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Familial Hypercholesterolemia Workup

  • Author: Mose July, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
Updated: Jul 10, 2016

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

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.


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.



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).

Contributor Information and Disclosures

Mose July, MD Fellow in Endocrinology, Diabetes and Metabolism, Marshall University School of Medicine

Mose July, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society

Disclosure: Nothing to disclose.


Omolola Bolaji Olajide, MD, FACE Associate Professor, Consultant, Department of Internal Medicine, Program Director, Fellowship Program, Section of Endocrinology, Joan C Edwards School of Medicine at Marshall University

Omolola Bolaji Olajide, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

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 and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Gregory William Rutecki, MD Professor of Medicine, Fellow of The Center for Bioethics and Human Dignity, University of South Alabama College of Medicine

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, Society of General Internal Medicine

Disclosure: Nothing to disclose.

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Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.
Table 1. LDLc Target levels and levels Indicating Therapeutic Lifestyle Changes (TLC) and Drug Therapy

Risk Category


LDLc Target level,



LDLc level Indicating TLC,



LDLc level for Considering Drug Therapy,


High risk:

CHD or CHD risk equivalent

(10-y risk >20%)


Optional goal <70

>100 >100
Moderately high risk:

More than 2 risk factors

(10-y risk 10-20%)


Optional goal <100

>130 >130

(100-129 may consider drug options)

Moderate risk:

More than 2 risk factors

(10-y risk 10%)

<130 >130 >160
Lower risk:

0-1 risk factor

<160 >160 >190

(160-189 LDL-lowering drug optional)

*The 2004 update recommended that when statin therapy is initiated in patients at high or moderately high risk, a dose and strength should be chosen that achieves at least a 30-40% LDLc reduction (see Table 3).
Table 2. Recommended Dietary Intake

Food Category


Typical US Diet




Diet for FH

Cholesterol, mg/d 500 < 200 100
Total fat, % energy (calories) 40 25-35 20
Saturated fat, % energy (calories) 14 < 7 < 6
Carbohydrate, % energy (calories) 45 50-60 65
Protein, % energy (calories) Approximately 15 15 N/A
Table 3. Statin and Statin Combination Approved Doses, Expected LDLc Decrease, and Dose Required for 30-40% LDLc Reduction



FDA-Approved Dose


Expected LDLc Decrease


Dose Required for 30-40% LDLc Reduction

Atorvastatin 10-80 mg daily 35-60% 10 mg
Fluvastatin 20-40 mg at bedtime 20-30% 40 mg qd/bid
40 mg bid 35% 40 mg bid
Extended-release fluvastatin

(Lescol XL)

80 mg at bedtime 35-38% 80 mg at bedtime
Lovastatin 20-80 mg at supper 25-48% 40 mg at dinner
Extended-release lovastatin


20-60 mg at bedtime 25-45% 60 mg at bedtime
Pravastatin 40-80 mg at bedtime 30-40% 40 mg at bedtime
Rosuvastatin 10-40 mg daily 40-60% 5 mg daily
Simvastatin 20-80 mg daily at bedtime 35-50% 20 mg at bedtime
Simvastatin + ezetimibe


10/20 mg

10/40 mg

10/80 mg

at bedtime

50-60% 10/20 mg at bedtime
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