• familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C), leading to an increased risk of premature atherosclerotic cardiovascular disease
    •  affected individuals have a 50% chance of passing the disease on to their offspring
  • it results from mutations affecting LDL receptor function or related pathways
  • the diagnosis of familial hypercholesterolemia (FH) is based on a combination of clinical criteria, family history, and genetic testing
  • several diagnostic criteria have been developed, including:
    • the Dutch Lipid Clinic Network (DLCN) criteria
    • the Make Early Diagnosis to Prevent Early Deaths (MEDPED) criteria
    • the Simon Broome criteria

Clinical presentation

Individuals with FH have varying clinical presentations, ranging from asymptomatic to severe cases. Lifestyle factors, genetic mutations, and additional cardiovascular risk factors can affect the severity of the condition.

  • premature coronary artery disease (CAD)
    • individuals with FH are at significantly increased risk of developing CAD (angina, myocardial infarction, or sudden cardiac death) at an early age compared to the general population
  • xanthomas  Xantoma tendinosum

    • tendon xanthomas are commonly observed in FH, typically affecting the Achilles tendon, extensor tendons of the hands, and patellar tendons
  • xanthelasma  Xanthelasma

    • cholesterol deposits around the eyes
  • corneal arcus    Arcus lipoides corneae

    • a grayish-white ring around the cornea is often seen in older individuals with FH
    • its absence does not rule out FH, especially in younger patients

Diagnostic evaluation

Laboratory tests

  • elevated levels of LDL-C are a hallmark of FH (see the diagnostic criteria)
  • total cholesterol and triglyceride levels may also be elevated, although not as consistently as LDL-C
  • laboratory tests are discussed in detail in the chapter on dyslipidemia

Diagnostic criteria

  • the Dutch Lipid Clinic Network (DLCN) criteria use a point system based on LDL-C levels, family history of hypercholesterolemia or premature coronary artery disease, clinical signs (such as tendon xanthomas or corneal arcus), and genetic testing
  • the total score can categorize the diagnosis as follows:
    • definite FH (>8 points)
    • probable FH (6-8 points)
    • possible FH (3-5 points)
    • unlikely (<3 points)

Family History

  • first-degree relative with premature coronary artery disease (CAD): 8
  • first-degree relative with tendon xanthomas: 6
  • first-degree relative with cholesterol levels consistent with FH: 5
  • second-degree relative with premature CAD: 4
  • second-degree relative with tendon xanthomas: 3
  • second-degree relative with cholesterol levels consistent with FH: 2

LDL Cholesterol (LDL-C) levels above specific thresholds based on age:

  • ≥ 8.5 mmol/L (330 mg/dL) in adults: 8
  • ≥ 6.5 mmol/L (250 mg/dL) in children: 8
  • ≥ 5.0 mmol/L (190 mg/dL)  in children under 16 years old: 6
  • ≥ 4.0 mmol/L (155 mg/dL) in children under 10 years old: 4

Physical Examination

  • tendon xanthomas: 6
  • corneal arcus in individuals < 45 years old: 4

Genetic Testing

  • documented pathogenic mutation in LDLR, APOB, or PCSK9: 8
  • The Make Early Diagnosis to Prevent Early Deaths (MEDPED) criteria are based on the age-specific total cholesterol (TC) levels and the presence of FH in first-degree relatives
    • adults (age ≥20 years): TC >290 mg/dL (7.5 mmol/L) for individuals with a family history of FH or premature coronary heart disease (CHD)
    • adolescents (age 10-19 years): TC >260 mg/dL (6.7 mmol/L) for those with a family history of FH or premature CHD
    • children (age <10 years): TC >230 mg/dL (5.9 mmol/L) for those with a family history of FH or premature CHD
  • the diagnosis is considered more likely if multiple family members across generations are affected or if very high cholesterol levels are observed in conjunction with family history
  • the definitive diagnosis can be further supported by genetic testing, identifying specific mutations in the LDLR, APOB, or PCSK9 genes
  • definite FH
    • children: total cholesterol levels > 6.7 mmol/L (260 mg/dL) or LDL-C levels > 4.0 mmol/L (155 mg/dL)
    • adults:  TC levels > 7.5 mmol/L (290 mg/dL) in adults or LDL-C levels > 4.9 mmol/L (190 mg/dL)
    • plus either tendon xanthomas in the patient or a first-degree relative (parent, sibling, child) or DNA-based evidence of an LDL receptor mutation, familial defective apoB-100, or a PCSK9 mutation
  • possible FH
    • same cholesterol levels but without the genetic evidence or tendon xanthomas, though there may be a family history of myocardial infarction or raised cholesterol

Genetic testing

  • FH is diagnosed through genetic testing by identifying mutations in the LDLR, APOB, or PCSK9 genes
  • FH is inherited in an autosomal dominant (AD) pattern ⇒ mutation in one copy of the gene is sufficient to cause the condition
    • the severity of FH varies depending on the specific mutation and other factors
    • homozygous familial hypercholesterolemia (HoFH) results from mutations in both alleles and is characterized by extremely high LDL-C levels (often >400 mg/dL (10.35 mmol/L)) and premature atherosclerotic cardiovascular disease (ASCVD), often manifesting in the first two decades of life
  • the absence of a detectable mutation does not exclude the diagnosis of FH, as not all genetic variants causing FH have been identified and there can be other genetic causes of the disease

LDLR (Low-Density Lipoprotein Receptor) gene mutations

  • the most frequent cause of FH
  • the LDLR gene provides instructions for making the LDL receptor, which plays a crucial role in removing LDL-C from the bloodstream by facilitating its uptake into cells
  • mutations in LDLR impair the function of the LDL receptor, leading to elevation of LDL-C levels
  • mutations may vary in severity, with some causing complete loss of LDL receptor function and others causing partial impairment

APOB (Apolipoprotein B) gene mutations

  • less common than mutations in LDLR
  • the APOB gene provides instructions for making apolipoprotein B-100 (apoB-100), a protein that forms part of LDL particles
  • mutations in APOB can lead to defective binding of LDL particles to the LDL receptor, impairing their uptake into cells and resulting in elevated LDL-C levels

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) gene mutations

  • PCSK9 is a protein that plays a role in regulating the number of LDL receptors on the surface of cells
  • mutations in PCSK9 increase the degradation of LDL receptors, which results in increased LDL-C levels due to reduced capacity of receptors to remove LDL-C from the bloodstream


Lifestyle modification and treatment of other vascular risk factors

Pharmacotherapy of dyslipidemia

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Familial hypercholesterolemia