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Approach to Hypertriglyceridemia Syndromes: the Importance of Distinguishing Between Primary and Secondary Etiologies

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Approach to Hypertriglyceridemia Syndromes: the Importance of Distinguishing Between Primary and Secondary Etiologies Cardiovascular and Metabolic Science www.ancam.org.mx Vol. 32 Suppl. 3 doi: 10.35366/100804 July-September 2021 Approach to hypertriglyceridemia syndromes: the importance of distinguishing between primary and secondary etiologies Acercamiento a los síndromes de hipertrigliceridemia: la importancia de distinguir entre etiologías primaria y secundaria Ivette Cruz-Bautista, MD, BSc* INTRODUCTION TRL and inflammation are in development to reduce residual ASCVD risk.7 Various methods ypertriglyceridemia (HTG) is a common for measuring residues exist; however, because Hclinical problem. Current medical cholesterol remnants lipoproteins (RLP-c) are guidelines define normal fasting plasma heterogeneous populations of different sizes triglycerides (TG) concentrations as less than and lipid composition, a direct assay has not 150 mg/dL. According to the European Society yet been developed.8 of Cardiology and European Atherosclerosis Society (ESC/EAS), mild-to-moderate common Metabolism of triglycerides and HTG (CHTG) is defined by TG concentrations triglyceride-rich remnant lipoproteins between 150-880 mg/dL, and severe HTG refers to ranks higher than 880 mg/dL.1,2 Enzymes such as diacylglycerol acyltransferase The prevalence of HTG varies among ethnic are responsible for TG synthesis. They originate groups; it is hugely prevalent in Hispanics. in the intestine built from dietary fatty acids In Mexico, the pervasiveness of mild-to- or free fatty acids (FFA) extracted from the moderate hypertriglyceridemia is around 31%, circulation or are newly synthesized in the with ~5% of the Mexican population showing liver. Microsomal triglyceride transfer protein critical HTG.3 Standards recommend advising (MTTP) unites lipids apolipoprotein B-48 (apo all subjects suffering from HTG on lifestyle B-48) or apo B 100 in the intestine or liver, modifications. For patients having CHTG, respectively, forming chylomicrons (CHY) which the main goal is to decrease cardiovascular enter plasma indirectly through lymphatics, risk by reducing low-density lipoprotein or very-low-density lipoprotein (VLDL) that cholesterol (LDL-c) and non-high-density transport TG, respectively. Hydrolysis of lipoprotein cholesterol (non-HDL-c) as well circulating CHY or VLDL particles type one or as apolipoprotein B levels (apo B). If the two by lipoprotein lipase (LPL) releases FFA *Unidad de investigación de patient has dangerous HTG, the chief goal is and produce chylomicron remnant, whose enfermedades to reduce the danger of pancreatitis.4 Recent clearance requires apolipoprotein E (apo E), metabólicas, Instituto epidemiologic and genetic studies establish TG- as apo B-48 does not have the low-density Nacional de Ciencias rich lipoproteins (TRL) and their leftovers rich lipoprotein receptor-binding domain and Médicas y Nutrición «Salvador Zubirán», in cholesterol (RCL) as essential contributors VLDL-remnant lipoproteins (intermediate Mexico City, Mexico. to atherosclerotic cardiovascular disease density lipoprotein, IDL), that can bind to low- (ASCVD).5,6 So novel therapies that target density lipoprotein receptor-related protein 1 Received: 08/07/2021 Accepted: How to cite: Cruz-Bautista I. Approach to hypertriglyceridemia syndromes: the importance of distinguishing between primary and 13/07/2021 secondary etiologies. Cardiovasc Metab Sci. 2021; 32 (s3): s236-s241. https://dx.doi.org/10.35366/100804 www.medigraphic.com/cms www.cardiovascularandmetabolicscience.org.mx Cardiovasc Metab Sci 2021; 32 (s3): s236-s241 @https://dx.doi.org/00.00000/00000 @ Cruz-Bautista I. Hypertriglyceridemia syndromes: primary etiologies s237 (LRP-1) in the liver. In contrast, another part, TG from CHT and VLDL to LDL and HDL, in under the action of hepatic lipase (HL), is exchange for cholesteryl esters.10 In a recent transformed into LDL. study, it is shown that apoB48-containing particles in subjects with HTG are released Atherobiology of RLP-c lipoproteins across the entire chylomicron-VLDL size range. This process persists for many hours, elevating their concentrations and adding to the RPL-c elements are partially TG-depleted post circulating population of particle remainders.11 lipolytic particles whose cholesterol content is more likely to cause atherosclerosis. Just The five steps for differential like LDL, RCL can invade the arterial intima.6 diagnosis in clinical practice Once there, fragments could even be trapped preferentially to LDL simply because of affinity 1. Syndromic diagnosis. In 1994, the European to extracellular proteoglycans. In contrast to Consensus12 established the initial approach LDL, apo C3 and apo E-enriched remnants to the patient affected by dyslipidemia. The can be directly taken up by macrophages in division in lipid phenotypes (Table 1) allows their native condition, without enzymatic elucidating the most frequent primary and modification or specific receptors, leading to secondary causes. However, syndromic foam cells’ formation.9 Beyond LDL, the RLP-c judgment has no impact on cardiovascular proteins transport up to 30% of the cholesterol prevention and may overestimate or load in postprandial conditions, meaning underestimate treatment. more cholesterol per particle than LDL does. 2. Family history. Screening closest relatives of Increased production and delayed catabolism patients with primary dyslipidemias (those of TGRL lead to its increase and greater showing cholesterol or triglycerides levels concentrations of RLP-c. APOC3 reduces higher than 300mg/dL, premature coronary VLDL and CHY lipolysis by inhibiting LPL heart disease, frequent pancreatitis events, and blocking TRL and RLP uptake by hepatic xanthomas, xanthelasmas, etcetera).13 receptors. Thus, HTG results from increased 3. Search for secondary causes. Environmental production or decreased catabolism of CHY origins should be excluded. A variety of and VLDL or VLDL alone; has a direct effect lifestyle factors and medical conditions on the composition of LDL and high-density can cause hypertriglyceridemia (Figure 1). lipoprotein (HDL), caused by elevated activity Common secondary roots include obesity, of cholesteryl ester transfer protein that shifts uncontrolled diabetes, hypothyroidism, Table 1: Syndromic diagnosis. Type TC TG HDL-C Mixed hyperlipidemia > 200 > 150 Hypertriglyceridemia Isolated < 200 > 150 Severe > 500 Hypoalphalipoporteinemia < 40 Hyperalphalipoproteinemia > 60 Hypercholesterolemia Isolated > 200 < 150 Severe > 300 TC = total cholesterol, TG = triglycerides, HDL-c = high-density lipoprotein-cholesterol. Cardiovasc Metab Sci. 2021; 32 (s3): s236-s241 www.cardiovascularandmetabolicscience.org.mx s238 Cruz-Bautista I. Hypertriglyceridemia syndromes: primary etiologies smoking, alcohol abuse, endocrinopathies, monogenic and polygenic determinants. and various commonly used drugs (Table 2).14 For example, Familial chylomicronemia 4. Etiological diagnosis. Most patients enduring syndrome (FCS, type 1), a rare form of HTG do not have a recognizable genetic monogenic HTG with an estimated one cause. Primary severe HTG has both in a million prevalence. Also consider the Hypertriglyceridemia 150-229 mg/dL 300-999 mg/dL > 1,000 mg/dL • Diet with high positive energy-intake balance and high fat or high glycaemic index Lifestyle • Alcohol consumption • Alcohol compsumption with > 2 and > 1 drink(s) per day in men and women, respectively • Obesity, type 2 diabetes, metabolic syndrome • Hypothyroidism • Untreated • Cushing’s syndrome, hypothyroidism Endocrinophaties • Ketoacidosis acromegaly • Lipodystrophy • Growth hormone • Ketoacidosis deficiency • NAFLD, NASH • Chronic kidney disease Renal causes X • Nephrotic syndrome + Primary • Organ transplantation cause • Glycogen storage diseases • Gaucher disease Storage diseases X • Cystinosis • Tay-Sachs disease • Niemann-Pick disease • Systemic lupus erythematosis Inflammatory disease • Rheumatoid arthritis X • Psoriasis • Kawasaki disease • Progeria werner Others • Pregnancy syndrome, Klinnefelter syndrome Figure 1: Secondary causes of hypertriglyceridemia. Cardiovasc Metab Sci. 2021; 32 (s3): s236-s241 www.cardiovascularandmetabolicscience.org.mx Cruz-Bautista I. Hypertriglyceridemia syndromes: primary etiologies s239 Table 2: Drugs associated with high triglycerides levels. Hormonal • Oral oestrogens (40%) • Selective estrogen receptor modulators (20%) • Steroids • Tamoxifen (20%) • Raloxifen (20%) • Clomiphene (40%) • Growth hormone therapy • Androgen deprivation therapy (15%) Cardiometabolics • Non cardioselective beta blockers (20%) • Thiazides (15%) • Diuretics (10%) • Bile acid sequestrants Immunosuppressants • Cyclosporine (20%) • Sirolimus (30%) • Tacrolimus (30%) • Interferon alpha (20%) Anti-cancer therapeutics • L-asparaginase • Cyclophosphamide • Tyrosin-kinase inhibitors (20-70%) Others • Retinoids (40%) • Protease inhibitors (100%), ITRN (50%), ITRNN (40%), INH, INTEG (0%) • Antidepressants y atypical antipsychotics (30%) • Propofol (20%) Hypertriglyceridemia 150-299 mg/dL 300-1,000 mg/dL > 1,000 mg/dL Familial combined hyperlipidemia 1:20 Dysbetalipoproteinemia Familial hypertriglyceridemia Familial combined 1:1,000-10,000 (HLP type V) 1:600 hyperlipidemia (FCHL) 1:20 Familial hypertriglyceridemia Familial chylomicronemia (HLP type IV) 1:50 syndrome (FCS) 1:1’000,000 Polygenic hypertriglyceridemia 1:30 Figure 2: Primary causes of hypertriglyceridemia. Cardiovasc Metab Sci. 2021; 32 (s3): s236-s241 www.cardiovascularandmetabolicscience.org.mx s240 Cruz-Bautista I. Hypertriglyceridemia syndromes: primary etiologies detection
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