Hypercholesterolemia
Currently, 620,000 familial hypercholesterolemia (FH) patients with extremely high level of blood cholesterol live in the United States. FH is defined as a set of genetic defects that cause substantial elevations of total cholesterol and low density lipoprotein (LDL) or so- called bad blood cholesterol levels from birth, resulting in an increased risk of early coronary heart disease and hardening of arteries.
A broader definition of FH identifies gene defects [LDL receptor (LDL-R), apolipoprotein (Apo) B, and PCSK-9] that are the most common cause of FH, accounting for 85% to 90% of all FH cases. Over 1000 (and counting) mutations in the LDL receptor gene have been identified. This disorder is an autosomal dominant disorder (an abnormal gene from one parent can cause the disease) that is passed down through families in two different forms:
Heterozygous
A genetic defect inherited from one parent that affects 1 in 300-500 people in North America and Europe.
Homozygous
A genetic defect inherited from both parents that affects approximately 1 of every 1000,000 individuals in North America and Europe. Homozygous FH typically results in severe atherosclerosis and heart disease during childhood and adolescence.
The Significance of Familial Hypercholesterolemia
Approximately 5% of heart attacks in patients under the age of 60 and 20% of heart attacks in individuals under the age of 45 are due to FH. In patients with untreated FH, the risk of premature heart disease increases 20 fold. FH is often diagnosed after the occurrence of a major coronary event and is clinically recognized by the extreme elevation of low-density lipoprotein cholesterol. In some populations, such as the French-Canadian and Dutch-Afrikaner populations, the prevalence of this disorder may be as high as 1 in 100 individuals.
Screening
Screening for cholesterol abnormalities should be considered in children who are two years of age if there is a family history of premature heart disease and high cholesterol. All individual should be screened for cholesterol abnormalities at the age of 20.
FH may be suspected in children and young adults under the age of 20 when their untreated fasting LDL-cholesterol levels are equal to or greater than 160 mg/dL. In adults over the age of 20, FH is suspected when their fasting LDL-cholesterol levels are equal to or greater than 190 mg/dL.
FH should be suspected if LDL cholesterol or non-HDL cholesterol levels are at or above the following:
LDL Cholesterol (mg/dl) | Non-HDL Cholesterol (mg/dL) | |
| Adults (>=20 years) | >=190 | >=220 |
| Children and adolescents (<20 years) | >=160 | >=190 |
Diagnosis in Adults and Children
The total cholesterol concentration in heterozygous FH patients typically ranges from 350 to 550 mg/dL, and in homozygotes, these levels can range between 650 and 1000 mg/dL. Heterozygous FH is one of the most common congenital metabolic disorders.
A diagnosis of familial hypercholesterolemia should strongly be considered if LDL cholesterol or non-HDL cholesterol levels are at or above the following :
LDL Cholesterol (mg/dL) | Non-HDL Cholesterol (mg/dL) | |
| Adults (>=30 years) | >=250 | >=280 |
| Adults (>=20-29 years) | >=220 | >=250 |
| Children and adolescents (<20 years) | >=190 | >=220 |
The following physical findings should prompt a clinician to suspect FH: tendon xanthomas, corneal arcus (gray or white deposits around the peripheral cornea) in patients under the age of 45, yellow-orange tuberous xanthomas (cholesterol-rich nodules), or xanthelasma (fat buildup under the skin). Patients with FH may have also elevated triglycerides. The absence of these physical signs does not rule out FH.
Genetic Testing
Genetic testing is usually not necessary for an FH diagnosis, but it may be helpful if the diagnosis is uncertain. However, according to statistics, 20% of the patients with a clinical presentation of FH do not show any genetic mutations. Therefore, the usage of genetic testing in the diagnosis of this disorder is limited.
Treatment
FH is a treatable disease, and early treatment is highly beneficial. Unfortunately, this disease is under-diagnosed and under-treated; according to estimations, only approximately 20% of patients are diagnosed, and among those, only a small percentage receives proper treatment.
Children and adults who are not able to reduce their LDL cholesterol below 190 mg/dL after lifestyle and diet changes require drug treatment. The goal of the treatment should be to reduce an individual’s LDL cholesterol by at least 50%. Statins and lifestyle management should be part of the initial treatment regimen for all adults with FH.
The patient’s blood pressure should be good controlled, and optimally, it should be below 140/90 mm Hg in the general FH population and 130/80 mm Hg in patients with additional risk factors for cardiovascular disease. The FH population also benefits from a daily baby aspirin (75-81 mg) regimen.
LDL Apheresis
LDL apheresis is a therapy that removes LDL-cholesterol from blood by running the blood through a machine. The FDA has approved LDL apheresis, and this treatment is recommended for patients who are not at their LDL goal after six months of drug therapy.
LDL Cholesterol (mg/dL) | Non-HDL Cholesterol(mg/dL) | |
| Functional heterozygous FH | >=300 | >=330 |
| Functional heterozygous FH with two additional risk factors or lipoprotein (a) >=50 mg/dL | >=200 | >=230 |
| Functional homozygous FH | >=300 | >=330 |
| Functional homozygous FH with two additional risk factors or lipoprotein (a) >=50 mg/dL | >=200 | >=230 |
Treatment during Pregnancy
Statins, ezetimibe, and niacin are contraindicated during pregnancy, but LDL apheresis and treatment with colesevelam may be considered.
Recommendations
Patients with uncontrolled familial hypercholesterolemia should be referred to a lipidologist for further comprehensive treatment and early cholesterol screening of first degree family members should be considered.
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