High blood cholesterol, known as hypercholesterolemia, is one of the metabolic problems that has gained the most social awareness. People are concerned about their cholesterol levels and try to keep them low.
However, what happens when this problem is something you’re born with? This leads us to familial hypercholesterolemia, a genetic form of dyslipidemia.
Excess is never good
Despite its bad reputation, cholesterol is an essential lipid in eukaryotic cells. It is found in their plasma membrane and is necessary for membrane fluidity and proper function.
In addition to being part of plasma membranes, it is a precursor of vitamin D, many sex hormones, corticosteroid hormones, and bile salts.
That’s why almost all cells can synthesize cholesterol in the smooth endoplasmic reticulum, using acetyl-CoA.
Breaking down cholesterol is a bit complicated. It is converted into bile acids and salts, added to bile, and excreted with feces. We cannot completely degrade it; we are much better at producing it.
Its regulation in the body is controlled by the cholesterol present in the endoplasmic reticulum of cells. The body takes into account the cholesterol incorporated from external sources (in the diet) and adjusts its synthesis depending on the amount ingested.
As a lipid, cholesterol is insoluble in water. To transport it, we need a workaround. It binds to large complexes called lipoproteins, which can hold cholesterol inside and move it throughout the body.
Cells that need cholesterol display receptors to capture lipoproteins traveling through the body. The main ones are:
- Low-density lipoprotein (LDL). Its main function is to transport cholesterol to cells that need it. High levels are strongly linked to cardiovascular diseases, earning it the nickname “bad cholesterol.” Optimal levels are recommended to be 100 mg/dL or less.
- Very low-density lipoprotein (VLDL). These originate in the liver and are precursors of LDL.
- High-density lipoprotein (HDL). These transport cholesterol to the liver. They can collect cholesterol from blood vessels and carry it to the liver, removing it from circulation, which is why it’s known as “good cholesterol.” Unlike LDL, higher concentrations are desirable, with optimal levels being above 60 mg/dL.
High cholesterol levels, especially in the form of LDL, cause cholesterol to adhere to arterial walls, narrowing them and forming arterial plaques. This begins with atherosclerosis, which can eventually lead to more severe cardiovascular diseases. This is known as hyperlipidemia.
Symptoms of hypercholesterolemia include leg cramps when walking, fat deposits on the skin and eyelids, chest pain, and blood circulation problems.
Cholesterol blood tests are simple and quick, focusing on checking cholesterol, LDL, and triglyceride levels.
Unlike other conditions, hypercholesterolemia is easy to understand. Cholesterol sticks to the arteries, hardens them, and reduces their space. This increases the risk of blockage and can lead to death.
Genetically Irremediable Excesses
Familial hypercholesterolemia causes elevated cholesterol levels, particularly in the form of LDL. We could say it’s hereditary cholesterol, a problem of high familial cholesterol. Due to the condition, it is resistant to conventional treatments, and controlling this lipid’s levels becomes difficult.
As if that weren’t enough, most forms of the disease are transmitted as autosomal dominant hypercholesterolemia. You only need to inherit one of the abnormal genes to develop the condition.
Since it is a condition from birth, it causes complications at a very early age. There is a risk of cardiovascular disease in childhood and adolescence, with cases of coronary disease recorded before the age of 20.
The incidence of the heterozygous form (one altered copy) is about 1 affected person in every 250 individuals. The homozygous form (both copies altered) is rarer, affecting 1 in 300,000 people, although this varies by population.
Among the causes, there are three genes that appear most frequently:
- LDLR. This gene encodes the LDL receptor and is the most commonly mutated gene. This is partly understandable when you consider that it has over 1,000 different recorded mutations. If the receptor doesn’t function properly, LDLs cannot interact with cells that need cholesterol, leading to a buildup in the blood. Affected individuals develop cardiovascular disease before the age of 50.
- APOB. This gene encodes apolipoprotein B, the major protein component of VLDLs and LDLs. Blood levels of this protein are measured as a representation of LDL and VLDL levels. In this case, mutations alter the ability of protein complexes to bind with the receptor. By preventing this binding, cells cannot take up these molecules, and cholesterol remains in circulation.
- PCSK9. This gene encodes proprotein convertase subtilisin/kexin type 9, a long name, we apologize. Its function is interesting; it binds to the LDL receptor, forming a complex that is later degraded by the cell. The more PCSK9 is produced, the fewer LDL receptors are present on the cell’s outer membrane, leading to higher cholesterol levels in the bloodstream.
These three genes account for 60-80% of all recorded cases of familial hypercholesterolemia, and all three are autosomal dominant. However, people who are homozygous for the mutated gene will experience a more aggressive form of the condition.
The disease can also be polygenic. While these genes can cause hypercholesterolemia on their own, the mutations are not mutually exclusive. In 50% of cases, the patient had mutations in more than one gene.
There are some genes that cause the disease but are recessive, such as the LDLRAP1 gene. Two abnormal copies are required to have hypercholesterolemia.
A Turning Point in Cholesterolemia: Statins and Their Effectiveness
Statins undoubtedly represented a turning point in the treatment of hypercholesterolemia.
Formally called HMG-CoA reductase inhibitors, they reduce circulating cholesterol levels.
HMG-CoA reductase is an enzyme involved in cholesterol synthesis. When statins inhibit this enzyme, the cholesterol pathway is blocked, preventing endogenous production by the body.
This group of drugs was sought deliberately. Researchers first identified HMG-CoA reductase as a therapeutic target, then looked for compounds to act on it. It was already known that this step was a key limiting factor in cholesterol biosynthesis.
In addition, there was a collateral advantage: by reducing cholesterol production in the liver, the organ produced more LDL receptors to capture cholesterol from the bloodstream.
The first statins had limited use due to toxicity and were mostly derived from fungal cultures. One of the first marketed was lovastatin, which is still in use today.
Fluvastatin was the first fully synthetic statin, entering the market at the same time as pravastatin.
Since then, new variants have emerged, such as simvastatin, rosuvastatin, and pitavastatin.
These are well-tolerated drugs that have been tested and refined for decades. For this reason, although there are other medications that either block other pathways or sequester bile acids, statins are dominant. Their use is even accepted in children, especially those with the much more severe homozygous forms.
Proper diet control, exercise, not smoking, monitoring blood pressure, and regular check-ups are also essential in preventing hypercholesterolemia.
The tellmeGen Advanced genetic test is another undeniable aid in prevention and treatment, with its pharmacogenetics section helping you better understand how each statin works in your body.