Familial hypercholesterolemia (FH) is the world’s most common autosomal dominant genetic disease. It’s one of many dyslipidemias – a group of metabolic diseases characterized by abnormal plasma levels of lipids or lipoproteins, caused by their increased synthesis or insufficient degradation. To understand the whole issue, it’s important to review some basics first:
· Lipids and steroid substances (cholesterol) are not well soluble in a water-based environment – thus they’re bound to lipoproteins which can be differentiated according to their different density. That gives them their typical names you might know – very low density lipoprotein (VLDL), low density lipoprotein (LDL) or high density lipoprotein (HDL).
· Each of the lipoproteins has different characteristics and effects. Low density lipoprotein, often called “the bad lipoprotein” can be transformed from VLDL or be synthetized de novo. The oxygenated (used) form of LDL is highly pathogenic, mainly due to its atherogenicity (causing atherogenesis - accumulation of substances in the inner wall of vessels causing their obstruction leading to e.g. a myocardial infarct).
In FH a mutation of the LDL receptors causes insufficient degradation resulting in an accumulation of LDL in the blood. Without sufficient treatment LDL deposits in tissue and can accelerate atherosclerosis resulting in premature coronary heart disease.
Homozygous patients are rare and have a prevalence of 1:300 000 to 1:400 000. Heterozygous FH has a prevalence of 1:300 in Europe and 1:200 to 1:250 in the United States[1]. Unfortunately, up to this day, FH is highly undiagnosed and not well treated. Since the disease is based on a genetic background, the biggest risk factor is a positive family history. There are statistically more cases of FH in some ethnicities, such as Ashkenazi Jews, French Canadian, Finnish, Lebanese or Dutch.
Monogenic inheritance is a kind of inheritance where a trait/disease is determined by the expression of a single gene or allele (specific type of a gene). Autosomal is describing that the problem occurs within the nonsexual chromosomes. Dominant means that only one copy of a mutation is needed in order to be effective. All of those characteristics lead to one thing – there are two types of patients: heterozygous (the ones that have only one copy of mutation) and homozygous (the ones that have both copies of a mutation). Patients with two pathogenic mutations are more severely affected by the disease than those with one pathogenic mutation.
FH patients usually have a functional mutation due to a defect on chromosome 19 in one of three genes - LDL receptor gene (apoB/E receptor), PCSK9 or apolipoprotein B gene. LDLR mutation is by far the most common (approx 90%).
Clinical features are rare and cardiovascular complications can often be the first symptom of familial hypercholesterolemia. General symptoms of higher cholesterol can be observed, such as:
o Xanthomas = lipid deposits in the skin and tendons
o Xanthelasmas = deposits of lipids typically on the upper eyelids
o Arcus lipoides cornae = lipid deposits forming rings in the peripheral cornea
o Hepatic steatosis, also known as fatty liver disease – a severe state which can lead to liver failure
o Coronary heart disease = reduction of blood flow to the heart muscle, causing symptoms such as shortness of breath, chest pain or sweating, manifesting as:
o Atherosclerosis of cerebral supply, peripheral arteries and aorta
Familial hypercholesterolemia can be diagnosed either on phenotypic criteria (elevated LDL-C levels, physical examination, personal and family history) or genetic testing. Genetic testing isn’t necessary for the diagnosis but can help in estimating the exact risk and settling treatment goals. In the past few years, many countries implemented laboratory examination of umbilical cord blood right after childbirth to secure early diagnosis.
Blood tests may show:
· A high level of total cholesterol (7-10 mmol/l heterozygous, 15-30 mmol/l at homozygous patients)
· A high level of LDL cholesterol (over 4,9 mmol/l by adults, severe cases can be over 13 mmol/l)
· Normal levels of triglycerides
Treatment of FH is crucial in managing the disease and preventing severe complications. The goal is to lower LDL-C by at least 50% from the pre-treatment value. Healthy eating habits and physical activity are an important part of the therapy, but FH can’t be treated with diet and exercise alone. Pharmacologic treatment (often as combination therapy of more agents) is necessary to achieve the therapy goals. The options are:
· Statins – a drug blocking an enzyme needed in cholesterol synthesis
· Ezetimibe – a drug blocking an absorption of cholesterol in intestine
· PCSK9 inhibitors – monoclonal antibodies blocking the synthesis of LDL cholesterol
It’s unfortunately not possible to avoid the disease due to its genetic background. The patient can only influence the impact on their health by adhering to a diet and treatment – if diagnosed early and properly treated, individuals with FH have an excellent prognosis.
As already mentioned, patients with FH have a higher risk of heart disease and death at a younger age. Without diagnosis or without treatment, heart attacks may occur already by the third life decade and the risk is rising with more rare and severe forms of the disease. The Prognosis highly depends on how closely the patient follows the treatment regime – adhering to a diet, exercising and using medications that can sufficiently lower cholesterol levels.
Talk to your doctor if you have close relatives with high cholesterol problems
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