Dyslipidemia PDF

REYES, SAPPAYANI, SUGATAN, TEJARES, MOSTAZA, SUBIJANO | EBPT 1 1 DYSLIPIDEMIA EPIDEMIOLOGY INTRODUCTION Total cholesterol and LDL-C levels r...

REYES, SAPPAYANI, SUGATAN, TEJARES, MOSTAZA, SUBIJANO | EBPT 1 1 DYSLIPIDEMIA EPIDEMIOLOGY INTRODUCTION Total cholesterol and LDL-C levels rise with age in both genders. Dyslipidemia refers to abnormal levels of lipids in the High cholesterol affects nearly half of American adults, but bloodstream, which poses a significant risk factor for the prevalence has improved in children. cardiovascular diseases Western diets contribute to elevated cholesterol. Dysregulation in these lipid levels, whether due to genetic Coronary heart disease (CHD) caused numerous deaths in dispositions or lifestyle factors, can lead to atherosclerosis the US in 2011. Many individuals with borderline-high and other CV complications cholesterol risk are unaware of their condition, and o Lipids, such as cholesterol and triglycerides, are treatment rates are low, especially among those with insoluble in plasma and require lipoproteins for symptomatic CHD. transportation. Risk factors for CHD include high cholesterol, smoking, o Lipoproteins are complexes of lipids and proteins that hypertension, diabetes, and low HDL-C levels. transport lipids throughout the body. 50% of all MIs and 70% of all deaths due to CHD occur in Dyslipidemia's most common and significant consequence is patients with known CHD premature coronary atherosclerosis. Lipid abnormalities increase the risk of coronary, ETIOLOGY cerebrovascular, and peripheral vascular arterial disease, Dyslipidemia can be caused by genetic abnormalities or collectively known as atherosclerotic cardiovascular disease environmental factors. (ASCVD). Primary dyslipidemia is inherited, while secondary o The ASCVD-risk assessment evaluates a 10-year dyslipidemia is acquired due to lifestyle, diseases, atherosclerotic cardiovascular disease incident, medications, or diet. defined as nonfatal myocardial infarction or coronary Genetic factors that increase lipid levels can be inherited heart disease and cause primary or familial dyslipidemia. INTESTINAL CHOLESTEROL ABSORPTION AND PRIMARY OF FAMILIAL DYSLIPIDEMIA TRANSPORTATION Primary dyslipidemias, often caused by genetic defects, can lead to elevated total cholesterol, LDL-C, TGs, or decreased HDL-C, increasing the risk of premature ASCVD. Different types of familial dyslipidemias include hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, disorders of HDL-C metabolism, and excess lipoproteins. Familial hypertriglyceridemia is characterized by elevated TGs ranging from 200 to 500 mg/dL, sometimes exceeding 1,000 mg/dL, and can cause eruptive xanthomas and acute pancreatitis. Homozygous familial hypercholesterolemia (HoFH) is rarer than heterozygous familial hypercholesterolemia (HeFH), occurring in one case per million and one case per 250 people, respectively. o Heterozygous gene dysfunction in HeFH typically results in LDL-C levels between 250 and 450 mg/dL, Cholesterol from food and bile is emulsified by bile acids while homozygous patients may have LDL-C into micelles, which then bind to intestinal enterocytes. concentrations above 500 mg/dL. Sterol transporters transport cholesterol and other sterols Tendon xanthomas, xanthelasmas, and arcus cornea, which from the micelles to the enterocytes. are cholesterol deposits in tendons, eyelids, and around the Triglycerides synthesized by absorbed fatty acids are cornea, can also occur in dyslipidemias. incorporated into chylomicrons, which are released into SECONDARY OR ACQUIRED DYSLIPIDEMIA lymphatic circulation and converted to chylomicron remnants by losing triglyceride. Can be caused by genetic disorders or acquired factors such as diet, drugs, disorders, and diseases. Hepatic LDL-receptor–related protein then takes up the chylomicron remnants. Excessive alcohol, anorexia, weight gain, high carbohydrate intake, and saturated fat can increase 3 MAJOR CLASSES OF LIPOPROTEINS cholesterol levels. Low-density lipoproteins (LDL) Certain medications, metabolism disorders, comorbid High-density lipoproteins (HDL) conditions, and diseases can also contribute to lipid Very low-density lipoproteins (VLDL) imbalances. o Primary carrier of triglycerides in the circulation Dyslipidemias are often a combination of primary and *Intermediate-density lipoprotein (IDL) secondary causes. o between VLDL and LDL and is included in LDL-C measurement  REYES, SAPPAYANI, SUGATAN, TEJARES, MOSTAZA, SUBIJANO | EBPT 1 2 PATHOPHYSIOLOGY FAMILIAL HYPERCHOLESTEROLEMIA LIPOPROTEINS AND CHOLESTEROL SDYNTHESIS Characterized by: o Selective elevation in the plasma level of LDL Lipoproteins, including chylomicrons, VLDL, LDL, and HDL, o Deposition of LDL-derived cholesterol in tendons vary in lipid and protein content, influencing their functions. (xanthomas) and arteries (atheromas) Lipoproteins play crucial roles in lipid and cholesterol o Inheritance as an autosomal dominant trait with metabolism, maintaining the body's balance homozygotes more severely affected than o Chylomicrons transport lipids, while HDL collects excess heterozygotes cholesterol. o LDL delivers cholesterol to tissues and returns to the liver Primary defect is the inability to bind LDL to the LDL for recycling or excretion. receptors. o VLDL carries lipids and TGs to tissues, and excess o Leads to lack of LDL degradation by cells and cholesterol is excreted into the bile. unregulated biosynthesis of cholesterol. o HDL retrieves excess cholesterol and returns it to the o Total Cholesterol & LDL-C are inversely proportional to liver. the deficit in LDL receptors LIPID METABOLISM AND TRANSPORT HOMOZYGOTES Lipoproteins are carrier proteins that help transport lipids Prevalence: 1 in a million through the bloodstream. Severe hypercholesterolemia (650-1,000 mg/dL) Apolipoproteins are proteins on the surface of lipoproteins Cutaneous Xanthomas and fatal CHD before the age of 20 that have various functions, including assembly, secretion, No functional LDL receptors and activation of enzymes. o Apolipoprotein B-containing lipoproteins, known as HETEROZYGOTES non-HDL, make up the lipid-delivery pathway, while ½ of the normal number of LDL receptors apolipoprotein A-1 or HDL participates in reverse total cholesterol of 300-600 mg/dL cholesterol transport. Cardiovascular events in their 30s and 40s HDL has two major protective roles in preventing atherogenesis: SECONDARY CAUSES OF LIPOPROTEIN ABNORMALITIES o Reverse cholesterol transport Hypercholesterolemia: hypothyroidism, nephrotic syndrome, o Upregulation of the ATP-binding cassette transporter malabsorption or ABCA-1 transporter. Hypertriglyceridemia: sepsis, Diabetes II, pregnancy All of these systems work together to maintain cholesterol Low HDL: malnutrition, obesity, drugs homeostasis. Drugs: B-blockers, thiazide diuretics, glucocorticoids, alcohol BIOSYNTHETIC PATHWAY FOR CHOLESTEROL PATHOGENESIS OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) The rate-limiting enzyme in this pathway is 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMG-CoA High levels of C-reactive protein (CRP) may be useful in reductase); identifying patients at risk of CAD. o (A)Exogenous pathway Atherosclerotic lesions arise from transport of plasma LDL o (B) Endogenous pathway into the extracellular matrix of the subendothelial space o (C) Reverse cholesterol transport LDL undergoes oxidation and glycation, and oxidized LDL LDL transports cholesterol to the tissues while HDL reverses this transport by transporting the cholesterol back to the liver. HMG-CoA reductase is the rate- recruit monocytes into the artery wall, which then become limiting enzyme for cholesterol synthesis and is the target of the lipid-lowering macrophages. Macrophages accelerate LDL oxidation and medication known as statins (HMG-CoA reductase inhibitors) apolipoprotein B accumulation and alters LDL-R receptors into “scavenger receptors” not regulated by cell content of cholesterol.  REYES, SAPPAYANI, SUGATAN, TEJARES, MOSTAZA, SUBIJANO | EBPT 1 3 Oxidized LDL promotes: DIAGNOSTIC TESTS o Coagulation (↑ plasminogen inhibitor levels) Elevated total cholesterol, LDL-C, triglycerides, o Vasoconstriction (endothelin expression) apolipoprotein B, hsCRP Oxidized LDL inhibits nitric oxide expression and is toxic to Decreased HDL-C macrophages if highly oxidized. Breakdown products of Other diagnostic tests: fatty acids and oxysterol are formed, which continue the o carotid ultrasound reaction leading to a massive accumulation of cholesterol. o coronary calcium score Cholesterol-laden macrophages become foam cells. This is o ankle-brachial index the earliest recognized cells of the arterial fatty streak. o heart catheterization Oxidized LDL provokes an inflammatory response TREATMENT DESIRED OUTCOMES mediated by chemo-attractants and cytokines. Prevent ASCVD-related morbidity and mortality, including Lipoproteins undergo aging depending on resident time in revascularization procedures, MI, an ischemic stroke. the vascular compartment, making them more susceptible to oxidation. CLASSIFICATION OF TOTAL-, HDL-CHOLESTEROL, AND Repeated injury and repair within a plaque eventually TRIGLYCERIDES IN ADULTS leads to fibrous cap. Maintenance of the fibrous plaque is ADULTS critical to prevent plaque rupture and subsequent coronary Total