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Diagnosis

FCS diagnosis is based on a three-step approach:

High triglyceride evaluation

Milky blood sample or triglyceride level >885mg/dl (>10 mmol/L)1

1

Identify candidates for FCS genetic testing

FCS score >92

2

Genetic test of possible affected genes

LMF1, ApoA5, ApoC2, GPIHBP1, CREB3L3, GPD1, GCKR3,4

3

Identify FCS patients

Use this diagnostic algorithm to identify FCS patients

FCS diagnostic algorithm

1 High triglyceride evaluation

Extremely high triglyceride levels (>10 mmol/L; 885mg/dl) or lipaemic blood (ie, fatty blood with milk-like appearance) require further assessment5, even in absence of typical FCS symptoms, such as abdominal pain.

High triglyceride levels can be caused by genetic factors or present as a result of other conditions or certain medications.3,5

The extent of elevation offers important clues about the cause.

FCS Algorithm

FCS Diagnostic Algorithm

Identify FCS patients by using this Diagnostic Algorithm.
Take the test by clicking your way through each question.

Does your patient have hypertriglyceridemia?

TG 200-885mg/dl
(2-9,9 mmol/l

TG >885mg/dl
(2-9,9 mmol/l)

Think of:

Primary Genetic1

> Familial Combined Hyperlipidemia
> Familial Hypertriglyceridemia
> Dysbetalipoproteinemia

Secondary

Alcohol, Obesity, T2DM,
Hypothyroidism, Oestrogen,
Corticosteroids

FCS score

Click here to calculate the FCS score
≥10 FCS very likely
≤9 FCS unlikely
≤8 FCS very unlikely
FCS score >7: consider genetic testing
FCS score <7: Reconsider other potential causes.

Test for these genes

Genes

LPL, APO A5, APO C2, APO C3, APO E, CREB3L3, GCKR, GPD-1, GPIHBP1, LMF-1

Genetic testing: report

Genes

LPL, APO A5, APO C2, CREB3L3, GCKR, GPD-1, GPIHBP1, LMF-1

Inheritance
  • Homozygous, recessive variants
  • Mixed heterozygous variants
  • Heterozygous co-dominant variants
Genes

LPL, APO A5, APO C2, APO C3, APO E, CREB3L3, GCKR, GPD-1, GPIHBP1, LMF-1

Inheritance

Heterozygous variants with large metabolic effects + SNPs.

Combination of common SNPs* / genetic polymorphisms with small effects in approx. 40 genes.

Sporadic severe HTG: one or NO marginally functional

Possible diagnosis

Monogenetic* HTG, also known as familial chylomicronemia syndrome: The genetic load is high enough to cause constant HTG, regardless of other factors such as additional mutations or lifestyle factors.

*Monogenetic: The genetic load is high enough to cause a constant HTG, regardless of other factors such as additional mutations or lifestyle factors.

Possible diagnosis

Polygenetic** HTG, also known as multifactorial chylomicronemia syndrome: A single mutation is not sufficient to cause a clinical phenotype. The severity of HTG is determined by cumulative/interactive effects of several genetic risk variants.***

**Polygenetic: A single mutation is not sufficient to cause a clinical phenotype. The severity of HTG is is determined by cumulative/interactive effects of several genetic risk variants.

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Does your patient have Hypertriglyceridemia?

MODERATE
Moderate = 200-880mg/dL (2 - 9,9 mmol/l)6

SEVERE
>885mg/dL (>10 mmol/l) FOR 3 CONSECUTIVE BLOOD ANALYSIS6

Moderate

Severe

Moderately high triglyceride levels
(1.7-10 mmol/L; 200-885 mg/dl) suggest:6

Secondary hypertriglyceridemia, associated with:

  • Obesity
  • Type 2 diabetes
  • Kidney disease
  • Hypothyroidism
  • Certain medications (e.g., thiazides, beta blockers, oestrogen, corticosteroids)

Primary (genetic) hypertriglyceridemia, associated with:

  • Familial combined hyperlipidemia
  • Familial hypertriglyceridemia
  • Dysbetalipoproteinemia

Individuals with moderately high triglyceride levels should be further evaluated for potentially increased risks of cardiovascular disease.6

Severely high triglyceride levels (>10 mmol/L; >885mg/dl) suggest:

A genetic defect, especially if the blood sample has been:5

  • Lipaemic (with milky appearance) on several occasions
  • The patient has reported abdominal pain (especially with signs such as tuberous xhantoma or lipemia retinalis)
  • The patient has a history of recurrent pancreatitis.

The execution of the FCS score5 might help to select patients for genetic test confirmation. Severe hypertriglyceridemia requires further evaluation because the patient might be a risk for acute pancreatitis.

Likely causes of severely high triglyceride levels are:

Polygenic Hypertriglyceridemia3

A single mutation is not sufficient to cause a clinical phenotype. The severity of HTG is is determined by cumulative/interactive effects of several genetic risk variants.*

  • Genetic propensity (>300 single nucleotid variants identified)
  • Major contribution of secondary factors (e.g., obesity or type 2 diabetes)
  • Estimated prevalence: 600
Monogenic hypertriglyceridemia3

The genetic load is high enough to cause a constant HTG, regardless of other factors such as additional mutations or lifestyle factors.

  • Genetic etiology (see Causes and Pathophysiology)
  • Minor contribution of secondary factors
  • Estimated prevalence: 100.000 - 1.000.000

*These risk variants include both heterozygous rare variants with major metabolic effects and frequent variants (polymorphisms) with minor effects. These mutations occur in combination with TG-increasing SNPs. A large number of SNPs with an effect on TG can also lead to polygenic HTG on its own.

Secondary factors Inheritance pattern Genes Polygenetic hypertriglyceridemia, multifactorial chylomicronemia syndrome Combination on / Sporadic hyperchylomicronaemia Permanent Severe HTG Monogenetic hypertriglyceridemia, familial chylomicronemia syndrome LPL, APO A5, APO C2, CREB3L3, GCKR, GPD-1, GPIHBP1, LMF-1 LPL, APO A5, APO C2, APO E, CREB3L3, GCKR, GPD-1, GPIHBP1, LMF-1 Homozygous coding mutation This refers to a genetic mutation that is present in both copies (alleles) of a particular gene in an individual. Composite heterozygous coding mutation Composite Heterozygous Coding Mutation: This indicates the presence of two different mutations in the two copies (alleles) of a gene in an individual. Composite heterozygous coding mutation + susceptibility variants This term implies a combination of two different mutations in a gene along with additional variants that increase susceptibility to a particular trait or condition. genetic load Genetic load refers to the cumulative burden of deleterious or disadvantageous genetic variants in an individual’s genome. It reflects the overall impact of genetic variations on the individual’s health or fitness. variants Variants are genetic differences, which can include mutations or any other alterations in the DNA sequence. They may or may not have an impact on the individual’s traits or health.

Adapted from Moulin 2018

2 Identify candidates for FCS genetic testing

In clinical practice there are several conditions characterized by high levels of triglycerides, some essentially genetic and some secondary to other diseases or medications.6

The FCS score

Due to their increased risk of acute pancreatitis, patients with severely high triglyceride levels should be evaluated further. The FCS score test may help identify candidates for FCS genetic testing.5

Click the Yes/No buttons in the score-tool below in order to start the test
(FCS diagnosing score adapted from Moulin 2018).

A printable version can be downloaded here

TRIGLYCERIDES
Score Yes / No
Your patients score
Has the patient had fasting TGs of >10 mmol/L for three consecutive blood analyses?a (+5)
• Has the patient had fasting TGs of >20 mmol/L at least once? (+1)
Has the patient had fasting TGs of <2 mmol/L at least once? (-5)
MEDICAL HISTORY
Does the patient have a history of pancreatitis? (+1)
Does the patient have unexplained recurrent abdominal pain? (+1)
Does the patient have a family history of familial combined hyperlipidaemia? (+1)
DIFFERENTIAL DIAGNOSIS
Have you excluded secondary factors (except pregnancy and ethinylestradiol)?b (+2)
Has the patient failed to respond to hypolipidaemic treatment (TG decrease <20%)? (+1)
How old was the patient when their symptoms first appeared?
 
 
 
<40 years (+1)
<20 years (+2)
<10 years (+3)

Reset

0
Your patients score

Score interpretation

FCS likelihood, based on the FCS score:

≥10

FCS very likely

≤9

FCS unlikely

≤8

FCS very unlikely

What next?

FCS score <7: Reconsider other potential causes.2 Click here to refamiliarize yourself with other causes of hypertriglyceridemia (HTG).

Consider genetic testing when FCS score ≥7.2

You might be able to order this yourself, or you may need to refer your patient to a specialist lipidologist.

  1. Plasma TG concentration measured at least one month apart. Eruptive xanthoma may be used as a surrogate for high TG levels (rare).5
  2. Secondary factors include alcohol, diabetes, metabolic syndrome, hypothyroidism, corticotherapy and additional drugs. If diagnosis is made during pregnancy, a second assessment is necessary to confirm diagnosis post-partum.5

3 Genetic testing

Genetic testing is suggested for individuals with the FCS score of 7 or higher.2 The list of specialized laboratories by country that perform FCS testing can be found at OrphaNet.

Additional diagnostic considerations: Phenotypic differentiation of FCS and MCS

In addition to the FCS score, the following phenotypic differentiation can help estimate whether a patient with severely high triglyceride levels has monogentic HTG, FCS, or polygentic HTG, MCS.

Genes relevant for FCS

Genetic request form

Phenotypic differentiation of FCS and MCS7

Features FCS MCS
Age of onset Childhood or early adolescence Adulthood
Body mass index Normal Overweight or obese
Recurrent acute pancreatitis Common Less common
Hospital admissions Common Less common
Lipoprotein pathology Increased number of chylomicron particles
Low LDL
Low HDL		 Increased number of chylomicron remnant particles
High VLDL
High ILDL
Atherosclerotic cardiovascular disease Less common Common
Metabolic syndrome Less common Common
Post-heparin LPL activity Very low Normal or slightly reduced
Response to traditional lipid-lowering treatment Absent Moderate or poor
Former designations Familial chylomicronemia, hyperlipoproteinemia type 1 (WHO) Mixed dyslipidemia, hyperlipoproteinemia type 5 (WHO)
Main lipoprotein disorder Variable increase in TG-rich lipoproteins: Chylomicrons, VLDL, chylomicron remnants and VLDL remnants  
Ass. Lipoprotein disorders Reduction of LDL and HDL  
Typical start Childhood or adolescence Adulthood
Clinical features
  • early recurrent pancreatitis
  • Failure to thrive
  • Abdominal pain
  • Nausea
  • Vomiting
  • Eruptive xanthomas
  • Lipaemia retinalis
  • Hepatosplenomegaly
  • Abdominal pain
  • Nausea
  • Vomiting
  • Eruptive xanthomas (rarer)
  • Lipaemia retinalis (rarer)
  • Pancreatitis (~1% risk per year)
Cardiovascular risk Only slightly increased Some indications of increased risk
Prevalence rate Rare, ~1:100,000 to ~1:1,000,000 Frequent, ~1:600
Influence of non-genetic factors on the phenotype Low High
Inheritance pattern Autosomal recessive, occasionally autosomal co-dominant Familial clustering, but no classic Mendelian inheritance
Genetic causes
  • Mutations in LPL, APO A5, APO C2, CREB3L3, GCKR, GPD-11, GPIHBP1, LMF-1.
  • Others could be identified in the future.
  • Heterozygous rare variants in LPL, APO A5, APO B, APO C2, APO C3, APO E, CREBH, GCKR, GPD-1, GPIHBP1 and LMF-1 with large phenotypic effects
  • Common variants (genetic polymorphisms, SNPs*) with small effects in ~40 genes identified in genome-wide association studies
Therapy goal
  • Prevention of recurrent pancreatitis and its consequences.
  • Prevention of recurrent pancreatitis and its consequences
  • Reduction of the cardiovascular risk

Table modified and supplemented according to Brahm (2015)
* SNPs = single nucleotide polymorphism = susceptibility variants = polymorphisms

Additional diagnostic considerations: Diagnosis of acute pancreatitis8

Two of the following:

1Lipase 3 x upper limit of normal  
2Abdominal pain Consistent with pancreatitis
  • Symptoms fail to resolve
  • Diagnosis remains in question
  • Concern for pathology/complications
3Abdominal imaging Findings of pancreatitis
Imaging does not need to be performed in every patient with pancreatitis
  • Peripancreatitis Abscess
  • Pancreatic Pseudocyst
  • Necrotizing Pancreatitis
  • Pancreatic Mass
  • Biliary Obstruction

References

  1. Baass A, et al. Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia (Review). J Intern Med 2020; 287: 340–348.
  2. Bashir et al. Atherosclerosis 391 (2024) 117476¸ https://doi.org/10.1016/j.atherosclerosis.2024.117476
  3. Bashir B, et al. Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome— Causes, Clinical Presentation, and Therapeutic Options. Metabolites. 2023; 13(5):621.
  4. Hegele RA, et al. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement Lancet Diabetes Endocrinol 2020; 8: 50–67.
  5. Moulin P, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an ”FCS score”. Atherosclerosis. 2018;275:265–272.
  6. Laufs U, et al. Clinical review on triglycerides. European Heart Journal (2020) 41, 99–109.
  7. Brahm AJ, Hegele RA, Chylomicronemia and current diagnosis and future therapies, Nat. Rev. Endocrinol. 11 (6) (2015) 352e362.
  8. Pancreatitis Pain: Causes, Symptoms, Diagnosis, Treatment. Available at: www.ezmedlearning.com/blog/pancreatitis-causes-symptoms-diagnosis-treatment.

Management

FCS management includes dietary control, pharmacological treatment, and treatment of acute pancreatitis.

Read more

Symptoms and complications

Learn more about the broad spectrum of signs and symptoms that are associated with FCS.

Read more

Causes and Pathophysiology

FCS is a monogenic disease with different pattern of inheritance. In 80-90% of patients with FCS, low activity of lipoprotein lipase (LPL) is caused by mutations in the gene that encodes this enzyme.

Read more

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