Understanding Familial Hypercholesterolaemia (FH)

Familial Hypercholesterolaemia (FH) is an inherited condition that causes an individual to retain high levels of cholesterol. Hypercholesterolaemia means an excess of cholesterol in the bloodstream and by familial we mean the condition appears within families. The specific type of cholesterol that FH individuals retain is low density lipoprotein (LDL) cholesterol.  

Low-Density Lipoprotein (LDL) cholesterol, often referred to as "bad" cholesterol, is a type of cholesterol that is considered a major risk factor for heart and blood vessel disease. LDL particles carry cholesterol to your cells. In contrast, High-Density Lipoprotein (HDL) cholesterol, often called "good" cholesterol, carries cholesterol from other parts of your body back to your liver. Your liver then removes the cholesterol from your body. HDL cholesterol is thus seen as protective against heart disease. Cholesterol is a fatty, waxy substance that's found in all cells of the body and has many important functions, such as making hormones, vitamin D, and substances that help you digest foods.


Atherosclerosis is the accumulation of fatty plaques inside the arteries that, over time, restrict blood flow and makes them more susceptible to damage. This results in an increased risk of:

  • coronary artery disease (CAD) - the narrowing of arteries that supply blood to the heart 
  • heart attack (or myocardial infarction, MI) - when one or more coronary arteries becomes so blocked as to stop supplying oxygen to the heart
  • stroke - when a blood vessel in the brain is blocked
  • peripheral artery disease (PAD)  - narrowing of the arteries supplying blood to the arms and legs 

Leonardo da Vinci (1452–1519) first observed atherosclerosis and stated that ‘vessels in the elderly restrict the transit of blood through thickening of the tunics' (tunic = an enveloping membrane or layer of body tissue[19421359]

Individuals with FH often begin developing atherosclerosis at a much young age.



Approximately 1 in 200 people have FH but the condition is under diagnosed and and under treated worldwide. A more severe form of FH occurs in 1 out of 150,000 people. Early diagnosis and treatment can significantly improve the prognosis and quality of life for people with FH.


Blood tests & family history

In adults, if:

  • total cholesterol of 7.5 mmol/L or greater, or
  • LDL cholesterol of 5 mmol/L or greater

then LH should be considered (especially with family history of premature ( <55 years) coronary artery disease).  



A diagnosis of FH also requires the presence of a variation in one of three genes that are associated with the LDL particle:

  • LDLR - encodes LDL receptor on the surface of cells and responsible for transporting LDL bound cholesterol into the cell. This is the most common variant. 
  • APOB - encodes a component of the LDL molecule
  • PCSK9 - encodes a protein that regulates LDL production

A functional variant in any one of these genes combined with blood test levels and family history provides a positive diagnosis for LH (see A Guide for General Practice).

Note: Mygene's DNA test includes the LDLR, APOB and PCSK9 genes and can help your doctor develop a diagnosis for FH.



Treatment includes:

  • statins, which inhibit an enzyme that the body uses to make cholesterol
  • PCSK9 inhibitors, which decrease the amount of LDL particle formation
  • plasmapheresis, a blood transfusion process which periodically removes cholesterol from the blood
  • liver transplantation from a FH negative donor


Genes vs Modern Environment

FH is associated with serious disease due to the retention of cholesterol, but it may be helpful to understand that in ancestral environments where there would have been long periods of food scarcity, particularly in foods that contain cholesterol such as animal based nutrients like meat and dairy, those genetic variants would confer a survival advantage:

  1. The Thrifty Gene Hypothesis: This is a theory suggesting that genes which enabled individuals to efficiently collect and process food to deposit fat during periods of food abundance were advantageous during human evolution. These "thrifty genes" would have been selected for in times when food sources were unpredictable. Therefore, a gene causing higher levels of LDL cholesterol might have helped our ancestors survive in times of scarcity by storing energy more efficiently. However, in the modern world where food is plentiful, this advantage can become a disadvantage leading to conditions like heart disease.

  2. Fertility Benefits: Some studies suggest a link between cholesterol levels and fertility, as cholesterol is a key molecule in the production of sex hormones. Therefore, individuals with high cholesterol levels could potentially have had a reproductive advantage.

  3. Survival Benefit in Acute Illness: Higher cholesterol levels might offer some protection in acute severe illnesses. Cholesterol has a vital role in the immune system and in the inflammatory response, and some studies suggest that higher LDL cholesterol levels might be protective against certain infections or diseases.

Unfortunately in today's world, rather than an evolutionary advantage, FH is a health challenge.


Plaques and stress 

Nerves run alongside blood vessels throughout the body. A recent finding has shown that in blood vessels that contain plaques, an increased density of sensory and sympathetic neurons develops outside the vessel next to plaque regions. It appears that once these neuronal/plaque circuits are established, they can cause the plaques to further increase in size when the sympathetic system is active.  

The sympathetic nervous system is a part of the autonomic nervous system (ANS), which controls various body functions that we don't consciously direct, such as heart rate, digestion, respiratory rate, salivation, and perspiration. The autonomic nervous system is divided into two main branches: the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is often referred to as the "fight or flight" system, as it prepares the body for action during times of stress, danger, or physical exertion.

When these plaques were investigated in mouse models of atherosclerosis and the neuronal links between the plaques and the mouse brain were severed, the plaques reduced in size [35477759].  

The findings of this study suggest that reducing sympathetic system activation, i.e., reducing stress, may reduce plaque growth.  

Notably, the sympathetic system also regulates constriction of blood vessels. In areas where there is an increased density of sympathetic neurons (due to plaques) vasoconstriction may be more pronounced. 


The role of inflammation

A discussion on atherosclerosis cannot be complete without mentioning the role of inflammation.

Inflammation plays a central role in the development and progression of atherosclerosis. In fact, atherosclerosis is now often viewed as an inflammatory disease:

  1. Injury to the Artery Wall: Atherosclerosis begins with damage to the inner lining of an artery, the endothelium. This damage can be caused by various risk factors, including high blood pressure, smoking, high levels of cholesterol, high blood sugar levels (as seen in diabetes), or simply aging.

  2. Inflammatory Response: This endothelial injury triggers an inflammatory response. The body sends signaling molecules (cytokines) and white blood cells to the site of injury to start the healing process.

  3. LDL Cholesterol Accumulation: The damaged endothelial cells express adhesion molecules that attract LDL cholesterol particles. These LDL particles penetrate the damaged endothelial lining and become trapped in the artery wall.

  4. Oxidation and Further Inflammation: Once inside the artery wall, the LDL particles undergo oxidation. The oxidized LDL particles are toxic to the endothelial cells and intensify the inflammatory response.

  5. Formation of Foam Cells: In response to the inflammation and presence of oxidized LDL, the body sends more white blood cells, including macrophages. The macrophages engulf the oxidized LDL, becoming laden with lipids and transforming into what are known as foam cells.

  6. Plaque Formation: Foam cells accumulate within the artery wall, releasing chemicals that attract more white blood cells and promote further inflammation, creating a vicious cycle. These events lead to the formation of a fatty streak and eventually a mature atherosclerotic plaque, characterized by a lipid-rich core covered by a fibrous cap.

  7. Plaque Rupture and Clot Formation: As the atherosclerotic plaques continue to grow, they can rupture, triggering the formation of a blood clot. The clot can obstruct the blood flow, leading to acute cardiovascular events such as a heart attack or stroke if the clot blocks a coronary or cerebral artery, respectively.

Vascular inflammation drives the onset of atherosclerosis and is responsible for acute thrombotic events. Unfortunately it's often a neglected treatment modality.