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Other Forms of Primary Hypercholesterolemia. Familial Combined Hyperlipidemia and Polygenic Or Common Hypercholesterolemia

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Other Forms of Primary Hypercholesterolemia. Familial Combined Hyperlipidemia and Polygenic Or Common Hypercholesterolemia Cardiovascular and Metabolic Science www.ancam.org.mx Vol. 32 Suppl. 3 doi: 10.35366/100788 July-September 2021 Other forms of primary hypercholesterolemia. Familial combined hyperlipidemia and polygenic or common hypercholesterolemia Otras formas de hipercolesterolemia primaria. Hiperlipidemia familiar combinada e hipercolesterolemia poligénica o común Alejo Díaz-Aragón, MD* Humberto Álvarez-López, MD‡ Edith Ruiz-Gastélum, MD§ amilial combined hyperlipidemia (FCHL) is manifestations, as lipid pathology and fatty liver Fa primary dyslipidemia whose prevalence disease.4 Mexican population, with a high rate ranges between 1 and 3%, although it is more of abdominal obesity and insulin resistance, is frequent in patients with coronary artery prone to suffer combined dyslipidemia and the disease. FCHL is found, for example, in 20% of lipid triad. In fact, several Mexican families have those under 60 years old who survived an acute been found affected with FCHL.5,6 myocardial infarction and up to 38% in those The genetic disorder helped by unhealthy survivors under 40 years.1,2 Due to the lack of lifestyle (high fat diet and sedentarism) increase robust diagnostic markers, in many patients the hepatic formation of VLDL, small and at high risk of some type of atherosclerotic dense LDL particles, and apo B100. Frequently, cardiovascular disease (ASCVD), the diagnosis FCHL is associated to low concentrations of of FCHL is not established. This dyslipidemia the protective lipoprotein HDL, combination has been characterized as a hereditary disorder that is known as atherogenic dyslipidemia (oligogenic, i.e., caused by just a few genes), or lipid triad. This combination can be also secondary to obesity/diabetes phenotypes, and autosomal, with variable penetrance. Several whose atherogenic power has been unveiled genetic abnormalities have been signaled as many years ago.7-9 responsible for FCHL, encompassing various As a heterogeneous, highly pleiomorphic clinical lipoprotein phenotypes. The lipid dyslipidemia, and still without well-defined profile of FCH is rather heterogeneous, which genetic alterations, universally accepted suggests a multifactorial origin in which a diagnostic criteria are lacking.2 Therefore, the variety of genetic abnormalities lead to various clinical approach demands the exclusion of * Cardiologist. pathogenic alterations of lipoproteins and their ‡ secondary causes of combined dyslipidemia. Hospital de metabolism. It has been identified the gene Especialidades As the phenotypic expression differs from Puerta de Hierro that encode the upstream transcription factor patient to patient, the concentrations of Andares. Guadalajara, 1 (USF1) as one of the principal contributors to total cholesterol (TC) and triglycerides (TG) Jalisco, México. this pathology.3 USF1 regulates the expression in members of the same affected family § Clínica de of multiple genes involved in glucide and lipid 8 Hipertensión y Riesgo show a great variability. The following Cardiovascular. metabolism. When it is inactivated in mice, could be valuable diagnostic clues, although ISSSTESON. brown adipose tissue is activated, enhancing none of them is indispensable or specific: Hermosillo, thermogenesis, decreasing triglyceridemia, 1) Familial history of premature ASCVD Sonora, México. and reducing insulin resistance and its (atherosclerotic events occurring in men Received: 30/06/2021 How to cite: Díaz-Aragón A, Álvarez-López H, Ruiz-Gastélum E. Other forms of primary hypercholesterolemia. Familial combined Accepted: hyperlipidemia and polygenic or common hypercholesterolemia. Cardiovasc Metab Sci. 2021; 32 (s3): s157-s159. https://dx.doi. 06/07/2021 org/10.35366/100788 www.medigraphic.com/cms www.cardiovascularandmetabolicscience.org.mx Cardiovasc Metab Sci 2021; 32 (s3): s157-s159 @https://dx.doi.org/00.00000/00000 @ s158 Díaz-Aragón A et al. Other forms of primary hypercholesterolemia under 55 years old, or in women under 65 hypercholesterolemia and hypertriglyceridemia, years). 2) Familial history of dyslipidemia (two reviewed in other sections of this text. or more first degree relatives with some type of dyslipidemia). 3) Combined total and LDL POLYGENIC OR COMMON hypercholesterolemia (> 240 and > 160 mg/ HYPERCHOLESTEROLEMIA dL, respectively) plus hypertriglyceridemia (> 200 mg/dL). In general, concentrations of Polygenic hypercholesterolemia is a frequent TC and LDL are not strikingly elevated, as in cause of elevated blood cholesterol secondary familial hypercholesterolemia. Concomitant to multiple gene mutations, expressed as single hypoalphalipoproteinemia (HDL-c less than nucleotide polymorphisms (SNPs), powerfully 40 mg/dL) is common. Hypertriglyceridemia influenced by environmental factors, mainly diet stimulates the production of small and rich in animal fat. Although they had already dense LDL particles, highly oxidizable and been identified 95 loci significantly associated atherogenic. 4) Apolipoprotein B100 elevated to lipid anomalies,14 more recently, the Global (> 120 mg/dL). 5) Absence of clinical or Lipids Genetics Consortium (GLGC) found biochemical data signaling secondary causes 62 more for a total of 157.15 Studies aimed of combined dyslipidemia as hypothyroidism, to distinguish between polygenic and familial nephrotic syndrome, chronic kidney disease, hypercholesterolemia (FH), have shown that pheochromocytoma, Cushing syndrome or only in 40-60% of patients with clinical FH can steroids consumption, and use of drugs like be demonstrated a monogenic defect, which retinoids, and some antiretroviral agents, involves the LDLR, Apo B or PCSK9 genes.16 A among many others. 6) Absence of tendinous major discovery was the finding that in many xanthomas. 7) Genetic studies: gene encoding patients with FH the genetic disturbance was USF1, and members of the gene cluster APOA1/ not monogenic but in essence polygenic.16-18 C3/A4/A5, that influence lipid metabolism, The genetic participation in common among others under scrutiny.1,2,9-11 hypercholesterolemia, does not lessen the The relationship between this hereditary crucial role of lifestyle, environmental, and dyslipidemia and the physiopathological clinical other metabolic factors, that greatly contribute complex composed by obesity/overweight, to rise LDL-c concentrations, especially in the insulin resistance, and diabetes mellitus, is later stages of life. But due to genetic influence, unclear. Very probably there is a bilateral and the frequency of this type of dyslipidemia complementary connection, in which the lipid is higher in subjects with familial history of pathology caused by defective genes is magnified ASCVD. By having LDL concentrations lower by the metabolic abnormalities secondary to than monogenic hypercholesterolemia, and the insulin resistance/hyperinsulinism binomial because in the polygenic form, the lipid disorder and diabetes syndromes. Contrariwise, persons appears late in life, the ASCVD episodes are also with FCHL also have the propensity to later (> 50 years of age), being, in general, less develop abdominal dysmetabolic adiposity, lethal that FHC. However, for being much more insulin resistance and diabetes. Modest frequent the polygenic than the monogenic increases in weight and insulin resistance were form, the epidemiologic impact of the former in associated with significantly higher probability the genesis of ASCVD is more important. A fact of FCHL in a multi-ethnic US population. worth noting is the best therapeutic and dietary The multi-ethnic study of atherosclerosis response of the polygenic form.19 (MESA) showed that in various ethnic groups, a modest increment of weight has different REFERENCES consequences in the development of combined dyslipidemia,12 what seems indicate again 1. Brouwers MCGJ, van Greevenbroek MMJ, Stehouwer the intricate binomial interaction between CDA, de Graaf J, Stalenhoef AFH. The genetics 13 of familial combined hyperlipidaemia. Nat Rev genes and environment. The therapeutic Endocrinol. 2012; 8: 352-362. management of this dyslipidemia follows the 2. Mata P, Alonso R, Ruíz-Gracia A, Díaz-Díaz JL. same general principles of the treatment of González N, Gijón-Conde T et al. Hiperlipidemia Cardiovasc Metab Sci. 2021; 32 (s3): s157-s159 www.cardiovascularandmetabolicscience.org.mx Díaz-Aragón A et al. Other forms of primary hypercholesterolemia s159 familiar combinada: documento de consenso. Aten 11. Naukkarinen J, Ehnholm C, Peltonen L. Genetics of Primaria. 2014; 46: 440-446. familial combined hyperlipidemia. Curr Opin Lipidol. 3. Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis 2006; 17: 285-290. AJ et al. Familial combined hyperlipidemia is associated 12. Paramsothy P, Knopp R, Bertoni AG, Tsai MY, Rue T, with upstream transcription factor 1 (USF1). Nat Genet. Keckbert SR. Combined hyperlipidemia in relation 2004; 36: 371-376. to race/ethnicity, obesity, and insulin resistance in 4. Laurila PP, Soronen J, Kooijman S, Forsstrom S, Boon the Multi-Ethnic Study of Atherosclerosis (MESA). MR, Surakka I et al. USF1 deficiency activates brown Metabolism. 2009; 58: 212-219. adipose tissue and improves cardiometabolic health. 13. Veerkamp MJ, de Graaf J, Stalenhoef AFH. Role of Sci Transl Med. 2016; 8: 22-41. insulin resistance in familial combined hyperlipidemia. 5. Aguilar-Salinas CA, Olaiz G, Valles V, Torres JM, Gomez Arterioscler Thromb Vasc Biol. 2005; 25: 1026-1031. Perez FJ, Rull JA et al. High prevalence of low HDL 14. Teslovich TM, Musumuru K, Smith AV, Edmonson cholesterol concentrations and mixed
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