Familial hypercholesterolemia



Biochemistry and nutrition


Biochemistry and metabolism
Metabolic disorders

Familial hypercholesterolemia


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Familial hypercholesterolemia

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The genetic inheritance of familial hypercholesterolemia is autosomal (recessive/dominant) .


USMLE® Step 1 style questions USMLE

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USMLE® Step 2 style questions USMLE

1 questions

A 32-year-old woman presents to clinic with deposits in the supraorbital area as seen in the photograph. She states that she developed these skin findings over the past year. She takes no medications, has no diagnosed medical conditions, and does not visit a primary care physician. Family history is positive for her mother having passed away at the age of 50 secondary to a massive myocardial infarction. A lipid panel reveals normal triglyceride levels and a total cholesterol level of 420 mg/dL. In addition to dietary modificationhy, which of the following is the most appropriate treatment for her condition?

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Content Reviewers:

Viviana Popa, MD

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 occur 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.