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Hypercholesterolemia, Familial: Differential Diagnoses & Workup

Author: Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Contributor Information and Disclosures

Updated: Aug 4, 2009

Differential Diagnoses

Dysbetahyperlipoproteinemia (type III hyperlipidemia)
Familial ligand defective apoB-100, familial defective apoB-100
Homozygous autosomal recessive hypercholesterolemia
Sitosterolemia (Phytosterolemia)

Other Problems to Be Considered

Familial combined hyperlipidemia
Hypothyroidism
Lipoprotein X
Nephrotic syndrome
Severe hypertriglyceridemia  
Polygenic hypercholesterolemia

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.

Imaging Studies

  • An echocardiogram is indicated for children with homozygous FH, especially those who have a murmur or symptoms suggestive of aortic stenosis or another valve abnormality.
  • 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.

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.

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).

More on Hypercholesterolemia, Familial

Overview: Hypercholesterolemia, Familial
Differential Diagnoses & Workup: Hypercholesterolemia, Familial
Treatment & Medication: Hypercholesterolemia, Familial
Follow-up: Hypercholesterolemia, Familial
Multimedia: Hypercholesterolemia, Familial
References
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References

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Further Reading

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Keywords

familial hypercholesterolemia, FH, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, monozygous hypercholesterolemia, low-density lipoprotein cholesterol, LDL cholesterol, LDLc, hypercholesterolemia, coronary artery disease, CAD, premature CAD, coronary atherosclerosis, xanthelasma, xanthoma, valvular abnormalities, heart valve anomaly, aortic stenosis, heart disease, corneal arcus, planar xanthoma, tendon xanthoma, tuberous xanthoma, ischemic heart disease, peripheral vascular disease, cerebrovascular disease, lipid abnormalities, lipid abnormality, lipid disorder

lipid disease, coronary heart disease, CHD, high cholesterol, bad cholesterol, acute myocardial infarction, acute MI, palpebral xanthomas, Achilles tendonitis, cutaneous xanthomas, Achilles tendon xanthomas

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Contributor Information and Disclosures

Author

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Gregory William Rutecki, MD, Associate Professor, Program Director, Department of Internal Medicine, Feinberg School of Medicine, Northwestern University
Gregory William Rutecki, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Nephrology, National Kidney Foundation, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Yoram Shenker, MD, Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison
Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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