SCREENING

FH still remains greatly underdiagnosed, so it is crucial to know whom to screen and to identify index cases.
FH should be suspected in individuals with the following findings.1

  • Extreme
    hypercholesterolemia

  • History of
    premature cardiovascular
    disease (CVD)

  • Physical
    examination findings

  • Family history

Extreme hypercholesterolemia

Adults (untreated):
  • LDL-C levels ≥ 190mg/dL
  • Total cholesterol levels ≥ 290mg/dL
Children/ adolescents (untreated):
  • LDL-C levels ≥ 190mg/dL
    (two successive occasions after 3 months diet)
  • LDL-C levels ≥ 160mg/dL, when there is a first-degree relative with premature CAD and/or baseline high LDL-C in one parent
  • LDL-C levels ≥ 130mg/dL, when a parent has a genetic dianosis of FH
  • Total cholesterol levels > 230mg/dL

Physical examination findings

  • Xanthomas

    (cholesterol deposit in tendons)

  • Xanthelasmas

    (yellowish, waxy deposits that can
    occur around the eyelids)

  • Corneal arcus

    (white, gray, or blue opaque ring in the coneal margin as a result of cholesterol deposition)

Read More About Signs And Symptoms Of FH

History of premature
cardiovascular disease (CVD)

  • Patients with Coronary heart disease (myocardial infarction, angina pectoris) requiring intervention or other cardiovascular diseases (e.g., ischemic stroke, peripheral vascular disease).
  • Premature Cardiovascular Disease CVD is typically defined as disease identified before age 55 years in males and before age 65 years in females.

Family history of any
of the followings

Diagnostic criteria

Establishing the diagnosis should be done as soon as possible for individuals suspected with FH.

Currently, there are multiple diagnostic criteria scores available for FH. They use various FH-related features to establish the diagnosis (e.g., LDL-C levels, history of CAD, physical examination findings, family history).1

One of the most commonly used diagnostic criteria is the Dutch Lipid Clinic Network (DLCN).
The European Atherosclerosis Society (EAS) recommends to use DLCN for diagnosing FH.2

Dutch Lipid Clinic Network (DLCN)2
EAS Criteria for the
Diagnosis of HoFH3

The DLCN score is a validated set of criteria based on

  • Family history of premature CVD in their
    family members

  • Their own CVD history

  • Untreated lipid levels

  • Physical signs

  • Genetic confirmation of two mutant alleles at the LDLR, APOB, PCSK9, or LDLRAP1 genes or ≥2 such variants at different loci, OR
  • Untreated LDL-C ~400 mg/dL or treated LDL-C ≥ 300 mg/dL* together with:
    • Cutaneous or tendon xanthorma before the age of 10 years, OR
    • Untreated elevated LDL-C levels consistent with HeFH in both parents

There are other available tools for FH diagnosis, such as Make Early Diagnosis to
Prevent Early Death Program (MEDPED) , Simon Broome Register Group (SBRG) 4

A web-based version of DLCN has been made available. Now you can use it easily to help diagnose FH in any suspected patient.

Easily calculate the score and get an accurate diagnosis if you suspect FH with the DLCN scoring tool

EXPLORE THE DLCN TOOL

Genetic Testing

Different Categories of
Patients May Undergo FH
Genetic Testing11

Read More About Genetics Of FH

The use of diagnostic tools that rely on the presence of physical features, premature CAD, and family history limits diagnostic efficacy and the goal of identifying all patients with FH because although these tools have higher specificity, they have lower sensitivity. Diagnostic accuracy is key; however, to best identify and subsequently treat the spectrum of patients with FH (inclusive of those with an identifiable pathogenic variant or variants [genotype positive], those without [phenotype positive, genotype negative], and those who do not undergo genetic testing), both genotype-positive and phenotype-positive definitions of FH should be used

Because the FH disease severity varies widely between different genes and within each gene, genetic testing is a complementary tool for diagnosing FH because it may determine treatment strategies and the need for screening of family members.4-6

Clinical only

  • Patient: treat LDL-C
  • Family: monitor LDL-C and consider treatment

Clinical and genetic

  • Patient: treat LDL-C
  • Family: mutation test, monitor LDL-C and consider treatment

Genetic only

  • Patient: treat LDL-C and consider treatment
  • Family: monitor LDL-C and consider treatment

The following clinical criteria should be met before genetic testing7

Criteria
Adults
LDL-C > 190 mg/dL
LDL-C > 190 mg/dL
With a known family history of FH
With a parent with FH
With a known family mutation
With parents deceased or unknown
With a family history equivocal or only suggestive of FH
With xanthoma or other physical findings of HoFH or at risk of HoFHa
With a family history of high cholesterol levels (total, non-HDL-C and LDL-C) consistent with FH
Based on age- and gender-specific LDL-C levelsb
With a clinical diagnosis of FH
With suspected HeFHc
With diagnosis of xanthoma or CHD in the family history
With suspected HoFHd
Children
FOOTNOTES

a - By 2 years of age
b - Ideally before puberty
c - Between the ages of 5 and 10
d - Earlier than 5 years of age

Cascade Screening

Cascade screening for FH is an evidence-based intervention that can reduce the
burden of morbidity and mortality from ASCVD and has been recommended by
national and international organizations2,8
  • Cascade screening is an active process to screen and test the relatives of the patients’ with genetic conditions that may “run in the family”.
  • As FH is dominantly inherited, cascade screening of family members can be highly effective to know whether any individuals in the family have FH.
  • Once a FH patient (index case) is identified, several cycles of cascade screening are required to identify all patients with FH in their family. Screening cycles are repeated (cascaded) for each relative diagnosed with FH, thereby expanding the number of potential cases detected.
Cascade screening8
Reverse cascade screening 9,10

  • Screen cycle 1

    Once an index patient with FH is identified, cascade screening starts with first-degree relatives (parents, siblings, children)

  • Screen cycle 2

    If the affected parent is identified, as many relatives as possible on that parent’s side of the family should be screened

  • Screen cycle 3

    Children of the affected parent’s siblings should also be screened because treatment in childhood is indicated for those who are affected

  • Screen cycle 4

    Each new FH case found via cascade screening then becomes an “index case” for broader cascading

Reverse cascade screening (or child-parent screening)
can be used to identify most families with FH in a population.

The process means:

Children are tested for the
LDL-C levels in routine immunizations
(normally at age 1–2 years)

If a child tests 'positive' (> 1.5 times the median LDL-C levels of age-specific population) the parents will be tested

There is a
96% chance
that is an affected parent will be correctly identified.
REFERENCES:
  1. Ison HE, et al. Familial Hypercholesterolemia. 2014 Jan 2 [Updated 2022 Jul 7]. In: GeneReviews®. Seattle (WA): University of Washington, Seattle. Available from: https://www.ncbi.nlm.nih.gov/books/NBK174884/
  2. Nordestgaard BG et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013; 34:3478a-3490a.
  3. Cuchel M, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023;44(25):2277-9
  4. National Institute for Health and Care Excellence. Familial hypercholesterolaemia: identification and management. Appendix F: Simon Broome criteria. 2008. Available at https://www.nice.org.uk/guidance/cg71/evidence/full-guideline-appendix-f-pdf-241917811. Accessed on 16 Nov 2022.
  5. De Castro-Orós I, et al. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl Clin Genet. 2010;3:53-64.
  6. Foody JM, et al. Familial hypercholesterolemia/autosomal dominant hypercholesterolemia: Molecular defects, the LDL-C continuum, and gradients of phenotypic severity. J Clin Lipidol. 2016;10:970-986.
  7. Migliara G, et al. Familial Hypercholesterolemia: A Systematic Review of Guidelines on Genetic Testing and Patient Management. Front Public Health. 2017;5:252.
  8. Knowles JW, et al. Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing. JAMA. 2017;318(4):381-382.
  9. Morris JK, et al. The evaluation of cascade testing for familial hypercholesterolemia. Am J Med Genet A. 2012;158A(1):78-84.
  10. Wald DS, et al. Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ. 2007;335(7620):599.
  11. Sturm AC, et al. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680