Familial Hypercholesterolemia Workup

Updated: Mar 07, 2017
  • Author: Mose July, MD, CCD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Workup

Laboratory Studies

The diagnosis of both homozygous and heterozygous FH is based primarily on the finding of severe LDLc elevations in the absence of secondary causes of hypercholesterolemia with triglyceride levels that are within the reference range or mildly elevated and HDL cholesterol (HDLc) levels that are within the reference range or slightly low. A probable diagnosis of heterozygous FH can be made if the LDLc level is greater than 330 mg/dL or if tendon xanthomas are present in a patient with an LDLc level above the 95th percentile. Definitive diagnosis can be made only with gene or receptor analysis.

A substantial increase in serum triglyceride levels should raise the possibility of another lipid disorder.

Lipid analysis

Cholesterol levels are severely elevated in children and adults with homozygous FH, with total cholesterol and LDLc levels greater than 600 mg/dL and triglyceride levels within the reference range.

In patients with heterozygous FH, LDLc levels are commonly higher than 250 mg/dL and usually increase with age. An LDLc level higher than 200 mg/dL in a patient younger than 20 years is highly suggestive of heterozygous FH or, possibly, familial ligand defective apoB-100 (see Pathophysiology). In adults, LDLc levels higher than 290-300 mg/dL suggest heterozygous FH.

Lipoprotein (a) may be measured because patients with both heterozygous FH and high levels of lipoprotein (a) (>30 mg/dL) have a worse prognosis than those with normal levels of lipoprotein (a). However, all patients with FH are at very high risk for CAD and because no data are available to suggest that lipoprotein (a) should be specifically targeted for treatment.

Tests to rule out secondary hypercholesterolemia

Other laboratory testing may be suggestive by findings discerned thorough history and physical examination.

In the absence of symptoms or signs suggestive of a particular disorder, a limited workup should be performed to rule out secondary hypercholesterolemia.

Basic tests to rule out diabetes, hypothyroidism, hepatic disease, and renal disease are usually sufficient.

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Imaging Studies

Patients with homozygous FH should receive Doppler echocardiographic evaluation of the heart and aorta annually and, if available, computed-tomography coronary angiography every 5 years or more frequently if clinically indicated, taking into account the radiation exposure and severity of subclinical disease.

Children with homozygous FH should be referred to a pediatric cardiologist for consideration of vascular imaging studies (Pet scan, determination of carotid intima medial thickness, coronary catheterization) that can direct treatment for hypercholesterolemia.

Radiographic imaging of the Achilles tendon helps accurately measure Achilles tendon xanthomas, but the findings do not change lipid management.

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Other Tests

Lipoprotein electrophoresis is expensive and is unnecessary for the diagnosis of FH. Moreover, in the absence of preparative ultracentrifugation, it has no place in the workup of any lipid disorder. If fasting lipid analysis reveals elevated triglyceride levels and the diagnosis of FH is in doubt, beta quantification (ultracentrifugation and electrophoresis) may be performed at a major lipid center or one of the few commercial sites in the United States and other countries that performs this procedure.

LDL receptor analysis can be used to identify the specific LDL receptor defect. However, this analysis can only be performed at certain research laboratories and is expensive; and the results have no impact on management. LDL receptor or apoB-100 studies can help distinguish heterozygous FH from the similar syndrome of familial defective apoB-100, but this finding would not alter treatment.

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Procedures

The presence of an unusually high LDLc level should make identifying a cutaneous lesion straightforward. Possible entities include xanthelasmas or xanthomas.

If identification of a cutaneous lesion is unclear and the diagnosis of heterozygous FH is uncertain, a biopsy can be performed. Both xanthelasmas and the xanthomas of FH contain accumulations of cholesterol. By contrast, eruptive xanthomas in patients with severe hypertriglyceridemia (levels >1000 mg/dL) contain triglycerides (fat).

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