Condition

Familial Hypercholesterolemia in Adults

Editors: Maria Sciammarella MD; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; Peter Oettgen MD

Overview and Recommendations
Background Information
History and Physical
Diagnosis
Management
Complications and Prognosis
Prevention and Screening
Guidelines and Resources
Patient Information
References

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Background Information

Description

autosomal codominant disorder of low-density lipoprotein cholesterol (LDL-C) metabolism, typically caused by mutation in 1 of 3 genes^1
,2
,3
,4
- low-density lipoprotein receptor (LDLR), most common
- apolipoprotein B (APOB)
- pro-protein convertase subtilisin/kexin 9 (PCSK9)
less common genetic determinants include
- low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) in < 1% of cases
- apolipoprotein E (APOE), signal transducing adaptor 1 (STAP1), lysosomal acid lipase (LIPA), adenosine triphosphate (ATP)-binding cassette subfamily G5 (ABCG5), or ABCG8 may also generate a familial hypercholesterolemia-like phenotype, but frequency is reported to be very low for each of these genetic determinants
- Reference - Int J Mol Sci 2018 Nov 1;19(11)

Types

types of familial hypercholesterolemia (FH)
- heterozygous form^1
  ,2
  ,3
  ,4
  - mutation in 1 candidate gene known to cause FH
  - in adults
    - total cholesterol between 310-550 mg/dL (9-14 mmol/L)
    - low-density lipoprotein cholesterol (LDL-C) between 190-400 mg/dL (5-10 mmol/L)
    - normal triglycerides
  - in children and adolescents
    - total cholesterol > 230 mg/dL (> 5.2 mmol/L)
    - LDL-C > 160 mg/dL (> 3.4 mmol/L)
    - normal triglycerides
- compound heterozygous form^1
  ,2
  ,3
  ,4
  - 2 different mutations in same or different candidate genes known to cause FH
  - similar phenotype as homozygous form including total cholesterol between 500-1,000 mg/dL (13-25.9 mmol/L), LDL-C > 600 mg/dL (15.5 mmol/L) in adults and children
- homozygous form
  - rare, more severe form of familial hypercholesterolemia²
  - most often caused by mutations in both copies (biallelic mutations) of LDLR, APOB, or PCSK9 genes^1
    ,2
    ,3
    ,4
  - biallelic mutations of FH-phenocopy genes (APOE, LDLRAP1, LIPA, ABCG5, and ABCG8) are associated with conditions that present similarly to FH including markedly elevated LDL-C levels (J Lipid Res 2024 Feb;65(2):100490)
  - total cholesterol between 500-1,000 mg/dL (13-25.9 mmol/L), LDL-C > 600 mg/dL (15.5 mmol/L) in adults and children^1
    ,2
    ,3
    ,4

Epidemiology

Incidence/Prevalence

reported prevalence of familial hypercholesterolemia is 1:200 to 1:250 worldwide (JAMA Cardiol 2020 Feb 1;5(2):217, correction in JAMA Cardiol 2020 May 1;5(5):613)
- heterozygous form
  - estimated 1:500 in many populations (including United States)^1
    ,2
    ,3
    ,4
  - estimated higher prevalence (as high as 1:50 in some populations) in communities with a founder gene including South African Ashkenazi Jews, South African Afrikaners, Christian Lebanese, French-Canadians, Asian Indians, Tunisians^1
    ,2
    ,3
    ,4
  - PubMed32439005Journal of the American College of CardiologyJ Am Coll Cardiol2020052675202553-256625531:313 worldwide estimate based on 10,921,310 persons in general population (J Am Coll Cardiol 2020 May 26;75(20):2553)
  - PubMed31116347JAMA cardiologyJAMA Cardiol2019070147685-6896851:339 in United States, based on 1,178,102 patients ≥ 16 years old in blood donor screening program (JAMA Cardiol 2019 Jul 1;4(7):685)
  - prevalence of monogenic familial hypercholesterolemia 1:836 based on study of 166,281 genotyped persons in Iceland (Arterioscler Thromb Vasc Biol 2021 Oct;41(10):2616)
  - 1:232 in Netherlands, based on study of 2,729 persons from 4 general practices (Ned Tijdschr Geneeskd 2000 Jul 22;144(30):1437 [Dutch])
- homozygous/compound heterozygous form estimated 1:160,000-1:1,000,000 in many populations (including United States)^1
  ,2
  ,3
  ,4
reported prevalence of cardiovascular disease in middle-aged patients with FH ranges from 22%-39%⁵

Etiology and Pathogenesis

Causes

autosomal codominant mutation in 1 of 3 genes^1
,2
,3
,4
- low-density lipoprotein receptor (LDLR) mutations
  - most common cause of FH, exact proportion of cases attributed to this mutation is unknown but reported to account for 60%-90%
  - over 1,600 LDLR pathogenic variants known to cause familial hypercholesterolemia
  - penetrance near 90% in patients with heterozygous LDLR pathogenic variant
- Arg3527Gln mutation in apolipoprotein B (APOB)
  - also called Familial Defective Apo B, reported less severe than typical FH caused by mutation in LDLR
  - exact proportion of cases attributed to this mutation is unknown but reported to account for anywhere from 1%-5% to 5%-10% of cases in Northern Europe (mutation rare in other populations)
  - encodes major protein ligand for LDLR
  - penetrance may be incomplete in patients with heterozygous APOB pathogenic variant
- gain-of-function mutations in pro-protein convertase subtilisin/kexin 9 (PCSK9) reported to account for ≤ 3%-5% of cases, least common cause of FH
  - penetrance near 90% in patients with c.318T>A (p.Ser127Arg) pathogenic variant, penetrance for other variants unknown
proportion of FH caused by de novo mutations unknown¹
STUDY SUMMARY
presence of multiple common small-effect low-density lipoprotein cholesterol-raising alleles associated with FH in mutation-negative patients
CASE-CONTROL STUDY: Lancet 2013 Apr 13;381(9874):1293
based on case-control study

321 patients with clinical diagnosis of FH but without identified FH-causing mutation (mutation-negative patients), 319 patients with clinical diagnosis of FH with identified FH-causing mutation (mutation-positive patients), and 3,020 patients without FH from 3 UK lipid clinics were included in analysis

in 319 mutation-positive patients
93.1% had mutation in LDLR

5% had mutation in APOB

1.9% had mutation in PCSK9

patients were genotyped for 12 common single nucleotide polymorphisms in 11 low-density lipoprotein cholesterol (LDL-C)-raising genes

correlation between elevated LDL-C and presence of LDL-C-raising alleles calculated by developing LDL-C-raising gene score

LCL-C-raising gene score also calculated for an additional 451 patients with FH without identified mutation and 273 patients with FH with identified mutation from a Belgian lipid clinic were analyzed

evaluated genes included PCSK9, CELSR2, APOB, ABCG8, SLC22A1, HFE, MYLIP, ST3GAL4, NYNRIN, LDLR, and APOE

mean weighted LDL-C-raising gene score in UK and Belgian patients
significantly higher in both mutation-negative and mutation-positive patients with FH compared to controls

significantly lower in mutation-positive patients with FH compared to mutation-negative patients with FH

authors suggest polygenic hypercholesterolemia be used to describe people who meet clinical criteria for familial hypercholesterolemia but lack one of the three identified FH-causing mutations

Reference - Lancet 2013 Apr 13;381(9874):1293, editorial can be found at Lancet 2013 Apr 13;381(9874):1255, commentary can be found in Nat Rev Endocrinol 2013 May;9(5):254

Pathogenesis

normal serum cholesterol metabolism through low-density lipoprotein receptor (LDLR) pathway
- LDLR functions as cell surface glycoprotein with high affinity binding to extracellular lipoprotein particles containing apolipoprotein B (APOB)
- LDLR:APOB complex is internalized by endocytosis then delivered to endosomes where the complex dissociates
  - LDLR recycles back to cell surface
  - APOB is degraded in lysosomes to release free cholesterol, which regulates the synthesis of LDLR in the cell; if there is an excess of free cholesterol, transcription of LDLR will be inhibited
- Reference - IUBMB Life 2010 Feb;62(2):125
increased serum low-density lipoprotein cholesterol (LDL-C) may occur through^1
,2
,3
- mutation in LDLR gene on chromosome 19p13 resulting in any of 5 major classes of LDLR defects
  - class I, LDLR is not synthesized
  - class II, LDLR is not properly transported to Golgi apparatus for cell surface expression
  - class III, LDLR does not properly bind LDL on cell surface due to defect in apolipoprotein B-100 or LDLR
  - class IV, LDL bound to LDLR does not properly cluster in clathrin-coated pits for endocytosis
  - class V, LDLR is not recycled into cell
- mutation in APOB gene on chromosome 2p24-p23, preventing LDL-C from binding to LDLR
- 2 gain-of-function mutations in pro-protein convertase subtilisin/kexin 9 gene (PCSK9) on chromosome 1p32, resulting in excessive degradation of LDLR
all mutations impair normal uptake and clearance of LDL-C by liver, causing high total and serum LDL-C levels, most often resulting in type IIa hyperlipidemia, but type IIb and type III hyperlipidemias may be seen, atherosclerotic plaque deposition in all major arterial beds, and clinical manifestations across various systems, including^1
,2
,3
- cardiovascular system
- skin
- eyes

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Images

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Asymmetric xanthelasma in familial hypercholesterolemia

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Tables

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Guideline Recommendations for Identifying Patients With Familial Hypercholesterolemia

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