of patients without biallelic variants, and the severe hypertriglyceridaemia trials mainly studied MCS with diabetes; percentage reductions therefore cannot be compared directly across trials [19, 20, 23]. Two matching-adjusted indirect comparisons (MAIC), both by authors linked to the sponsor of olezarsen, found no significant differences between olezarsen and plozasiran (TG −15.5%, 95% CI −76.2 to 45.2; pancreatitis risk ratio 0.70, 95% CI 0.07–6.66) or between olezarsen and volanesorsen (TG −27.4%, 95% CI −69.4 to 14.5), with wide confidence intervals that do not allow equivalence to be concluded [95, 96]. The Balance article and the FDA label give different estimates of the primary effect because of different imputation methods and estimators, and the article counts episodes whereas the label counts patients [19, 91]. Pancreatitis was not the primary endpoint in FCS, and event numbers are small: in Balance, 1 of 22 patients with 80 mg versus 7 of 23 with placebo; in PALISADE, 2 of 26 with 25 mg versus 5 of 25 [19, 20]. In severe hypertriglyceridaemia, the 85% relative reduction corresponds to an absolute difference of about 4 percentage points over one year (4.8% versus 0.7%), and the sponsor of plozasiran estimates a number needed to treat of 24 over one year in the overall population and of 3 in patients with prior pancreatitis [19, 89]. The SHASTA results come from press releases, with no peer-reviewed publication or regulatory assessment to date, and the August press release presents TG reductions sometimes relative to baseline and sometimes “relative to placebo” [89, 94]. Controlled trials lasted about one year; open-label extension data show partial attenuation of the volanesorsen effect (reductions between −35% and −60% in months 3 to 24 of CS7) [23]. The CT angiography substudy of Essence-TIMI 73b (468 patients with TG ≥150 mg/dL and cardiovascular risk) showed that olezarsen lowered TG by 63.9% but did not change noncalcified coronary plaque volume at 12 months (difference +2.98%; 95% CI −3.4 to 9.3; p=0.36), a negative result for the hypothesis of atherosclerotic benefit in moderate hypertriglyceridaemia [97].

The post hoc analysis of PALISADE in the 67 participants with prior pancreatitis showed incident pancreatitis in 5 of 22 with placebo and 2 of 45 with plozasiran (hazard ratio 0.17; 95% CI 0.03–0.87), with lower severity and fewer hospitalisations for abdominal pain [98]. In PALISADE, the subgroups with and without genetic confirmation had a similar response, which underpins the European indication based on clinical criteria [1, 5].

7.10. Gene therapy: alipogene tiparvovec

Alipogene tiparvovec is an AAV1 vector carrying the complementary DNA of the LPL S447X variant, administered by multiple intramuscular injections as a single dose of 1×10¹² genome copies/kg [57]. In the open-label CT-AMT-011-02 trial, the postprandial peak of labelled chylomicrons fell by 79% and the area under the curve by 93% at 14 weeks, with no changes in nonesterified fatty acids, glycerol, glucose, or insulin [57]. In clinical studies with 27 patients, the TG reduction was sustained up to 26 weeks, and after 6 years reductions in the incidence of pancreatitis and acute abdominal pain were described [39, 99]. The European marketing authorisation restricted the indication to adults with genetically confirmed LPL deficiency, with detectable LPL protein and severe or multiple episodes of pancreatitis despite fat restriction [24]. The authorisation expired on 28 October 2017, because the holder did not seek renewal, citing lack of demand; the planned phase 2 trial was withdrawn and the study of effect duration was terminated for commercial reasons [24, 81]. In the apoC-III inhibitor trials, 11% of APPROACH patients had received alipogene tiparvovec on average 8 years earlier, and one woman became pregnant about one year later without a rise in TG [23, 53]. Gene therapy is not applicable to apoC-II deficiency, for which mimetic peptides have been studied: a synthetic apoC-II fragment (amino acids 44–79) lowered TG for 13 to 20 days after a single injection in the two index patients [7, 34].

7.11. Developments in the past 12 months (October 2025 to October 2026)

Also registered are open-label extension trials of olezarsen in FCS (through 2028), of olezarsen in patients previously treated with volanesorsen (primary endpoints of platelet, renal, and hepatic safety), of long-term plozasiran (SHASTA-10; n=710) and of plozasiran in severe hypertriglyceridaemia with pancreatitis risk (SHASTA-5; n=288), a phase 1/2 trial of RN0361 in hypertriglyceridaemia and FCS, a long-term orlistat trial in type 1 hyperlipoproteinaemia, and a plozasiran trial in Chinese patients with FCS, completed in 2024 [81]. MUIR-3 (plozasiran) was completed in June 2026, with no results disclosed in the sources consulted [81, 89]. Pegozafermin, an FGF21 (fibroblast growth factor 21) analogue, lowered TG by about 60% and is in phase 3 in severe hypertriglyceridaemia without genetic FCS [5]. GeneReviews lists inhibitors of microsomal triglyceride transfer protein (MTP), apoC-III, and ANGPTL3 as therapies in development [2, 100]; ANGPTL3, ANGPTL3/8, or ANGPTL4 inhibitors are being studied in persistent chylomicronaemia with residual LPL [2, 5].

Terminated, withdrawn, or negative trials include the extension of pradigastat (a DGAT1 [diacylglycerol acyltransferase 1] inhibitor) in FCS, terminated because the size of the benefit no longer justified continuation; the evinacumab trial for pancreatitis prevention in severe hypertriglyceridaemia, terminated by sponsor decision; BROADEN (volanesorsen in familial partial lipodystrophy), terminated early; the phase 2 trial of alipogene tiparvovec, withdrawn; the alipogene effect-duration study, terminated for commercial reasons; and a phase 2 trial of the anti-ANGPTL3 ASO vupanorsen in FCS completed with only 3 patients [81]. The GENIALL registry of patients treated with Glybera® (n=16) was completed in 2023 [81]. The absence of published results from these studies in the sources consulted does not mean that no data exist.

7.12. Guidelines and recommendations

Sources: [1, 2, 4, 5, 18, 83].

The sources diverge on points with practical consequences. The ESC/EAS 2025 update formally recommends only volanesorsen, the only inhibitor authorised in the EU at the time of writing, without mentioning olezarsen or plozasiran in the recommendations table, although the text notes that anti–apoC-III RNA therapies lower TG by up to about 80%; the NLA, which postdates the US approvals, favours olezarsen and plozasiran and anticipates the replacement of volanesorsen [1, 83]. As for the diagnosis required for treatment, the EU requires genetic confirmation for olezarsen and volanesorsen and accepts clinical criteria for plozasiran, the US labels indicate “adults with FCS” without requiring a genotype, the European panel states that the score should not condition access, and Spagnuolo and colleagues argue that clinical need, rather than genotype, should determine access [18, 19, 21–23, 44]. Regarding fibrates and omega-3 fatty acids, the NLA allows an empirical trial of minimal efficacy, the NLA/ASPC consensus considers them first line to try in all chylomicronaemia, and the European panel considers them ineffective in FCS [1, 5, 18]. GeneReviews contraindicates fish oil supplements and accepts pharmaceutical omega-3 preparations as having no deleterious effects, whereas Saudubray lists omega-3 fatty acids for the APOA5 and GPIHBP1 forms [2, 29]. Regarding lomitapide, the NLA advises against its use, whereas the Italian series identified no new safety signals over 33 months [1, 87]. The ESC/EAS recommendation rests on APPROACH and on an individual-patient-data meta-analysis of three controlled volanesorsen trials in patients with TG >500 mg/dL (n=207), which showed a significant reduction in the risk of acute pancreatitis over a median follow-up of 8.1 months [83, 101]. None of the FCS documents uses GRADE methodology.

7.13. Acute pancreatitis

Diagnosis requires 2 of 3 criteria: persistent acute epigastric pain radiating to the back, lipase ≥3× ULN, and characteristic imaging; lipase may not rise, and TG may already be falling when the patient arrives at the hospital, so the absence of a marked elevation does not exclude this etiology [1]. Management follows standard pancreatitis care, with some specific features [1, 2, 31]:

In apoC-II deficiency, infusion of normal plasma supplies the cofactor and has been used to treat pancreatitis and correct the hypertriglyceridaemia [31, 34]. In three infants with confirmed deficiency, fresh frozen plasma at 10 mL/kg twice daily for 3 days lowered TG by up to 98.3% within 72 hours and allowed the diet to be established; this is a case series and off-label use, as a bridge during the crisis and not as chronic therapy [7, 51].

7.14. Therapeutic plasma exchange

A single plasma exchange session lowers TG by 49% to 97%, but the effect is transient, and there is no evidence for serial outpatient sessions [1]. Complications include citrate-induced hypocalcaemia (the NLA text says “hypercalcaemia”, probably an error), allergic reactions, haemodynamic instability, infection, thrombosis, and bleeding, and rarely toxic epidermal necrolysis and anaphylactic shock [1]. The NLA restricts its use to severely ill inpatients and severe gestational hypertriglyceridaemia [1]. In the newborn with TG of 38,000 mg/dL and heart failure, plasma exchange normalised TG and cardiac function [31]. GeneReviews considers that plasma exchange and antioxidants do not appear to be necessary in the acute phase or in the long term [2].

7.15. Agents to avoid

Agents that increase endogenous TG should be avoided: alcohol, oral oestrogens (including oral contraceptives), thiazide and other diuretics, isotretinoin and other retinoids, glucocorticoids, SSRIs (sertraline is cited), beta-blockers, and atypical antipsychotics; over-the-counter fish oil supplements are contraindicated because they may increase TG and chylomicrons [1, 2, 31]. Oestrogen-containing contraceptives are contraindicated in FCS, with a report of pancreatitis and postpartum hepatic vein thrombosis [1]. Bile acid sequestrants and niacin may worsen hypertriglyceridaemia [1]. The full list of drugs that raise TG is given in section 6.8.

7.16. Pregnancy and lactation

Pregnancy in a woman with FCS is high risk and should be managed by a team including high-risk obstetrics, a dietitian experienced in lipid disorders, and a lipidologist; the risk of pancreatitis peaks in the third trimester, and surrogacy has been proposed as an option [1]. Preconception planning includes a medication review: the European SmPCs for olezarsen, plozasiran, and volanesorsen recommend, as a precaution, avoiding their use in pregnancy, and the olezarsen SmPC recommends effective contraception in women of childbearing potential; the FDA labels state that no human data are available and that animal studies showed no adverse developmental effects at multiples of the human dose, with lower pup weight or survival at high doses [19–23].

Sources: [1, 2, 53, 102–105].

Structured multidisciplinary follow-up was associated with less pancreatitis: in Larouche's series, 7% of pregnancies in women with FCS who received such follow-up had pancreatitis, versus 39% of those who did not (p=0.01) [53]. Table S2 of the NLA document compiles 19 reports of pregnancy in women with FCS or severe chylomicronaemia, with TG up to 16,350 mg/dL, control by a diet of 1 to 4 g of fat per day, plasma exchange, parenteral nutrition, or fibrates, and outcomes ranging from healthy term delivery to neonatal death and fetal losses at 24–25 weeks [1]. After apoC-III inhibitors, the data are anecdotal: one patient became pregnant 8 weeks after a single dose of plozasiran and had no pancreatitis (section 10); in the United Kingdom, two pregnancies have been described in women treated with volanesorsen: in one, the pregnancy was discovered at 38 weeks, after 3 years of treatment, with a healthy delivery at 39 weeks and no pancreatitis; in the other, the drug had been stopped 6 months earlier, pancreatitis occurred at 22 weeks, volanesorsen was restarted at 23 weeks, and delivery occurred at 35 weeks [53, 71, 106]. These cases do not demonstrate fetal safety.

Postpartum, in women who are not breastfeeding, fibrates and/or omega-3 fatty acids may be used with the diet; in breastfeeding women, diet alone, because fibrates pass into breast milk [1]. Volanesorsen was detected in very small amounts in mouse milk, and the SmPC recommends deciding between breastfeeding and treatment [23].

7.17. Children, adolescents, and transition

In children, diet is the only therapy with an indication; the indications for olezarsen, plozasiran, and volanesorsen are for adults, and the paediatric olezarsen trial (2 to <18 years) began in July 2026 [6, 19, 23, 81]. Fibrates and omega-3 fatty acids are supported only by isolated cases, and orlistat is an option [1]. Paediatric follow-up includes height, weight, head circumference, developmental screening, regular lipid profiles and fat-soluble vitamin levels, and family education on food labels, meals, and symptoms of pancreatitis [1]. Adherence is easier until about age 14 years and becomes difficult in adolescence, with increased energy needs, dietary autonomy, and alcohol; some girls have their first pancreatitis at puberty [1]. Transition to adult care should anticipate these risks, oestrogen-free contraception, and access to apoC-III inhibitors from age 18 years [1, 5].

7.18. Perioperative and inpatient setting

The sources consulted contain no perioperative recommendations specific to FCS. The elements applicable to hospital admission are the list of TG-raising drugs, which includes propofol, total parenteral nutrition, and glucocorticoids, the GeneReviews warning about intravenous lipid emulsions, and the need to maintain fat restriction in hospital meals [1, 2, 5]. Heparin should not be used to lower TG [1]. Lipaemia-induced pseudohyponatraemia may prompt unnecessary sodium correction [31].

7.19. Surgery and transplantation

There is no surgical treatment for FCS. Abdominal surgery enters the history of the disease mainly as unnecessary exploratory laparotomy, when chylomicronaemic pain mimics an acute abdomen, and as treatment of the complications of necrotising pancreatitis [2, 31]. A 2026 report describes living-donor liver transplantation in an 8-year-old child with familial hypertriglyceridaemia and recurrent acute pancreatitis, with normalisation of TG within 6 weeks and TG of 75 mg/dL at 11 months; the abstract does not give the molecular diagnosis, so it is not possible to know whether this was FCS, and it is a single case with no place in routine practice [107].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

FCS has autosomal recessive inheritance, and the parents of an affected individual are presumed to be heterozygous; molecular testing of the parents is recommended to confirm heterozygosity, establish variant phase, and assess recurrence risk [1, 2]. If only one parent is a carrier, with confirmed parentage, a de novo variant in the proband or a postzygotic variant in a mosaic parent should be considered, and, in apparent homozygosity, an undetected exon deletion on the other allele or uniparental disomy [1, 2, 108]. Consanguinity increases prevalence [1, 68].

8.2. Cascade testing and heterozygotes

Heterozygote detection requires knowledge of the familial variants; the lipid phenotype of heterozygotes does not predict genetic status, and elevated TG in a relative do not equate to heterozygosity, because hypertriglyceridaemia from other causes is common in adults [2, 31]. For APOA5 and GPIHBP1 heterozygotes, the phenotype is often normal in the absence of secondary factors [2]. Counselling of heterozygotes includes control of secondary factors (alcohol, weight, diabetes, oestrogens) and monitoring of the lipid profile, without labelling them as having a disease [1, 2].

8.3. Reproductive planning

Determination of genetic risk and discussion of prenatal and preimplantation diagnosis should ideally take place before pregnancy, with genetic counselling offered to young adults who are affected, heterozygous, or at risk [2]. Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [2]. For a woman with FCS, reproductive counselling covers the maternal risk of pancreatitis (about 120 times that of the obstetric population) and of fetal complications, oestrogen-free contraception, planned discontinuation of drugs without pregnancy safety data, and the option of surrogacy [1, 2, 21, 53]. In vitro fertilisation with oral oestrogens worsened hypertriglyceridaemia in a patient with variants in APOA5 and CREB3L3 [1].

8.4. Minors

Testing of minor siblings has a direct clinical benefit, because it allows the diet to begin before symptoms, and is therefore recommended in infancy [2]. Carrier testing in asymptomatic minors who are not at risk of disease has no immediate clinical consequence, and the sources consulted make no specific recommendation on this scenario.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The spread of these estimates stems from their measuring different things: expert estimates, regulatory records, clinical scores, and phenotypic prevalences of chylomicronaemia. None of the sources consulted presents a measured population-based genetic prevalence of FCS. In the North American health system, pancreatitis occurred in 28–30% of patients with persistent chylomicronaemia, and younger age, Hispanic ethnicity, pancreatitis, and higher TG predicted persistence [5].

9.2. Ancestry and founder effect

Quebec is the region with the highest reported prevalence, owing to the founder effect of the LPL variant p.(Pro234Leu) (historically P207L), which accounts for most alleles in the French Canadian population [2, 31, 35]. The variant p.(Gly215Glu) (G188E) is common in Europe [31]. Prevalence is also higher with founder effects or consanguinity in the Middle East, South Africa, and South Asia, according to indirect attribution in the NLA/ASPC consensus [5].

The distribution of genes varies with ancestry. In the United Kingdom, among 114 genetic FCS cases, LPL was the gene in 52.6% (60 patients), non-LPL genes in 45.6% (GPIHBP1 22, APOA5 17, LMF1 7, APOC2 6), and digenic inheritance in 1.7%; LPL accounted for 60.9% in patients of European ancestry and 47.1% in those of non-European ancestry, in whom GPIHBP1 reached 30.9% [28]. In the British registry, FCS was associated with non-European ancestry, particularly South Asian, and with consanguinity, and northwest England had the most cases per million [28, 68, 74]. In the Canadian cohort, only 45.5% of FCS patients were of European ancestry, versus 94.0% of MCS patients [44]. The European panel cautioned that the score may perform less well in Europeans, given the smaller founder effect than in Canadians [18].

The sources consulted contain no epidemiological data from Portugal or Brazil. The only Portuguese link found is the coauthorship of a researcher from the Unidade Local de Saúde de São João (Porto) on an indirect comparison between olezarsen and volanesorsen [96]. This absence in the sources does not demonstrate an absence of published data.

9.3. Special populations

In pregnancy, FCS multiplies the risk of pancreatitis and preterm delivery, with data from 116 pregnancies at clinics in Canada and France (section 3.9) [53]. In children, the NAFCS score applies only from age 1 year, and the NLA recommends teams including a lipidologist, endocrinologist, dietitian, geneticist, and gastroenterologist [1, 4]. Older adults may be diagnosed late, as with the 70-year-old man homozygous for an LPL variant who responded to volanesorsen with a 74% reduction in TG [56]. In FCS with diabetes, the diet should favour more complex carbohydrates rather than more fat, and apoC-III inhibitors require glucose monitoring [1, 20]. Patients weighing <70 kg have a higher risk of thrombocytopenia with volanesorsen [23].

9.4. Reference networks and patient organisations

In the EU, FCS falls within MetabERN, the European reference network for hereditary metabolic disorders, in the peroxisomal and lipid metabolism disorders subnetwork (group 2.02, disorders of lipoprotein metabolism, including 2.02.b, hypertriglyceridaemias), with the unified European U-IMD registry [25]. The FCS Foundation (USA) and Action FCS (United Kingdom, formerly the LPLD Alliance) are the patient organisations cited in the sources; the NLA also mentions a patient group on a social network and the NAFCS calculator [1, 18, 26, 27]. The volanesorsen marketing authorisation is linked to a registry of patients with FCS [23]. MedlinePlus maintains a page on familial lipoprotein lipase deficiency [2].

10. Illustrative Clinical Case

10.1. Infant with homozygous LMF1 deficiency (Kumar et al., 2026)

A 5-month-old boy from Odisha (India), the first child of nonconsanguineous parents, born at term by caesarean delivery and exclusively breastfed, was brought to the paediatric emergency department for a suspected snakebite on the back, with no local or systemic signs of envenomation and a normal clot retraction test [17]. The blood sample had a milky-white appearance, with a creamy supernatant visible within minutes (Figure 1A of the article), and the appearance persisted in a sample drawn two weeks after discharge (Figure 1B) [17]. There was no history of abdominal pain, vomiting, pancreatitis, failure to thrive, or hospitalisations, and the family history was negative for premature cardiovascular disease, pancreatitis, and dyslipidaemias [17]. At 5 months, length was 65 cm (+0.34 SD), weight 6 kg (−1.15 SD), and head circumference 42 cm; there were no xanthomas, organomegaly, or signs of lipodystrophy, and funduscopy showed bilateral lipaemia retinalis (Figure 2) [17].

TG were 8014 mg/dL (the article gives 207.2 mmol/L, but the correct conversion is about 90.5 mmol/L), total cholesterol 640 mg/dL, HDL cholesterol 11 mg/dL, and LDL cholesterol 10 mg/dL; glucose and thyroid, liver, and kidney function were normal, amylase was 23 U/L and lipase 30 U/L, abdominal ultrasound was normal, and the parents' lipid profiles were normal [17]. A targeted genetic panel identified the LMF1 variant NM_022773.4:c.697C>T p.(Arg233Ter) in the homozygous state, in exon 5 (chr16:g.893039G>A in GRCh38), classified as pathogenic in ClinVar [17, 50].

Breastfeeding (about 600 mL/day, with about 23 g of fat, roughly 50% of calories) was stopped and replaced by a skimmed milk powder formula with MCT (85 g/day in 5 feeds, about 410 kcal) and sucrose (10 g per feed, about 190 kcal), with fat reduced to about 20% of calories; one month later, TG were 5040 mg/dL (56.9 mmol/L) and the serum remained lipaemic [17]. At 6 months (7 kg), complementary feeding was started with khichdi (rice, lentils, and vegetables), 120 mL with 2 mL of MCT oil four times daily, and mashed fruit with 1 mL of MCT oil twice daily, for a total of about 700 kcal, with fat at 11% of calories [17]. At 10 months, fasting TG were 307 mg/dL (3.5 mmol/L) and the serum no longer had a lipaemic layer (Figure 1C); at 18 months, weight was 12 kg (+1.26 SD) and TG 225 mg/dL, with no episodes of pancreatitis or abdominal pain and with appropriate growth and development [17].

The authors reviewed 14 published biallelic LMF1 cases, all presenting between ages 23 and 65 years, and consider this the first infant described [17]. The case illustrates three points: incidental detection through lactescent serum, an age at presentation far younger than that described for LMF1 in the reference sources, and the response of chylomicronaemia to a diet with 11% fat and MCT. Management is consistent with the NLA recommendations for infants (low-fat, MCT-rich formula; <10–15% of calories at weaning) [1]. The figures consulted are Figure 1 (serial serum tubes with TG of 8014, 5040, and 307 mg/dL; https://pmc.ncbi.nlm.nih.gov/articles/PMC13634674/figure/luag164-F1/) and Figure 2 (bilateral lipaemia retinalis; https://pmc.ncbi.nlm.nih.gov/articles/PMC13634674/figure/luag164-F2/) [17].

10.2. Pregnancy after a single dose of plozasiran (Larouche et al., 2026)

A 34-year-old woman from Quebec with FCS meeting the genetic and clinical criteria of PALISADE was compound heterozygous for LPL p.(Pro234Leu) (P207L) and p.(Asn318Ser) (N291S); she had had TG >10 mmol/L since adolescence, previous eruptive xanthomas, recurrent abdominal pain, fatigue, two episodes of pancreatitis in the preceding 5 years, and a BMI of 30.5 kg/m² [71]. In her first pregnancy (2020, at age 32), with a strict diet and insulin for gestational diabetes, TG reached 45 mmol/L (3986 mg/dL) in the third trimester; delivery was by caesarean section at 39 weeks, and six months later she had necrotising pancreatitis with TG of 73 mmol/L (6636 mg/dL) [71]. In PALISADE, she received plozasiran 25 mg SC on 14 September 2022; TG fell from 24.4 mmol/L (2158 mg/dL) to 0.81 mmol/L (72 mg/dL) at 30 days (−97%; −92% at day 90) [71]. While using transdermal oestrogen contraception (Evra® patch), an unplanned pregnancy was detected 8 weeks after the dose, and she received no further doses [71]. With a diet of <10–15% of calories from fat and insulin for gestational diabetes in the third trimester, TG did not exceed 10 mmol/L (880 mg/dL) throughout the pregnancy according to the results (8 mmol/L according to the discussion of the same article), with no pancreatitis during pregnancy or postpartum; a 4.1-kg, 47.5-cm girl was delivered by caesarean section at 39 weeks, with Apgar scores of 3, 8, and 7 at 1, 5, and 10 minutes, breastfed without problems and with normal development at 1 year [71]. The figure consulted shows TG from screening to the end of the study, with the injection on day 1 and pregnancy confirmed 8 weeks later (https://pmc.ncbi.nlm.nih.gov/articles/PMC12677934/figure/jmd270052-fig-0001/) [71].

This second case departs from recommended practice in two respects: the patient was using oestrogen-containing contraception, which the NLA contraindicates in FCS, and exposure to plozasiran occurred in early gestation, a situation the European SmPCs recommend avoiding for lack of data [1, 22]. A single case without an adverse outcome does not demonstrate the fetal safety of plozasiran.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Life expectancy and morbidity depend mainly on pancreatitis. Without effective treatment, 65–90% of patients have pancreatitis during their lifetime, with recurrences every 3 to 5 years, pancreatitis mortality of 5–6%, and a risk of chronic pancreatitis, exocrine insufficiency, and type 3c diabetes [1, 39]. Biallelic FCS does not appear by itself to increase atherosclerotic risk, although some patients with additional risk factors have events (section 3.5) [1, 5]. With a strict diet, the hyperchylomicronaemia and its manifestations resolve, and GeneReviews considers morbidity and mortality preventable with TG <2000 mg/dL [2, 31]. In the apoC-III inhibitor trials, pancreatitis over 12 months fell from 30% to 5% with olezarsen and from 20% to 8% with plozasiran, in patients with frequent prior pancreatitis [19, 20]. The long-term efficacy and safety of these drugs, the possibility of liberalising dietary fat, and their use in children remain unknown, because the controlled data cover about one year [1]. The psychosocial and occupational impact is high (section 3.4) [66].

11.2. Surveillance

The sources do not define intervals for screening for type 3c diabetes and exocrine pancreatic insufficiency, which should be considered after repeated episodes of pancreatitis, or for pancreatic imaging outside acute episodes [1, 2]. Other components of the lipid profile do not need routine measurement [2].

12. Summary and Concluding Remarks

Familial chylomicronaemia syndrome results from biallelic variants in one of the five genes that ensure intravascular lipolysis of chylomicrons: LPL, which accounts for half to four fifths of cases depending on ancestry, GPIHBP1, APOA5, APOC2, and LMF1. Loss of any element of the pathway produces the same phenotype: TG in the thousands of mg/dL that do not normalise, lactescent fasting plasma, low LDL cholesterol and apoB, a high TG/total cholesterol ratio, and recurrent acute pancreatitis, accompanied by eruptive xanthomas, lipaemia retinalis, and hepatosplenomegaly. The LPL form usually begins in childhood; the others have more variable onset, sometimes in late adulthood, although neonatal APOC2 forms and infants with LMF1 deficiency have been reported.

Diagnosis requires distinguishing FCS from multifactorial chylomicronaemia, which is about 50 to 100 times more common, arises in adults with excess weight, diabetes, alcohol use, or drugs, and responds to correction of these factors. The TG/TC ratio, apoB, the absence of TG <2 mmol/L, and the European (≥10 points) and North American (≥45 or ≥60 points) scores guide suspicion; the five-gene panel with CNV analysis confirms the diagnosis in about three quarters of patients with a high score, and a negative result does not exclude it. The NLA/ASPC classification of persistent chylomicronaemia allows treatment according to risk, regardless of genotype. Lipodystrophy, dysbetalipoproteinaemia, anti-LPL or anti-GPIHBP1 autoantibodies, glycogen storage disease Ia, and GPD1 deficiency are the main monogenic or acquired differentials.

A diet with ≤20 g of fat per day, or 10–15% of energy, with MCT and essential fatty acids, remains the cornerstone of treatment at all ages and is the only option with an indication in children. Fibrates, fish oil, and statins have minimal efficacy. ApoC-III inhibitors have changed the management of adults: olezarsen (80 mg monthly) and plozasiran (25 mg every 3 months) are approved in the USA and the EU, and volanesorsen only in the EU, with intensive platelet monitoring; they lower TG by about 40% to 80% and reduce the incidence of pancreatitis in one-year trials. Indications differ between jurisdictions in whether genetic confirmation is required, and the 2025 European guidelines formally recommend only volanesorsen. Alipogene tiparvovec ceased to be available in 2017.

Pregnancy is the period of highest risk, with pancreatitis in about 4 of every 10 women with FCS in a Canadian and French series, and benefits from structured multidisciplinary follow-up with frequent TG monitoring. Genetic counselling follows the recessive model, with testing of siblings in infancy so that the diet can begin before symptoms appear. Long-term data on apoC-III inhibitors, their use in children and pregnant women, their effect on dietary liberalisation, genetic epidemiology outside North America and the United Kingdom, including Portugal and Brazil, and guidelines using GRADE methodology are the main gaps.

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