Familial
Hypercholesterolemia

What is FH? 1,2

Familial hypercholesterolemia (FH) is a genetic disorder of the lipoprotein metabolism, which is characterized by significantly elevated low-density lipoprotein-cholesterol LDL-C . 1,2 FH includes

F+H

  • Familial: The underlying cause is a genetic defect that is passed down through families

  • Hypercholesterolemia: High LDL-cholesterol

In patients with FH, chronic exposure to high circulating cholesterol levels
is a risk factor that leads to1,2

  • Atherosclerotic plaque deposition in the coronary arteries and proximal aorta

  • Increased risk of (premature) atherosclerotic cardiovascular disease (ASCVD) (e.g. angina, myocardial infarction, stroke)

  • High mortality rates

Adapted from Nordestgaard BG, et al. Eur Heart J. 2013

FH is inherited as a monogenic autosomal dominant trait (Read more about genetics of FH here). Patients with FH can be categorized as having

Homozygous familial hypercholesterolemia (HeFH)

Homozygous familial hypercholesterolemia (HoFH)

Burden of FH in Asia

An estimated
30 million people worldwide could be affected by FH
but prevalence estimates between studies vary substantially.3

  • Global FH prevalence:*
    4 in 1000 people3
    *pooled estimate of 0.4%

  • Asia FH prevalence:*
    5 in 1000 people3
    *pooled estimate of 0.46%

Heterozygous familial hypercholesterolemia (HeFH)

  • Based on the extrapolations used, there are 13.7 to 34.3 millions people affected by HeFH worldwide.4 In South-east Asia region only, between 3.6 and 9 million individuals may have HeFH.4
  • The prevalence of HeFH is highest in middle income countries such as Thailand. Up to 24.8 millions in middle income countries are living with HeFH.4

Homozygous familial hypercholesterolemia (HoFH)

  • Based on the extrapolations used, in South-east Asia region only, between 1.8 and 11.3 thousand individuals may have HoFH.5

Signs and
symptoms 1,6,7

Patients with HoFH or compound HeFH present with distinctive and severe clinical manifestations very early in life (< 10 years old). On the other hand, patients with HeFH are, by and large, asymptomatic in childhood and adolescence and typically diagnosed by screening methods.7

Primary clinical manifestations (dermatological and ocular)6,7

  • Xanthoma
  • Xanthelasma
  • Corneal Arcus

  • Xanthomas are the most common skin lesions in FH. They are composed of monocyte -derived foam cells (accumulation of lipids inside the cells) and connective tissue.

    Achilles tendon xanthoma
    "Skin-colored subcutaneous nodule, smooth and firm, attached on Achilles tendon"

    Tuberous xanthoma
    "flat, or elevated and rounded, yellowish nodules on the skin over joints, especially on elbows and knees"

    Cutaneous xanthoma8 in a 3-year-old patient at flexures of the wrist and in other regions with mechanical stress.

  • Xanthelasma are the most common type of cutaneous xanthomas. They are sharply demarcated, yellowish, flat or minimally elevated, soft/semisolid plaques. It is distributed symmetrically, occurs most commonly near the inner canthus of the eyelid, more often on the upper rather than the lower lid.

    *courtesy of images from patients at King Chulalongkorn Memorial Hospital

  • Corneal Arcus is described as a gray-white-yellowish opacity, 1–1.5 mm thick, located at the periphery of the cornea. It is formed by the deposition of lipids in the stroma of cornea.

    *courtesy of images from patients at King Chulalongkorn Memorial Hospital

Secondary clinical manifestations7

Severe atherosclerosis

including multiple vascular beds, including coronary, cerebral, and peripheral vascular system.

Calcific aortic valve stenosis
and aortic root disease

including aortic stenosis due to cholesterol and inflammatory cell infiltration.

Genetics of FH 1,2,4

FH is inherited as a monogenic autosomal codominant trait, so patients with FH can be categorized as HeFH or HoFH. Mutations in key proteins involved in LDL metabolism are the underlying cause of FH, and lead to reduced uptake of LDL by hepatocytes and thus elevated serum LDL-C levels.1,2,4

Heterozygous familial
hypercholeste
rolemia
(HeFH)

Homozygous familial
hypercholeste
rolemia
(HoFH)

(Heterozygous or Homozygous)
mutations in genes encoding key
proteins involved in LDL uptake

Elevated
plasma LDL-C

Defective LDL uptake in hepatocytes

Key proteins involved in LDL uptake9,11

LDL in blood stream is taken up by hepatic and extra-hepatic tissues through LDL-receptors locating on the cell membrane. There are four proteins involved in this process.

LDLR, low-density lipoprotein receptor; LDLRAP1, LDLR adaptor protein 1; PCSK9, proprotein convertase subtilisin/kexin type 9

Types of mutations
causing FH4,10,12,13

Gene Mechanism of gene mutation Prevalence
LDLR LDLR is absent or has decreased capacity to clear LDL from the circulation 85–90%
(most common)
APOB Mutations impair binding of LDL to the LDLR, reducing LDL uptake 5–10%
PCSK9 Gain-of-function mutations increase PCSK9 activity, leading to increased LDLR degradation and decreased surface expression of LDLR, thus reducing uptake of LDL Rare
LDLRAP1 Loss-of-function mutations in the protein required for clathrin-mediated internalization reduce the uptake of the LDLR–LDL complex Rare

FH and CVD risk

FH is associated with a significantly increased CVD risk because elevated low-density lipoprotein cholesterol (LDL-C) in FH leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events.1

Elevated plasma LDL-C

Cholesterol retention in the arterial
wall and foam cell formation within
the intima of arteries lead to
occlusive atherosclerosis

Patients with FH are at significantly
increased risk of CHD and MI

Lifetime CVD Event Rates in FH
is 4 times higher than
Non-FH Patients14

Untreated patients with HoFH are likely to develop
CHD as teenagers and die from acute MI as early as 4
and before reaching 20 years of age15

Adults with the FH phenotype, defined as LDL-C
≥ 190 mg/dL, were associated with ~5-fold increase
in long-term CHD and ASCVD risk compared with
those with LDL-C < 130 mg/dL16

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. Mytilinaiou M, et al. Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management. Front Pharmacol. 2018;9:707.
  3. Akioyamen LE, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open. 2017;7(9):e016461.
  4. 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.
  5. 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
  6. Varghese MJ. Familial hypercholesterolemia: A review. Ann Pediatr Cardiol. 2014;7(2):107-17.
  7. Rallidis LS, et al. The value of physical signs in identifying patients with familial hypercholesterolemia in the era of genetic testing. J Cardiol. 2020;76(6):568-572.
  8. Nohara A, et al. Homozygous Familial Hypercholesterolemia. J Atheroscler Thromb. 2021; 28(7): 665–678.
  9. Sniderman AD, et al. The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol. 2014;63(19):1935-47.
  10. De Castro-Orós I, et al. The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations. Appl Clin Genet. 2010;3:53-64.
  11. Soutar AK and Maoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. A Nat Clin Cardiovasc Med. 2007;4(4):214-225.
  12. 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.
  13. Goldberg AC, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-S8.
  14. Villa G. et al. Prediction of cardiovascular risk in patients with familial hypercholesterolaemia. Eur Heart J Qual Care Clin Outcomes. 2017;3:274-280.
  15. Reiner Z. Management of patients with familial hypercholesterolaemia. Nat Rev Cardiol. 2015;12:565–575.12.
  16. Perak AM, et al. Long-Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype. Circulation. 2016;134:9-19.