Familial hypercholesterolemia

Definitions & Key takeaways

Familial hypercholesterolemia (FH) is an autosomal dominant condition in which there are abnormally high levels of LDL cholesterol in the blood. The condition increases a person's risk for heart disease and other serious health problems. FH is caused by defects in one of several genes that control the amount of cholesterol in the blood. People with FH can present with xanthomas (fats build up under the skin), xanthelasma (fats build up in the eyelids), fatty liver, and pancreatitis.

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With familial hypercholesterolemia, familial means the disease runs in families, so it has a genetic predisposition, hyper means excess and lastly cholesterolemia refers to the level of cholesterol in the blood.
So, familial hypercholesterolemia is a genetic disorder associated with high levels of cholesterol in the blood. Now, cholesterol is a lipid molecule, so a type of fat, that normally helps maintain the structure of cell membranes, and is a precursor to steroid hormones, bile acids, and vitamin D.
There are two main types of cholesterol: LDL or Low Density Lipoprotein which is sometimes called “bad cholesterol,” nad HDL or High Density Lipoprotein which is sometimes called “good cholesterol.” But good and bad is overly simplistic, and like all things - the subtleties matter.
LDL is produced by the liver and it carries cholesterol out to the rest of the body. If all of the cholesterol from LDL is not completely distributed to the peripheral cells, then HDL brings some of that cholesterol back from the peripheral tissues and sends it to the liver.
Now, what makes LDL bad and HDL good is that, whenever there’s a high blood concentration of LDL, the LDL can be ingested by macrophages that sit along vessel walls, forming atherosclerotic plaques.
Over decades, large atherosclerotic plaques can lead to myocardial infarctions, strokes, and peripheral vascular disease.
That’s why we want to keep LDL blood levels under control. On the other hand, HDL can remove cholesterol from cells and that can help reverse the process of atherosclerosis.
Now, our body usually keeps LDL cholesterol levels in check by clearing our excess LDL from the plasma. This is mainly done by the LDL receptors present on the surface of the liver cells.
First, the LDL molecules bind to the LDL receptors, which are clustered in specialized regions of the cell membrane called coated pits.
After binding, the coated pits along with the receptor-bound LDL are internalized by invagination, and they form coated vesicles inside the cell.
Next, the LDL receptor releases the LDL in the cytoplasm, and it gets recycled back to the cell surface. At the same time, the coated vesicles fuse with an intracellular organelle called a lysosome.
Inside the lysosomes, LDL molecules are enzymatically degraded and free cholesterol molecules are released, which then cross the lysosomal membrane to enter the cytoplasm.
From the cytoplasm, free cholesterol can be used for cell membrane synthesis and other metabolic processes. Now, in familial hypercholesterolaemia, mutations occurs in the LDL receptor gene.
There are over 900 different types of mutations that can cause familial hypercholesterolemia - but luckily, they’ve been grouped into 5 major classes.
Class one mutations mainly affect the quantity of synthesized LDL receptors, so there are less available receptors to take up LDL from plasma.
Class two mutations affect the intracellular transport of LDL receptors back to the cell surface. Class three mutations affect the binding of LDL to LDL receptors.
With class four mutations, LDL LDL receptor proteins can bind to LDL efficiently, but they’re not located in the coated pits So even if they bind to LDL, the internalization of LDL fails.
Lastly, class five mutations affect the recycling of LDL receptors to the cell surface, which ultimately lowers the total number of functional LDL receptors present on the cell surface.
Now, all these mutations have one thing in common, that is, they decrease the clearance of LDL from the plasma, which results in accumulation of LDL cholesterol in the circulation.
These excess cholesterols are then engulfed by the monocytes-macrophages and vascular walls resulting in premature atherosclerosis.
Now, familial hypercholesterolemia is an autosomal dominant type of genetic disorder, so you only need one mutated gene from either parent to get the disease.
If only one mutated gene is present, and its counterpart from the other parent is normal, the person is a heterozygote, and if both genes have the mutation, the person is a homozygote.
So, clinical signs and symptoms present at a far younger age, and they’re more severe in homozygotes than in heterozygotes.
Speaking of which, symptoms of familial hypercholesterolemia are related to how excess cholesterol is deposited in various places of our body as xanthomas, which are yellowish collections of cholesterol that can appear in various places around the body.
For example, there can be tendon xanthomas in the tendons of the hands, elbows and knees, and they are especially common in the Achilles tendon.
Another such common place is around the eyelids, which is often referred as Xanthelasma palpebrarum. When excess cholesterol is deposited in the arterial walls, it can narrow the arterial lumen causing signs of ischemia, which differ depending on the affected organ.
For example, when the coronary arteries are affected, that can block blood flow to the heart muscle, causing chest pain during physical effort, which is called angina pectoris.
If blood flow is cut off entirely, that may even cause a heart attack. Similarly, when cerebral arteries are blocked, that can cause signs of an ischemic stroke, like weakness on one side of the body, slurring of speech, dropping of one side of the face and loss of balance.
Diagnosis of familial hypercholesterolemia is done with lipid profile tests, which show high levels of total cholesterol and LDL.
Confirmatory diagnosis, however, can only be done by genetic testing, which identifies the specific mutation in the LDL receptor gene.
Treatment of familial hypercholesterolemia mainly aims to reduce LDL levels in the blood in order to decrease the risk of cardiovascular disease.
Lifestyle modifications include quitting smoking, alcohol, and lowering the amount of saturated fats in the diet, like those found in dairy and fast food.
Medications like statins can also be given to lower cholesterol levels. All right, as a quick recap, familial hypercholesterolemia is a genetic disorder in which individuals have high levels of cholesterol in the blood.
The excess cholesterol is often deposited in various places of our body causing xanthomas in the tendons, around the eyelids, and atherosclerotic plaques inside the blood vessels.
Atheroclerotic plaques may cut off blood supply to organs like the heart or the brain, causing a heart attack or ischemic stroke, respectively.
Treatment involves lifestyle modifications and medications like statins.