DIAGNOSIS

FH is an autosomal dominant condition, screening patients with family history of early heart disease or FH is essential to providing optimal management of this condition.1 FH is commonly diagnosed based on clinical criteria; however, there is genetic testing available. The genetic test should identify mutations in the low-density lipoprotein reception (LDLR) gene, the apolipoprotein B (apoB), or the proprotein convertase subtilisin/kexin (PCSK9) genes.1


Consider an FH diagnosis if a patient meets the following criteria:

    • Family  history premature coronary heart disease (CHD) [age < 55 in men, <65 in women]3,4
    • High low-density lipoprotein cholesterol (LDL-C) while off treatment [20 yr +: > 190 mg/dL; <20 yr: > 160 mg/dL]2,3,5 

      *Treated >124mg/dL2,3,5


F + H = FH

Family history of early cardiac events + High cholesterol


The presence of xanthomas, corneal arcus and xanthelasmas before the age of 60 are highly suggestive of FH, more specifically homozygous FH (HoFH), although sitosterolemia should be ruled out as a cause.6 Individuals affected by homozygous FH possess two mutant alleles at the LDLR, ApoB, PCSK9 or LDLRAP1 gene loci.1,6 Individuals may also be genetically compound heterozygotes but may phenotypically look homozygous with severely elevated LDL-C and physical symptoms.1,6 Assessment of family history of high LDL-C and premature coronary heart disease is crucial for HoFH diagnosis.6

There are currently three accepted resources for FH diagnosis: the Simon Broom criteria, the Med Ped Criteria, and the FH Dutch Lipid Clinic Criteria:


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MANAGEMENT

Although other risk factors such as diet and lifestyle should be addressed, individuals with FH require early, aggressive and lifelong therapeutic medical interventions.4,6,7

The target levels of LDL-C for adults with FH6
50% reduction in pre-treatment LDL-C level with:
– LDL-C < 100 mg/dL if individual does not have established coronary heart disease or other risk factors
– LDL-C < 70 mg/dL if individual has established coronary heart disease or other risk factors

Adults
In addition to risk reduction through lifestyle modifications, such as exercise and heart-healthy diet, there are several therapy options for adults with FH.

    • Statins – The mainstay of treatment for FH, high-dose statins are used to reduce the risk of cardiovascular events and progression of atherosclerosis through LDL-C reduction. Also, in order to achieve target LDL-C, combination therapy may also be required with Ezetimibe, Bile Acid Sequestrants, and/or Niacin. Patients may be intolerant to statins.6
    • Ezetimibe – In combination with statins, Ezetimibe can be used for more severe forms of FH to lower LDL-C by reducing hepatic secretion of ApoB.6
    • Bile Acid Sequestrants – Bile Acid Sequestrants work with statins to upregulate hepatic LDLRs.6
    • Niacin – Niacin could be considered in combination with statins when plasma LDL-C and Lp(a) are not at target.6
    • Lomitapide – A microsomal triglyceride transfer protein inhibitor, lomitapide can be used in patients with homozygous FH to reduce hepatic production and secretion of very low-density lipoproteins, and potentially other lipoproteins.6
    • Mipomersen – Mipomersen is an antisense 20-mer oligonucleotide that inhibits ribosomal translation by binding to complementary sequence messenger RNA encoding apoB. It is used in patients with homozygous FH.6
    • PCSK9 Inhibitors – Through the inhibition of LDLR expression, PCSK9 inhibitors reduce LDL-C in circulation. They have also been shown to lower plasma apoB, total cholesterol, and Lp(a).6
    • Lipoprotein Apheresis – Lipoprotein apheresis removes apoB-containing lipoproteins from the blood. This therapy is for patients with homozygous, compound heterozygous or severe heterozygous FH who are statin-intolerant. Additionally, lipoprotein is effective for pregnant women with severe forms of FH.6

Children and Adolescents


Samuel Gidding, MD
 “FH should be recognized as a disease where medical treatment of heterozygous forms begins at age 8-10 years and homozygous forms begins at diagnosis.”

    • It is recommended that statin therapy be initiated at age 8 to 10 years for children and adolescents with heterozygous FH.8
    • Statin therapy should be initiated at the time of diagnosis for children with homozygous FH.6,8
    • Children and adolescents with FH should be treated with satins that are indicated as appropriate for this age group.6
    • Ezetimibe or Bile Acid Sequestrants can be prescribed in combination with statins in children or adolescents whose LDL-C levels do not reach target levels.6
    • Lomitapide and Mipomersen can be prescribed in for patients with homozygous FH to reduce hepatic production and secretion of very low-density lipoproteins, especially if apheresis is not available.6
    • Lipoprotein Apheresis should be considered for children with homozygous FH by the age of 5 and no later than age 8.6
 

FAMILY SCREENING

The Centers for Disease Control and Prevention (CDC) has designated FH as a Tier 1 Genomic Application, indicating that FH poses a significant public health burden but there are clear hypercholesterolemia guidelines for management and prevention available.9

Lipid testing with or without genetic testing of all first degree relatives, known as family cascade screening, should be encouraged for all individuals with FH because:

  • FH is an autosomal dominant genetic condition

Each first-degree relative of an individual with FH has a 50% chance of also having FH.10

  • FH should be diagnosed in childhood and proactively treated

Therapy should be initiated between the ages of 8-10 for children with heterozygous FH.8

 

As family cascade screening proceeds, newly identified FH cases provide additional relatives who should be considered for screening. Family cascade screening may help identify patients at an earlier age, increasing the proportion of individuals with FH receiving timely and appropriate treatment. Also, it is a cost-effective means of finding undiagnosed FH patients and is cost-effective in cost per year of life saved.16

Family Cascade Screening
























The FH Foundation can assist with family cascade screening. Please contact the FH Foundation at 626-465-1245 or at FINDFH@thefhfoundation.org.



References

1. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004;160:407-20

2. Gonzalez-Santos L, Underberg J. Electronic chart review of a multispecialty internal medicine practice evaluating appropriate identification of patients with familial hyperlipidemia. J Clin Lipidol 2011;5:229

3. Stone NJ, Robinson JG, Lichtensetin AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(Suppl.2):S1-45

4. O’Brien E, Roe MT, Fraulo ES, Peterson ED, Ballantyne CM, Genest J, et al. Rationale and design of the familial hypercholesterolemia foundation Cascade Screening for Awareness and Detection of Familial Hypercholesterolemia registry. Am Heart Journal 2014;167(3):342-349

5. Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5:S9-17

6. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. Int J Cardiol 2014;171:309–325

7. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011;5:S1-8

8. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, Ose L, Averna M, Boileau C, Boren J, Bruckert E, Catapano AL, Defesche JC, Descamps OS, Hegele RA, Hovingh GK, Humphries SE, Kovanen PT, Kuivenhoven JA, Masana L, Nordestgaard BG, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AFH, Steinhagen-Thiessen E, Stroes ES, Taskinen M, Tybjaerg-Hanse A, Wiklund O. Familial hypercholesterolemia in children and adolescents: gaining decades of life by optimizing detection and treatments. Eur Heart J2015, doi:10.1093/eurheartj/ehv157

9. Genomics Implementation. Centers for Disease Control and Prevention. 2015. http://www.cdc.gov/genomics/implementation/toolkit/FH_1.htm

10. Goldstein JL et al. Familial hypercholesterolemia. In: Scriver C et al. Editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:2863–2913