By: Prof. Dr. Seyed Saeid Zamanieh Shahri, MD and Prof. Dr. Sonia Sayyedalhosseini, MD

Pathophysiology of the Disease:

1) Lipoproteins and Fat Transport in the Blood

Fats are not soluble in the plasma water and are packaged as lipoproteins for transport in the body. These particles have:

• A core rich in triglycerides and esterified cholesterol,

• A shell of phospholipids and free cholesterol,

• And apolipoproteins such as ApoB, ApoA, ApoE.

right2730500 Any disorder in the production, conversion, or clearance of these particles can lead to a persistent increase in plasma lipids.

2) Exogenous Pathway (Fats Derived from the Intestine)

After dietary fats enter the intestine, they are incorporated with specific apolipoproteins into chylomicrons and enter the bloodstream. An enzyme called lipoprotein lipase (LPL) breaks down the triglycerides in chylomicrons within tissue capillaries, releasing fatty acids for consumption or storage. If LPL activity is reduced, or if there is a defect in cofactors such as ApoC-II, or an impairment in the hepatic clearance of chylomicron remnants occurs, blood triglycerides can reach significantly high levels.

3) Endogenous Pathway (Lipoproteins Produced in the Liver)

The liver produces VLDL, triglycerides and It sends cholesterol to the tissues. VLDL is converted to IDL and then to LDL in the bloodstream. LDL is the main carrier of cholesterol and accumulates in the plasma if its uptake by the liver is impaired.

4) LDL Receptor and the Role of PCSK9

LDL uptake occurs mainly through LDL receptors on the surface of liver cells. A protein called PCSK9 directs these receptors toward degradation in lysosomes; as a result, increased PCSK9 activity reduces the number of receptors available on the cell surface and keeps blood LDL levels high. Recent genetic and epidemiological studies have shown that mutations in these receptors, APOB, and PCSK9 play a key role in the majority of cases of familial hypercholesterolemia.

5) Role of Lipoprotein(a)

Lp(a) is a particle similar to LDL that is paired with a protein called Apo(a) and has a unique looped structure. The level of this particle is mainly genetically controlled and has been reported to be independently associated with the risk of atherosclerotic diseases.

6) Structural Disorders of Particles

Studies of LDL particles have shown that small, dense LDLs behave differently from large LDLs and are associated with a more atherogenic pattern. Additionally, research on the lipidome and proteome composition of HDL indicates that the functional quality of HDL (for example, its ability to remove cholesterol from macrophages) depends on its internal composition, not just on HDL-C level.

Causes of Disease:

1) Primary (Genetic) Hyperlipidemia

In this group, genetic changes directly alter lipoprotein pathways. Important examples include:

• Familial Hypercholesterolemia (FH):

In this condition, mutations in the LDLR gene are commonly observed, and to a lesser extent, the APOB, PCSK9, and LDLRAP1 genes are involved. Large-scale studies have shown that most cases of FH can be explained by harmful variants in these genes, although in some patients, the causative mutation has not yet been identified.

• Combined Familial Hyperlipidemia:

In this pattern, both LDL and triglycerides may be elevated, and the genetic background is more complex.

• Familial Lp(a) Elevation:

Lp(a) levels are strongly controlled by the LPA gene and remain relatively stable from early life.

2) Secondary (Acquired) Hyperlipidemia

Lipid elevation can result from various other conditions; for example:

• Insulin resistance and diabetes

• Obesity and fatty liver

• Hypothyroidism

• Cushing syndrome and other endocrine disorders

• Chronic kidney diseases

• Certain medications (e.g., some hormonal and immunologic drugs)

• Alcohol and certain dietary patterns in these cases contribute to hyperlipidemia by altering VLDL synthesis, reducing LDL clearance, or impairing triglyceride breakdown. To be continued