GeneFacts

Saturday, Oct 25th

Last update07:29:48 PM GMT

You are here: Diagnosis

Diagnosis

Print PDF

Diagnosis is based on clinical and laboratory findings and family history.

Diagnostic Testing and Evaluation

Familial Hypercholesterolemia evaluation should be initiated when any of the following is present:

  • LDL > 190 mg/dl in adults
  • Corneal arcus at < 45 years old
  • Tendon xanthomas at any age (should be sought for by careful palpation, not just visual inspection)
  • Yellow-orange tuberous cutaneous xanthomas or xanthelasma  at any age
  • First-degree relative with LDL >190 mg/dl (or very high cholesterol if exact numbers unknown), premature coronary artery disease (CAD), and/or xanthomas.
  • First-degree relative with known familial hypercholesterolemia

Diagnostic criteria

The diagnosis of familial hypercholesterolemia is often made based upon the Dutch Lipid Clinic Network criteria, but other criteria are available .

Dutch Lipid Clinic Network criteria for making a phenotypic diagnosis of familial hypercholesterolemia in adults [Jansen et al. 2004]

Criteria Score

Family History

 

First degree relative with known premature coronary and/or vascular disease (men aged <55 years, women aged <60 years)
OR
First degree relative with known elevated LDL-cholesterol the 95th percentile for age and sex

1

First degree relative with tendinous xanthomata and/or arcus cornealis
OR
Children aged <18 years with LDL-cholesterol above the 95th percentile for age and sex

2

Clinical History

 

Patients with premature coronary artery disease (men aged <55 years, women aged <60 years)

2

Patients with premature cerebral or peripheral vascular disease (men aged <55 years, women aged <60 years)

1

Physical Examination

 

Tendinous xanthomata

6

Arcus cornealis before 45 years of age

4

Investigation (Labs)

 

LDL-cholesterol (mg/dL)

LDL ≥330

8

 

LDL 250-329

5

 

LDL 190 - 249

3

 

LDL 155 - 189

1

Diagnosis

Total Score

Definite FH

>8

Probable FH

6–8

Possible FH

3–5

Unlikely FH

<3

First Diagnostic Steps

  • Fasting lipid analysis including total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides,
  • Assess family history
    • Family history suggestive of familial hypercholesterolemia (see Risk Assessment > Genetic Red Flags)
    • Family member with a known mutation in a causative gene
    • Family lifestyle/environmental history that could contribute to cardiovascular disease risk
  • Assess patient medical history
    • Symptoms of cardiovascular disease or tendon xanthomas
    • Lifestyle/environmental history that could contribute to cardiovascular disease risk
  • Physical examination for cutaneous and tendon xanthomas and corneal arcus
  • Exclusion of possible secondary causes of hypercholesterolemia such as thyroid disease, diabetes, nephrotic syndrome
  • Measurement of lipoprotein (a) because high levels (>30 mg/dL) can have worse prognosis than those with normal levels.

Testing Strategy

  • Laboratory, history and physical examination as described in First Diagnostic Steps
  • Genetic testing may confirm diagnosis or inform ambiguous cases, but cannot rule out the diagnosis.
    • Genetic testing is positive in 80% of individuals meeting clinical criteria for definite familial hypercholesterolemia
    • Genetic testing is positive in 50% of individuals meeting clinical criteria for probable familial hypercholesterolemia
    • Genetic testing can be used to definitively determine the status of family members, but lipid analysis may be more cost-effective in those individuals
    • Genetic testing may be most useful for at-risk relatives with an equivocal LDL level or individuals with suspected familial hypercholesterolemia but for whom the diagnosis is uncertain and/or with limited family history information (e.g. adoption, limited family structure).

Tests that are NOT helpful

  • Advanced lipoprotein testing beyond a standard fasting lipid panel is not typically needed. 
  • LDL receptor activity analysis usually has no impact on management.

Subsequent Diagnostic Evaluation

  • Biopsy of questionable cutaneous lesions can clarify xanthoma diagnosis though is not usually needed.
  • Echocardiogram for all homozygotes, and heterozygotes who have symptoms or signs of aortic stenosis.
  • Vascular imaging studies such as carotid ultrasound, coronary calcium scanning, coronary CT are sometimes useful especially in children or those with homozygous FH when a treatment decision would be altered by the results of those studies.

Lifestyle/Environmental Contributors to Disease

Other traditional risk factors for atherosclerosis, including:

  • Smoking
  • Obesity
  • Diet high in saturated fat and cholesterol
  • Sedentary lifestyle
  • Diabetes
  • Kidney disease (decreased GFR)

Differential Diagnosis

Conditions with similar clinical exams

  • 27-hydroxylase deficiency (Cerebrotendonous xanthomatosis): Involves xanthomas but with normal LDL levels.  Other distinguishing features include dementia, ataxia and cataracts.
  • Dysbetahyperlipoproteinemia (Type III hyperlipidemia): May involve xanthomas.
  • Sitosterolemia (phytosterolemia): May involve xanthomas but with normal or only mildly elevated LDL levels. Distinguished by autosomal recessive inheritance.

Conditions with similar laboratory findings

  • Secondary Hypercholesterolemia: Secondary to obesity, diabetes, hypothyroidism, or kidney disease.
  • Autosomal recessive hypercholesterolemia: Heterozygotes have normal LDL. Homozygotes have LDL exceeding 400 mg/dL.
  • Dysbetahyperlipoproteinemia (Type III hyperlipidemia)
  • Familial combined hyperlipidemia: Involves elevated triglycerides in combination with elevated LDL. Disease-causing gene(s) unknown.

Consensus Statements and Guidelines

National Lipid Association Expert Panel on Familial Hypercholesterolemia. Goldberg et al. 2011. Familial Hypercholesterolemia: Screening, Diagnosis, and Management of Pediatric and Adult Patients. Journal of Clinical Lipidology, 5(3S): S1-S51.