Familial hypercholesterolemia (FH) is a common autosomal dominant disorder resulting from mutations leading to impaired hepatic clearance of low-density lipoprotein (LDL) from the circulation.
All of the following statements are true regarding heterozygous FH except that
It occurs in 1 in 5,000 persons. Homozygous FH occurs in 1 in 1 million individuals while heterozygous FH in 1 in 500 individuals. The other statements are true.
Phenotypic presentation of FH has been demonstrated to be caused by various mutations associated with all but one of the following:
LDLRAP1 mediates internalization of LDL-C via clathrin-coated pits, and loss-of-function mutations would decrease LDL-C clearance. Defects in apolipoprotein B (apoB). The LDL-R on the hepatocyte binds to apoB (acts as ligand, binding LDL particle to receptor) on the LDL particle inducing internalization via clathrin-coated pits (mediated by LDLRAP1) and endocytosis of the complex. Defects in the receptor itself or the apoB molecule may reduce LDL-C clearance. The protein PCSK9 can bind to the LDL/LDL-R complex and when internalized prevents recycling of the LDLR to the hepatocyte surface. A gain in function mutation of PCSK9 (by further reducing recycling of LDL-Rs) has been shown to be associated with increase in LDL-C and CVD.
A 31-year-old man is referred to you for hyperlipidemia assessment. He has no previous cardiovascular history himself and denies any first-degree relatives with a history of CHD although his father and paternal uncle are treated for elevated cholesterol and triglycerides (TGs). He reports that two uncles and a cousin have had heart attacks at young ages. His physical examination reveals a body mass index (BMI) of 32, arcus cornea and xanthelasmas but no xanthomas, and a blood pressure (BP) of 150/80 mmHg. His fasting lipid profile is as follows: total cholesterol (TC) 300 mg/dL, TGs 430 mg/dL, high-density lipoprotein cholesterol (HDL-C) 50 mg/dL, direct LDL-C 202 mg/dL. Fasting blood glucose is 112 mg/dL.
Which primary dyslipidemia is this patient most likely to have?
Familial combined hyperlipidemia. Familial combined hyperlipidemia is a common dyslipidemia (1 in 33 to 1 in 100 individuals) characterized by complex inheritance. Xanthomas are rarely present (unlike in heterozygous FH), but xanthelasmas and arcus cornea can be seen. They are generally overweight, are hypertensive, and have insulin resistance or diabetes. Affected individuals generally exhibit a TC of 250 to 350 mg/dL, LDL-C of 200 to 300 mg/dL, and TG of >140 mg/dL (two-thirds of patients have TG of 200 to 500 mg/dL). Patients with polygenic hypercholesterolemia (1 in 20 to 1 in 100 individuals) have alterations in the function or expression of several key proteins involved in LDL metabolism including defective LDLR and apoB100, and the presence of the apoE4 allele (which has a higher affinity for the LDL-R than the other apoE isoforms leading to downregulation of LDL-R). They have similar elevations in LDL-C as familial combined hyperlipidemia except they do not generally have elevated TG. Hyperapobetalipoproteinemia is associated with increased apoB synthesis. TG may be normal or elevated and arcus cornea and xanthelasmas may be present. However, LDL-C is typical below 160 mg/dL. Familial endogenous hypertriglyceridemia is associated with increased hepatic VLDL formation and TG of 200 to 500 mg/dL but without significant elevations in LDL-C and is not consistently linked with increased CVD risk.
Which of the following statements regarding FH is NOT true?
Lomitapide has been approved to treat homozygous and heterozygous FH. Homozygous FH occurs in 1 in 1 million individuals. TC levels are generally >600 mg/dL, with LDL-C levels six- to eightfold higher than average. Without treatment, death from MI occurs in the first or second decades of life. In addition to the xanthomas observed in heterozygotes, FH homozygotes are commonly affected by interdigital xanthomas; tuberous xanthomas on the hands, elbows, buttocks, and feet; and planar xanthomas on the posterior thighs, buttocks, and knees. The mainstay of therapy for FH homozygotes is LDL apheresis and has been associated with stabilization or regression of atherosclerotic lesions and improvement in symptoms. Since immediate reductions in LDL-C of 50% to 80% rebound quickly, the process is performed every 2 to 4 weeks to keep intrapheresis LDL-C ≤120 mg/dL.
Both mipomersen and lomitapide were FDA approved in 2013 as orphan drugs for management of patients with homozygous FH only. Mipomersen is a subcutaneously injectable RNA antisense oligonucleotide. Lomitapide blocks microsomal TG transport protein (a key protein in assembly and secretion of apoB-containing lipoproteins in the liver and intestines) reducing hepatic secretion of VLDL. These therapies have a small target population, require risk evaluation and mitigation strategy limiting use to specialized centers, and have concerns with liver toxicity and hepatic steatosis due to accumulation of TGs not secreted into VLDL.
Several clinical diagnostic criteria for FH exist, with the 15-year Simon Broome Register Group being the most commonly used. Definite FH is as defined above. Possible FH by this criteria is defined as (a) above PLUS and (b) MI before age 50 in second-degree relative, or before 60 in first-degree relative or elevated cholesterol in first-degree relative, or >290 mg/dL in second-degree relative.
Recent statistics from the American Heart Association (AHA) Statistical Update in 2014 report that all of the following regarding dyslipidemia in the United States are true EXCEPT that:
National Health and Nutrition Examination Survey (NHANES) data through 2006 reported that 10.3% of adolescents (12 to 19 years) have abnormal lipid levels. In adolescents between the ages of 12 and 19, the number of individuals with one or more abnormal lipid level is higher at 20.3% and increases further to 42.9% in association with obesity. All the other facts noted are true. The AHA has established TC <170 mg/dL in children and <200 mg/dL in adults as one of seven goals for ideal cardiovascular health. In one survey in 2010, 38.1% of children and 52.7% of adults did not meet these criteria. Although average adult TC levels have been dropping over the past two decades from 208 to 197 mg/dL, obesity and lack of physical activity (two factors associated with dyslipidemia and diabetes risk) have been on the rise. From 2011 to 2012 only 20.7% of adults and 49.5% of adolescents, respectively, achieved recommended activity levels. These facts and more can be found in the most recent Heart Disease and Stroke Statistics-2014 Update from the AHA published in Circulation.
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