Combined Familial Hyperlipidemia


Combined hyperlipidemia is inherited oligogenically, (a few genes) is a form that occurs with hypercholesterolemia (high cholesterol levels) characterized by increased concentrations of LDL, cholesterol and triglycerides, often accompanied by a decrease in HDL.
It is the most common inherited lipid disorder, occurring in about one in 100 people. In fact, nearly one in five individuals who develop coronary artery disease before age 60 has this disorder.


There is agreement that triglyceride values ​​higher than 500 mg / dl also increase the risk of pancreatitis, so in these situations treatment should be given quickly.
Other causes apart from genetic causes are alcohol, drugs (thiazides, beta-blockers, antipsychotics and oral estrogens, among others) diets rich in fats or carbohydrates and sedentary lifestyle.
There is a phenotypic diversity of familial hypercholesterolemia and there is usually an increase in lipoprotein (a) and a decrease in the LDL receptor.
In addition, there is an increase in apoprotein B, which is a protein involved in lipid metabolism, being the main protein constituent of very low-density lipoproteins (VLDL) and low-density (LDL, or bad cholesterol).
An alternation between hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia or even temporary normalization of the lipid concentration can be found, the cause of these fluctuations is unknown.
Hereditary factors are the most common cause. A diet high in saturated fat and cholesterol increases the levels of cholesterol and triglycerides in the blood.
Other disorders, such as diabetes mellitus, kidney disease, and hypothyroidism, can promote hypertriglyceridemia.
Certain medications, such as estrogens, corticosteroids, retinoids, protease inhibitors, thiazide diuretics, and beta-blockers, can cause hypertriglyceridemia.
Obesity increases the risk of hyperlipidemia. Chronic and excessive alcohol use increases the risk of hypertriglyceridemia.
Smoking and not exercising can lead to hyperlipidemia. Steroid uses, alcoholism, hypothyroidism, oral contraceptives, chronic renal failure, hypopituitarism, and nephrotic syndrome are other contributors to hyperlipidemia.
Acquired combined hyperlipidemia is extremely common in patients suffering from other diseases from metabolic syndrome (syndrome X), type II diabetes mellitus, hypertension, central obesity.


Excessive production of free fatty acids leads to increased VLDL synthesis by the liver.
Initially, most VLDL is converted to LDL until this mechanism is saturated, after which VLDL levels rise.
Monogenic dyslipidemias are caused by rare DNA variants and have a strong impact on the phenotype. Genetic testing for monogenic dyslipidemias can be clinically useful. Polygenic dyslipidemias are due to multiple common genetic variants.
Currently, 25 monogenic dyslipidemias have a well-established molecular genetic basis. These tend to be characterized by extreme levels of cholesterol.
Severe hypertriglyceridaemia is 50 to 100 times more likely to be polygenic than monogenic, but genetic testing can be helpful in certain ways.
Both conditions are treated with drugs such as fibrates, which act on peroxisome proliferator-activated receptors (PPARs), specifically PPARα, to decrease the production of fatty acids.
Statins, statins are HMG-CoA reductase inhibitors, this enzyme catalyzes an essential step in the mevalonate pathway, the conversion of HMG-CoA to mevalonate, which is a key metabolite in cholesterol biosynthesis.
They can also decrease LDL levels by increasing the hepatic reuptake of LDL due to increased expression of the LDL receptor.
Other drugs used are ezetimibe, chenodexosicolic acid, omega 3 in high doses and in some cases monoclonal antibodies Anti PCSK9
Normally, LDL cholesterol is removed from the blood by binding to specific receptors in the liver.
PCSK9 reduces the number of these receptors in the liver, causing LDL cholesterol levels to be higher than they should be.
These drugs, called monoclonal antibodies, are a type of specialized protein, designed to bind to a target substance in the body, in this case, they block PCSK9, increasing the number of receptors available to help eliminate LDL cholesterol and thus reduce it.
-Naukkarinen J, Ehnholm C, Peltonnen L. Genetics of familial combined hyperlipidemia. Cur Opinion Lipidol. 2006; 17: 285-290.
-Brown EE, Sturm AC, Cuchel M, et al. Cite: Genetic testing in dyslipidemia: A Scientific declaration of the National Lipids Association. J Clin Lipidol 2020.
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