SUPERStudy: Familial hypercholesterolemia (FH) 

from www.supertestscores.com

Introduction: Familial hypercholesterolemia (FH) is a group of autosomal dominant and recessive disorders of lipoprotein metabolism characterized by strikingly elevated low-density lipoprotein-cholesterol (LDL-C), the presence of xanthomas, and premature atherosclerosis. 

Epidemiology: Homozygous 1 in 1 million; Heterozygous 1 in 500  

Pathogenesis: Pathogenic variations in the following four genes can cause FH: (1) LDLR, which encodes the LDL receptor (the most common variant; gene located on the short arm of chromosome 19) (2) ApoB, a protein that facilitates binding of LDL to the LDL receptor (3) PCSK9, which encodes a protein that normally reduces production of LDL receptors, so variants actually protect from hypercholesterolemia; and (4) ARH, a rare cause of FH that requires pathogenic variants in both alleles (autosomal recessive inheritance).

   When LDL receptors or apoprotein B-100 are deficient, LDL is unable to be taken into the liver for processing. This results in increased plasma LDL levels. Over 60% of total body LDLR is in the liver, and the decreased clearance of LDL particles by this organ has a particularly potent effect on plasma LDL-C levels. Hypercholesterolemia is present from birth. LDL particles begin to be retained in arterial sites early on in life and their uptake by macrophages turn them into foam cells, the fundamental building block of an atherosclerotic plaque. 

Clinical Manifestation 

Tendon xanthoma: Excessive cholesterol deposits on the achilles tendon, dorsum of the foot, extensor tendons of the hand, and the tibial tuberosity. 

Xanthelasma: Cholesterol deposits in the eyelid 

Cutaneous xanthoma: Yellow-orange lesions on the skin 

Tuberous xanthomas: soft, painless nodules on elbows and buttocks 

Heart: Coronary artery disease as early as 4 years of age; Supravalvular aortic stenosis; Premature heart disease is common with onset before age 45 years in men and 55 years in women. 

Diagnosis 

-Detailed family history; genetic testing

-Heterozygous FH: Plasma total cholesterol is usually greater than 300 mg/dL; LDL cholesterol usually exceeds 250 mg/dL; normal plasma triglycerides; normal HDL and VLDL levels.

-Homozygous FH: total cholesterol >600 mg/dL, LDL cholesterol >500

Treatment 

Goal: LDL-C reduction of greater than 50%

Low-fat, low-cholesterol diet and exercise 

Pharmacotherapy: start HMG CoA reductase inhibitors at a young age; ezetimibe; bile acid sequestrants; PCSK9 inhibitors; niacin; LDL apheresis, a procedure similar to hemodialysis.

Screening: Screening for this disease can begin as early as age 2 to 3 years if suspicion is high.It is important to screen relatives who are at risk for FH by measuring LDL levels and by identifying the pathogenic genetic variant in the family and utilizing that for screening.