NOTES NOTES DYSLIPIDEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Metabolic disorders: abnormal lipid levels, with ↑ cardiovascular, other disease risk ▪ Lipids: water-insoluble organic molecules contribute to normal metabolic process ▫ Building blocks for cell membranes ▫ Energy source ▫ Fat-soluble vitamin absorption (needed) ▫ Key molecule components (e.g. steroids, prostaglandins, bile acid) ▫ Fat storage ▪ Lipoproteins: triacylglycerol (TAG), cholesterol, phospholipids, apolipoproteins ▪ Classiﬁed according physicochemical characteristics ▫ Lipid density, the apolipoproteins types contained (↓ density → ↑ lipid relative to protein) ▪ Lipoprotein types: chylomicrons, very low-density lipoprotein (VLDL), lowdensity lipoprotein (LDL), and high-density lipoprotein (HDL) ▪ Optimal lipid levels ▫ Total cholesterol: 75–169mg/dL (ages ≤ 20 years); 100–199mg/dL (ages > 21 years) ▫ LDL: < 70mg/dL (cardiovascular disease/ very high risk individuals), < 100mg/dL (individuals with multiple cardiovascular disease risk-factors), < 130mg/dL (low cardiovascular disease risk individuals) ▫ HDL: > 40mg/dL ▫ Triglycerides: < 150mg/dL TYPES ▪ Types organized by Fredrickson classiﬁcation Type I ▪ ↑ triglycerides > 99th percentile; ↑ 256 OSMOSIS.ORG chylomicron level Type IIa ▪ Total cholesterol level > 90th percentile; ↑ LDL level; familial hypercholesterolemia Type IIb ▪ Total cholesterol/triglyceride level > 90th percentile; ↑ LDL, VLDL levels; combined hyperlipoproteinemia Type III ▪ Total cholesterol, triglyceride levels > 90th percentile; ↑ VLDL remnants, chylomicron levels; familial dysbetalipoproteinemia Type IV ▪ Total cholesterol level > 90th percentile, triglyceride level > 90th percentile likely; ↑ VLDL, low HDL level; endogenous hyperlipidemia Type V ▪ Triglyceride level > 99th percentile; ↑ VLDL, chylomicron levels; familial hypertriglyceridemia RISK FACTORS ▪ Western diet (e.g. ↑ reﬁned carbohydrate, ↑ calorie, ↑ dietary fat levels) ▪ Physical inactivity ▪ Risk ↑ with age ▪ Genetic/epigenetic inﬂuence COMPLICATIONS ▪ Atherosclerosis → cardiovascular, cerebrovascular disease; pancreatitis, cholelithiasis (some cases)
Chapter 43 Dyslipidemia SIGNS & SYMPTOMS ▪ Asymptomatic until atherosclerosis progresses, produces complications ▪ Abdominal adiposity ▫ Dyslipidemia correlation ▪ Lipid-related skin eruptions (e.g. xanthomas) ▪ Corneal arcus ▫ Lipid deposition in peripheral cornea ▪ Clinical presentation suggests lipid-related vascular disease DIAGNOSIS OTHER DIAGNOSTICS ▪ Pooled risk calculation: lipid levels + variables (age, sex, blood pressure, blood glucose level, smoking status) TREATMENT MEDICATIONS ▪ Hyperlipidemia ▪ Low, moderate, high statin therapy based on risk ▪ Non-statin therapy (bile acid sequestrants, ﬁbrates) OTHER INTERVENTIONS ▪ Risk reduction (hyperlipidemia) LAB RESULTS ▪ Genetic testing as indicated Blood studies ▪ Lipid proﬁle ABETALIPOPROTEINEMIA osms.it/abetalipoproteinemia PATHOLOGY & CAUSES ▪ Rare autosomal-recessive disorder ▫ MTTP gene mutation in encoding microsomal triglyceride transfer protein (MTP) ▫ AKA Bassen–Kornzweig disease ▪ MTP: required for hepatic, intestinal assembly of apolipoprotein B (apo B), lipids → ↓ serum apo B-containing lipoproteins (e.g. chylomicrons, LDL, VLDL) → impaired fat-soluble vitamin (A, D, E, K) transport ▫ Vitamin E most susceptible to deﬁciency ▫ Normally transported from small intestine to liver by chylomicrons, delivered to peripheral tissues via VLDLs COMPLICATIONS ▪ Malabsorption, failure to thrive; retinal degeneration, ophthalmoplegia; peripheral neuropathy; cerebellar dysfunction (Friedreich-type spinocerebellar ataxia) SIGNS & SYMPTOMS ▪ Impaired fat absorption ▫ Initially presents (infancy) with gastrointestinal symptoms ▫ e.g. poor feeding/weight gain, failure to thrive, gastrointestinal problems (e.g. nausea, abdominal distension, steatorrhea) ▪ Neurological (related to vitamin E malabsorption) ▫ ↓ deep tendon reﬂexes, progressive ataxia, dysarthria, neuropathy, lowerextremity spasticity OSMOSIS.ORG 257
▪ Ocular (related to vitamin A malabsorption) ▫ Vision impairment, retinitis pigmentosa; strabismus, nystagmus, ophthalmoplegia (eye muscle paralysis) DIAGNOSIS LAB RESULTS ▪ ↓ ↓ triglycerides ▪ ↓ ↓ total cholesterol ▪ Lipoprotein electrophoresis → abetalipoproteinemia ▪ Peripheral blood-smear analysis → ↑ ↑ acanthocytes (red blood cell (RBC) with spiked membranes); normocytic anemia ▪ ↓ ↓ alpha-tocopherol, gamma-tocopherol (vitamin E) ▪ ↑ transaminases (present hepatic steatosis) OTHER DIAGNOSTICS ▪ Sensory nerve conduction studies ▫ Reduced nerve action potential amplitude; normal conduction velocity TREATMENT OTHER INTERVENTIONS ▪ Address neurological symptoms ▫ Vitamin E ▪ Address gastrointestinal symptoms ▫ Reduced fat-intake ▪ Supplement fat-soluble vitamins ▫ A, D, K 258 OSMOSIS.ORG Figure 43.1 Accumulation of lipids in the enterocytes of an individual with abetalipoproteinemia leads to a clear appearance.
Chapter 43 Dyslipidemia FAMILIAL HYPERCHOLESTEROLEMIA osms.it/familial-hypercholesterolemia PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → ↑ ↑ low density lipoprotein cholesterol (LDL-C) levels → early-onset atherosclerotic disease ▫ Caused by receptor-mediated LDL-C catabolism-encoding gene mutation ▫ Individuals often still experience ↑ LDL-C levels despite ↑ lipid-lowering therapy ▫ LDL receptor mutation classes involve altered receptor synthesis/function ▪ LDL-mediated atherscelerotic plaque formation ▫ Abnormal lipid metabolism → hyperlipidemia (LDL; especially those containing B-100 apolipoproteins) → subendothelial LDL retention → LDL oxidation → ↑ LDL by macrophages → foam cell formation → cytokine, growth factor release from foam cells → smooth muscle cell migration from vascular media to intima, ﬁbrous cap formation, chronic inﬂammation → atherosclerotic plaque → cardiovascular, cerebrovascular, other sequelae potential COMPLICATIONS ▪ Coronary artery calciﬁcation ▪ alvular cholesterol deposits → aortic stenosis ▪ Accelerated athersclerotic placque formation → myocardial infarction → sudden cardiac death ▫ Homozygous FH: possible sudden cardiac death before age 20 SIGNS & SYMPTOMS ▪ Evidence of atherosclerotic cardiovascular disease (e.g. angina) ▪ Evidence of aortic stenosis, left ventricular outﬂow obstruction (e.g. exertional dyspnea) ▪ Xanthoma presence (usually before age 10) ▫ Tendon xanthomas: Achilles tendon (commonly) ▫ Cutaneous xanthomas: planar xanthomas on palms, soles of hands/ feet (may be painful) TYPES Heterozygous FH ▪ LDL-C ≥ 160mg/dL (children); ≥ 190mg/dL adults (one ﬁrst-degree relative diagnosed with premature coronary artery disease/ similar LDL-C levels) ▪ Positive genetic testing for LDL-C receptor defect Homozygous FH ▪ LDL-C ≥ 400mg/dL, (one/both parents clinically diagnosed with FH) ▪ Positive genetic testing for LDL-C receptor defect Figure 43.2 Numerous tendinous xanthomata on the hand of an individual with familial hypercholesterolemia. OSMOSIS.ORG 259
▪ Xanthelasmas: soft, yellow, cholesterolﬁlled plaques (usually appear on eyelid’s medial aspect) ▪ Corneal arcus: white/grey ring around cornea DIAGNOSIS ▪ Positive family history ▪ Characteristic ﬁndings upon physical examination LAB RESULTS ▪ Genetic testing ▪ ↑ total cholesterol, LDL-C (LDL > 90th percentile for age/sex) ▪ Normal/↓ HCL-C TREATMENT MEDICATIONS Figure 43.3 Xanthelasmata around the eyes of an individual with familial hypercholesterolemia. ▪ High-intensity statin therapy ▪ Cholesterol-absorption inhibitors ▫ Monotherapy or in conjunction with statin therapy ▪ PCSK9 inhibitor/monoclonal antibodies ▫ Binds to PCSK9 → inhibits hepatic LDL receptor-binding → ↑ LDL receptors available to clear LDL → ↓ LDL-C levels HYPERLIPIDEMIA osms.it/hyperlipidemia PATHOLOGY & CAUSES ▪ ↑ serum total cholesterol, LDL-C ▪ Lipids enter circulation via exogenous pathway via gut/endogenous pathway (hepatic synthesis) → lipoproteins transport circulating lipids to various tissues CAUSES ▪ Primary: genetic abnormalities (e.g. familial hypercholesterolemia), defective apoprotein B (familial) ▪ Secondary: Cushing syndrome, excessive alcohol intake, uncontrolled diabetes mellitus, chronic kidney/liver disease, certain drugs (glucocorticoids, beta blockers, thiazide diuretics, HIV 260 OSMOSIS.ORG antiretroviral regimens, oral estrogen replacement) RISK FACTORS ▪ Genetic predisposition ▪ Diet/other lifestyle factors (e.g. physical inactivity, high-fat diet) ▪ Pregnancy temporarily increases serum cholesterol ▪ Biologically-male > biologically-female individuals (premenopausal) COMPLICATIONS ▪ Cardiovascular disease (e.g. angina, myocardial infarction) ▪ Cerebrovascular disease (e.g. stroke)
Chapter 43 Dyslipidemia ▪ Peripheral vascular disease ▪ Cholelithiasis ▪ Pancreatitis (triglycerides > 500mg/dL) SIGNS & SYMPTOMS ▪ Cardiovascular/cerebrovascular disease evidence ▪ Xanthomas: cutaneous/found/along tendon sheaths (tendinous xanthoma) ▪ Corneal arcus DIAGNOSIS ▪ Physical examination → presence of risk factors/cardiovascular disease symptoms ▪ History of cardiovascular diseasecharacteristic symptoms LAB RESULTS ▪ Fasting lipid proﬁle: ↑ total cholesterol, ↑ triglycerides, ↑ LDL, ↓ HDL TREATMENT ▪ Address secondary hyperlipidemia causes MEDICATIONS ▪ Statin therapy OTHER INTERVENTIONS ▪ Non-statin therapy ▫ E.g. ﬁbrates, ﬁsh oil supplements containing eicosapentaenoic acid/ docosahexaenoic acid concentrate; nicotinic acid (not as monotherapy) Figure 43.4 Blood drawn from an individual with hyperlipidemia. OSMOSIS.ORG 261
HYPERTRIGLYCERIDEMIA osms.it/hypertriglyceridemia PATHOLOGY & CAUSES ▪ Elevated serum triglyceride levels CAUSES Primary: genetic mutation (primary) ▪ Familial hypertriglyceridemia ▪ Familial combined hyperlipidemia ▪ Chylomicronemia ▪ Dysbetalipoproteinemia (APOE mutations) ▪ Lipoprotein lipase deﬁciency ▪ Apolipoprotein C-II deﬁciency (APOC2 mutations) ▪ Apolipoprotein A-V variants (APOA5 mutations) Secondary: consequence of disease states ▪ Diabetes (especially poor glycemic control) ▪ Obesity ▪ ↑ reﬁned carbohydrate diet ▪ Nephrotic syndrome ▪ Chronic renal failure ▪ Hypothyroidism ▪ Pregnancy (temporarily increased serum triglycerides) ▫ Certain drugs (glucocorticoids, beta blockers, thiazide diuretics, HIV antiretroviral regimens, retinoids, oral estrogen replacement) RISK FACTORS ▪ Inﬂuence of diet/other lifestyle factors (e.g. physical inactivity, ↑ fat diet) ▪ Genetic predisposition COMPLICATIONS ▪ ↑ atherosclerotic plaque formation risk → cardiovascular, cerebrovascular events ▪ Pancreatitis (serum triglycerides > 1000mg/ dL) 262 OSMOSIS.ORG SIGNS & SYMPTOMS ▪ Clinical atherosclerosis manifestations ▫ May not be evident until complications develop ▪ Xanthomas, xanthelasmas ▫ Usually associated with hereditary forms ▪ Lipemia retinalis: creamy appearance within retinal blood vessels ▫ May be seen with severe hypertriglyceridemia DIAGNOSIS ▪ Physical examination → presence of risk factors/cardiovascular disease symptoms ▪ History of cardiovascular disease symptoms LAB RESULTS ▪ Fasting lipid proﬁle: ↑ triglycerides ▫ Normal: <150mg/dL ▫ Mild hypertriglyceridemia: 150–499mg/ dL ▫ Moderate hypertriglyceridemia: 500– 886mg/dL ▫ ↑↑/severe hypertriglyceridemia: >886mg/dL TREATMENT ▪ Address secondary causes MEDICATIONS ▪ Statin therapy OTHER INTERVENTIONS ▪ Non-statin therapy ▫ E.g. ﬁbrates, ﬁsh oil supplements containing eicosapentaenoic acid/ docosahexaenoic acid concentrate; nicotinic acid (not as monotherapy)