Familial hypercholesterolemia (FH) is an autosomal dominant genetic condition. Screening patients with a family history of early heart disease or FH is essential to providing optimal management of this condition.

There are two types of FH. The first and most common type is heterozygous FH (HeFH) occurring in 1 in 250 people worldwide. Homozygous FH (HoFH) is much less common, occurring in 1 in 250,000 people around the world. Someone with HoFH has inherited two FH genes, one from each parent. If left untreated, HoFH can lead to heart attack and stroke in childhood.

An FH diagnosis should be considered if someone has:

  • A family history of early heart disease, meaning younger than 55 in men and younger than 65 in women
  • High low-density lipoprotein (LDL) cholesterol while off treatment, over 190 mg/dL in adults and over 160 mg/dL in children.

An HoFH diagnosis should be considered if someone has:

  • One or both parents with a clinical or genetic diagnosis of FH
  • LDL cholesterol over 560 mg/dL or over 400 mg/dL with aortic stenosis or xanthomas before the age of 20

FH Diagnostic Criteria

There are currently four accepted resources for FH diagnosis.

Simon Broome Diagnostic Criteria for FH

PointCriteria
1Total cholesterol levels > 290 mg/dL (7.5 mmol/L) or LDL-C > 190 mg/dL (4.9 mmol/L) in adults.

Total cholesterol levels > 260 mg/dL (6.7 mmol/L) or LDL-C > 155 mg/dL (4.0 mmol/L) in children.

2Tendon xanthomas in the patient or tendon xanthomas in a first or second degree relative.
3DNA-based evidence of an LDL-receptor mutation, familial defective apo B-100, or a PCSK9 mutation.
4Family history of myocardial infarction before age 50 in a second degree relative or before 60 in a first degree relative.
5Family history of elevated total cholesterol > 290 mg/dL (7.5 mmol/L) in an adult first or second degree relative.

Family history of elevated total cholesterol > 260 mg/dL (6.7 mmol/L) in a child, brother, or sister 16 years or younger.

DIAGNOSIS
Definite familial hypercholesterolemia = 1+2 or 3
Possible familial hypercholesterolemia = 1+4 or 5

 

The Simon Broome Diagnostic Criteria cannot be used to diagnose children with HeFH.

Dutch Lipid Clinic Network Diagnostic Criteria for FH

Criteria     Point
  Family History

    First degree relative with known premature* coronary and vascular disease OR

    First degree relative with known LDL-C level above the 95th percentile

1
    First degree relative with tendinous xanthomata and/or arcus cornealis OR

Children aged less than 18 years with LDL-C above the 9th percentile

2
  Clinical History
    Patient with premature* coronary artery disease2
    Patient with premature* cerebral or peripheral vascular disease1
  Physical Examination
    Tendinous xanthomata6
    Arcus cornealis prior to age 454
  Cholesterol Levels mg/dL (mmol/L)
    LDL-C ≥ 330 mg/dL (≥8.5)8
    LDL-C between 250 - 329 mg/dL (6.5 - 8.4)5
    LDL-C between 190 - 249 mg/dL (5.0 - 6.4)3
    LDL-C between 155 - 189 mg/dL (4.0 - 4.9)1
  DNA Analysis
    Functional mutation in the LDLR, apo B, or PCSK9 gene8
  DIAGNOSIS
    Definite familial hypercholesterolemia   >8
    Probable familial hypercholesterolemia  6 - 8
    Possible familial hypercholesterolemia  3 - 5
    Unlikely familial hypercholesterolemia   <3

*Premature = < 55 years in men; <60 years in women

 

MedPed Diagnostic Criteria for FH

FH is diagnosed if total cholesterol exceeds these cutpoints in mg/dL (mmol/L)
  Age  First degree relative with FH  Second degree relative with FH  Third degree relative with FH  General population
<20220 (5.7)230 (5.9)240 (6.2)270 (7.0)
20 - 29240 (6.2)250 (6.5)260 (6.7)290 (7.5)
30 - 39270 (7.0)280 (7.2)290 (7.5)340 (8.8)
>= 40290 (7.5)300 (7.8)310 (8.0)360 (9.3)

Total cholesterol cutpoints for FH is dependent upon the confirmed cases of FH in the family. If FH is not diagnosed in the family, then the cutpoint for diagnosis is as per "general population."

Genetic Testing

While FH is commonly diagnosed based on clinical criteria, there is genetic testing available. The genetic test should identify mutations in the low-density lipoprotein reception (LDLR) gene, the apolipoprotein B (apoB), or the proprotein convertase subtilisin/kexin (PCSK9) genes.

Management

Although risk factors such as diet and lifestyle should be addressed, individuals with FH require early, aggressive and lifelong therapeutic medical interventions.

Medical guidelines from the American College of Cardiology and the American Heart Association in 2018 give clear recommendations for the LDL Safe Zone based on risk factors.

  • These guidelines recommend an LDL level below 100 mg/dL for everyone with the exception of those with cardiovascular disease.
  • For someone who already has cardiovascular disease, no matter their untreated LDL level, the recommendation is to get LDL below 70 mg/dL.

Today, there are multiple treatments for FH available and several more in development. You can learn about FH treatment options here and HoFH treatments here.