Clinical Chemistry - 07 Lipids and Lipoproteins

CLINICAL CHEMISTRY CLASSIFICATION OF FATTY ACIDS LIPIDS & LIPOPROTEINS • OUTLINE • Lipids • o Fatty Acids o Phospholipid o Cholesterol o Triglyceride (TAG) • Lipoproteins o Lipoproteins (LPP) o Apolipoprotein o Major Lipoproteins o Chemical Composition of LPP o Minor Lipoproteins o Abnormal Lipoproteins • Lipid Transport & Lipoprotein Metabolism o 4 Major Pathways o Exogenous Pathway o Endogenous Pathway o Intracellular Cholesterol Transport Pathway o Reverse Cholesterol Transport Pathway o Enzymes in Lipoprotein Metabolism Disorders associated with Lipids and Lipoproteins o Familial Hypercholesterolemia o Familial Dysbetalipoproteinemia o Abetalipoproteinemia o Hypobetalipoproteinemia o Niemann-Pick Disease o Tangier Disease o Lipoprotein Lipase (LPL) Deficiency o LCAT Deficiency o Tay Sachs Diseases o Anderson’s Disease o Sitosterolemia o Fredrickson-Levy Classification of o Hyperlipoproteinemia • • • Based on number of carbon atoms: o Short Chain: 4-6 carbon o Medium Chain: 8-12 carbon o Long Chain: >12 carbon Based on the presence of double bonds: o Saturated Fatty Acids o Unsaturated Fatty Acids Saturated Fatty Acids: o No double bonds o Ends with “-anoic acid” Unsaturated Fatty Acids o With one or more double bonds o Ends with “-enoic acid” o Configuration: o Cis – hydrogen molecule of carbon atoms with double bond is on the same side ▪ Forms a kink (bend) LIPIDS • • • • They are commonly referred to as fats, composed mostly of carbon-hydrogen bonds. o Composition are hydrocarbon chains They are the sources of fuel and provide stability to cell membrane. (lipid bilayer) o Triglycerides and fatty acids undergo lipolysis which undergoes gluconeogenesis to form energy o Lipid bilayer - composed of lipids such as phospholipids and cholesterol Important in diagnosis of atherosclerosis (deposition of fat in major blood vessels which may damage blood vessel tissues leading to acute myocardial infarction) Forms of lipids (according to abundance): o Phospholipids - most abundant o Cholesterol o Triglyceride o Fatty acids o Fat-soluble Vitamins ▪ Vitamin A, D, E and K FATTY ACIDS • • • • • • • • Monomer/building block of lipids Simple linear chain of carbon-hydrogen bonds that has a carboxyl group and methyl group on each end. Found as constituent of phospholipid or triglyceride. Mainly derived from hydrolysis of triglyceride (adipose tissue) Mostly bound to albumin (esterified) Small amount is found in plasma (unesterified) Additional source of energy Provide substance for conversion to glucose (gluconeogenesis) o Trans - Hydrogen molecule of carbon atoms with double bond is on the opposite side PHOSPHOLIPID • • • • • • aka conjugated lipid The most abundant lipids derived from phosphatidic acid Originated in the liver and intestine Amphipathic lipid containing: o Two fatty acids (hydrophobic/non-polar tail) – interior of membrane; hydrocarbon chain o Glycerol backbone (hydrophilic/polar head) – extend to the exterior; found intracellularly or extracellular Major component of cell membrane (lipid bilayer) RV: 150-380 mg/dL o CF: 0.01 (g/L) FORMS OF PHOSPHOLIPIDS • • Phosphoglyceride (70-80%) o Phospholipid with glycerol backbone and an alcohol group attached on the phosphate group o Most abundant type of phospholipid in cell membrane o Essential for lipoprotein structure (for transporting lipid) o Lecithin/Phosphatidyl choline (70%) ▪ Most abundant ▪ Phosphoglyceride with choline linked to the phosphate group ▪ Measured in ratio with sphingomyelin to assess fetal lung maturity in amniotic fluid o Cephalin/Phosphatidyl ethanolamine (10%) ▪ Ethanolamine - alcohol group o Phosphatidyl serine ▪ Serine - alcohol group o Phosphatidyl inositol ▪ Inositol - alcohol group Sphingomyelin (20%) o Phospholipid with sphingosine backbone o Component of cell membranes (RBC, brain, nerve tissues) o Reference material during 3rd trimester (Fetal Lung Maturity) – constant concentration than lecithin • • • • • SOURCES OF CHOLESTEROL • • PHOSPHOLIPIDS • • • • • Precursors: o Bile acids – fat emulsifiers o Steroid hormones (progestins, glucocorticoids, mineralocorticoids, androgens, estrogens) o Vitamin D ▪ Small amount of cholesterol are converted to 7dehydrocholesterol (by sunlight) to form Vitamin D3 Essential component of all biological membrane (lipid bilayer) Transport and excretion is promoted by estrogen Not catabolized by cells (not an energy source) Absorbed in small intestine in action of enterocyte protein Exogenous (Diet) – 15% o From food intake o Causes hypercholesterolemia Endogenous – 85% o Synthesized by the liver o HMG-CoA is the target of Statin drugs o Hepatic cirrhosis is the #1 cause of hypocholesterolemia. ▪ Hepatic cirrhosis - Total liver malfunction o Liver problems affect cholesterol synthesis Rarely measured in the laboratory o Phospholipids are not atherogenic (can cause atherosclerosis Acts as lung surfactant o Decreasing surface tension within alveolar space preventing alveolar collapse during expiration. Participates in cellular metabolism and blood coagulation Important substrate for lipoprotein metabolizing enzymes: o Lecithin-Cholesterol Acyl Transferase (LCAT) o Lipoprotein Lipase o Hepatic Lipase Gestational marker (Fetal Lung Maturity) o Deficiency: neonatal respiratory distress syndrome (RDS) o Lecithin/Sphingomyelin Ratio: ≥2.0 mg/dL (mature fetal lung) o Method: Thin-layer Chromatography + Densitometry ▪ Chromatography - separation ▪ Densitometry - quantification o Specimen: Amniotic fluid (amniocentesis) ▪ Collection should be < 39 weeks of gestation CHOLESTEROL • • Second most abundant lipid An unsaturated steroid alcohol (Amphipathic): o Three 6-carbon rings (A, B, C) o Singe 5-carbon ring (D) o Single hydrocarbon side chain tail (connected to C17) FORMS OF CHOLESTEROL • o All are nonpolar except to hydroxyl group of ring A Cholesterol Ester (CE) – 70% o Most abundant o Found in plasma and serum o Hydrophobic – with fatty acids esterified in the hydroxyl group of the A ring ▪ Facilitated by LCAT ▪ Esterification - fatty acid connection o Not found in the surface of lipid layers o • Lecithin-Cholesterol Acyl Transferase (LCAT) ▪ Normally present in human plasma ▪ Catalyzes esterification of cholesterol (HDL) by transferring fatty acids from lecithin to cholesterol ▪ Synthesized in the liver ▪ Enables HDL to accumulate cholesterol as cholesterol ester ▪ Activated by Apo-1 Free Cholesterol (FC) – 30% o Aka unesterified/unbound cholesterol o Found in plasma, serum and RBC o Amphipathic – hydroxyl group is not esterified o Produced via lysosomal hydrolysis o Used for membrane, hormone and bile synthesis. DIAGNOSTIC SIGNIFICANCE • • • • • • • • RV (Desirable): <200 mg/dL o Conversion factor: 0.026 (mmol/L) Interpretation of values: o Borderline: 200-239 mg/dL o High Cholesterol: ≥240 mg/dL Evaluates risk for atherosclerosis, myocardial and coronary arterial occlusions Most atherogenic lipid o Cholesterol can cause atherosclerosis because it is hard to control; least affected by diet & not catabolized for energy; can only be controlled with medication Elevated serum cholesterol directly related with myocardial infarction Marker: thyroid and liver function. o Liver dysfunction = decreased cholesterol o Measures synthetic function of liver o Thyroid hormones aid in cholesterol metabolism o Low thyroid hormone = high cholesterol Essential in the diagnosis and management of lipoprotein disorders (affect level of cholesterol) Used to monitor effectiveness of lifestyle changes and stress management. • • • • 2nd most atherogenic lipid o TAG can be a source of energy and can be controlled o TAG is greatly affected by diet; decrease TAG-rich food control TAG levels Causes turbidity in serum/plasma (before or after overnight standing) It evaluates suspected atherosclerosis and measures the body’s ability to metabolize fats. (using Lipase) TAG and Cholesterol – most important lipids in management of coronary heart disease (CHD) LIPOPROTEINS LIPOPROTEIN (LPP) • • • • Lipids with specialized proteins (apolipoproteins) Function: transport TAG and cholesterol to sites of energy storage and utilization Cholesterol & TAG in plasma is always bound to lipoproteins. Spherical in shape (10nm – 1μm): o Free Cholesterol & Phospholipid: surface; amphipathic o Triglyceride and Cholesterol Esters: central/core region; hydrophobic APOLIPOPROTEIN TRIGLYCERIDE (TAG) • • • • Neutral lipid Ester linkage of three fatty acids and glycerol backbone o When metabolized, these fatty acids are released into the cells and converted into energy. o Facilitated by lipoprotein lipase, epinephrine, & cortisol. Main storage of lipid in man (adipose tissue). o Can be used as source of energy during fasting states An average person ingests, absorbs, resynthesizes, and transports about 60-130grams of fat daily in the body, mostly in the form of triglyceride. o Low caloric intake: low triglyceride levels. DIAGNOSTIC SIGNIFICANCE • Reference value: o Conversion Factor: 0.0113 (mmol/L) o Normal: <150 mg/dL o Borderline High: 150-199 mg/dL o High TAG: 200-499 mg/dL o Very High TAG: ≥500 mg/dL ▪ Indicate pancreatitis (deficiency in lipase) ▪ TAG is hydrolyzed by lipase produced in pancreas • • • • • Located on the surface of lipoprotein. Aids in solubility of lipids and also in their transfer from the GI tract to the liver. Interacts with specific cell-surface receptors and directs lipids to the correct target organs and tissues. Amphipathic alpha helix – a structural motif responsible for the ability of lipoprotein to bind lipids Maintains structural integrity of lipoprotein. SIGNIFICANT APOLIPOPROTEINS Major Plasma ApoLPP Lipoprotein Function /Description conc. Chromosome Location (mg/dL) A-I HDL, CM Activates LCAT 90-130 11 A-II HDL Inhibits lipoprotein and 30-50 1 hepatic lipases and increases plasma TAG A-IV LCAT cofactor 11 (a) Lp(a) Bound to ApoB-100 by 6 disulfide bond B-100 VLDL, IDL, Ligand for the LDL 80-100 2 LDL receptor thus critical in the uptake of LDL by cells B-48 CM Exclusively found in CM <5 2 Major Plasma ApoLPP Lipoprotein Function /Description conc. Chromosome Location (mg/dL) C-I CM, LDL Inhibit uptake of VLDL 4-7 19 and CETP in the liver C-II CM, LDL Activated lipoprotein 3-8 19 lipase that stimulated TAG hydrolysis C-III CM Inhibits lipolysis of TAG8-15 11 rich lipoprotein D HDL Activates LCAT 3 E CM, LDL, Ligand for LDL receptor 3-6 19 IDL and CM remnant receptor Facilitation of uptake of chylomicron remnant and IDL *Apo E-4 isoform – shown to have increased risk of developing Alzheimer’s disease • Important Apolipoproteins o A-1 - most abundant o B-100 - second most abundant o B-48 - exclusive for chylomicrons o (a) - exclusive in Lp(a) MAJOR LIPOPROTEINS STANDING PLASMA TEST • • • • • • • HIGH DENSITY LIPOPROTEIN (HDL) • • • • • CHYLOMICRONS (CM) • • • • • • • Largest and least dense of the lipoprotein particles o Gives turbidity or milky appearance on serum (postprandial) o Readily float at the top of plasma giving creamy layer (after few hours or overnight at 4 C ̊ ) Produces from the intestine from dietary fat Transports dietary TAG to liver, muscle, and fat deposits. Non-atherogenic lipoprotein (do not cause atherosclerosis) o Due to large size, they do not fit in blood vessel Major composition: 90% TAG (nonfasting plasma) + 1-2% Protein Apolipoprotein: Apo B-48, Apo A-I, Apo C and Apo E o Apo B-48 - exclusive to CM Density: <0.95 g/mL • • • • • • • • • • • Pre-β Lipoprotein Transport endogenous TAG from the liver to muscle, fat deposit and peripheral tissue (arteries) Atherogenic lipoprotein Second lightest lipoprotein Prolonged high fat diet leads to elevated TAG in VLDL particle Always floating in the middle of serum creating homogenous turbidity before and after overnight standing. Major composition: o 65% TAG (fasting plasma) + 6-10% Protein + 16% CE Apolipoprotein: Apo B-100, Apo C and Apo E o Apo B-100 - most abundant Density: 0.95-1.006 g/mL α-lipoprotein good lipoprotein/cholesterol The smallest lipoprotein but the most dense Produced in the liver and intestine Maintains equilibrium of cholesterol in peripheral cells o Transport excess cholesterol from peripheral tissues and return it to liver (Reverse Cholesterol Transport) Two types: o HDL2 – more efficient in delivering lipids to liver o HDL3 Major Composition: Phospholipid (30%) + 45-50% Protein + 20% CE o Lipoprotein with the least amount of lipid Apolipoprotein: Apo A-I (abundant), Apo A-II, Apo C Density: 1.063-1.210 g/mL LOW DENSITY LIPOPROTEIN (LDL) • • • • • VERY LOW DENSITY LIPOPROTEIN (VLDL) • • aka Overnight standing test, Refrigerator test Used to differentiate CM and VLDL If serum/plasma is turbid Sample: Serum/plasma Procedure: o Store sample at 4 C ̊ overnight in vertical position Only test in clinical chemistry that do not use reagent Interpretation of Result: o Chylomicrons - There is creamy later on top of the sample but the supernatant is clear. o VLDL - No creamy layer on top but has turbid supernatant o Chylomicrons & VLDL - Creamy layer on top of sample and turbid supernatant • • • • β-lipoprotein Synthesized by the liver o End product of VLDL catabolism in the liver Most abundant lipoprotein (50% of total lipoprotein fraction) Transport dietary cholesterol to peripheral tissue (arteries) o Bad cholesterol (atherogenic) Primary target of cholesterol lowering therapy o 1% decrease LDL = 2% decrease in risk of atherosclerosis Important in assessing patients with or without coronary heart disease (CHD) Major composition: 50% CE + 18% protein & phospholipid o Most cholesterol-rich lipoprotein o Most atherogenic lipoprotein Apolipoproteins: Apo B-100 (abundant), Apo E Density: 1.019-1.063 g/mL DIAGNOSTIC SIGNIFICANCE • High-Density Lipoprotein o Indirect marker for atherosclerosis o Diagnostic values: ▪ Conversion factor: 0.025 mmol/L ▪ Reference value: 40 mg/dL ▪ High risk (CHD, AMI): <35 mg/dL ▪ Cardioprotective: ≥65 mg/dL • Prevents deposition of cholesterol in blood vessels • Low-Density Lipoprotein o Diagnostic values: ▪ Optimal: <100 mg/dL ▪ Above optimal: 100-129 mg/dL ▪ Borderline: 130-159 mg/dL ▪ High: 160-189 mg/dL ▪ Very High: ≥190 mg/dL ▪ 160 mg/dL: indication of therapy (medication) o May lead to acute myocardial infarction • • • • CHEMICAL COMPOSITION OF LPP Triglyceride CM VLDL LDL HDL 80-95% 45-65% 4-8% 2-7% Cholesterol Free Protein Phospholipid Ester Cholesterol 2-4% 1-3% 3-6% 1-2% 16-22% 4-8% 15-20% 6-10% 45-50% 6-8% 18-24% 18-22% 15-20% 3-5% 26-32% 45-55% LIPID TRANSPORT & LIPOPROTEIN METABOLISM 4 MAJOR PATHWAYS • • MINOR LIPOPROTEINS INTERMEDIATE DENSITY LIPOPROTEIN (IDL) • • • • • • VLDL remnant – intermediate product of VLDL catabolism Subclass of LDL – IDL are converted to LDL It migrated either in pre-β or β region (electrophoresis) Positive IDL – abnormal o Should be converted readily to LDL o Seen in Type 3 dysbetalipoproteinemia due to deficiency of Apo E-III Major apolipoprotein: Apo B-100 Density: 1.006-1.019 g/mL LIPOPROTEIN (a)/Lp(a) • • • • • • • Similar to LDL (density and composition) Has variable migration (electrophoresis): pre-β, or sometimes between LDL and albumin Similar structure with plasminogen aka Sinking pre-β lipoprotein o similar to LDL but migrates to pre- β region Independent risk factor for atherosclerosis o Normally present in the blood (fasting or non-fasting) o >30 mg/dL – risk of premature CHD and stroke Major apolipoprotein: Apo B-100, Apo(a) (only in Lp(a) Density: 1.045-1.080 g/mL Floating β-lipoprotein o Has the density of VLDL by ultracentrifugation (<1.006 g/mL) Abnormally migrating β-VLDL o Migrates with LDL in the β region (electrophoresis) VLDL rich in Cholesterol o Has more cholesterol content than VLDL Found in Type 3 hyperlipoproteinemia or dysbetalipoproteinemia • • Exogenous Pathway o Transport dietary lipids from intestine to the liver and peripheral cells Endogenous Pathway o Transfer hepatically derived lipids (TAG) to peripheral cells for energy metabolism Intracellular Cholesterol Transport Pathway o Maintains cellular homeostasis of cholesterol Reverse Cholesterol Transport Pathway o Remove excess cellular cholesterol from peripheral cells and return it to the liver for excretion. EXOGENOUS PATHWAY • • • • • • Involves absorption of triglyceride and cholesterol from intestine to the liver and peripheral cells. Largely mediated by chylomicrons o Upon diet, CM usually increase CM are released into lymph and then enters the circulation When released to the circulation, CM acquire apolipoproteins from HDL (Apo E and Apo C-II) Apo E – ligand for uptake of lipid by liver Apo C-II – activated Lipoprotein lipase found in endothelial cells will hydrolyze triglyceride from chylomicrons to free fatty acids. o Liberated fatty acids will bind with albumin then taken up my muscle cells (to be used as energy) o Chylomicrons are transformed into smaller particles (chylomicron remnants) in the process o Readily removed by the liver o Lipoprotein lipase - facilitate the hydrolysis of TAG to fatty acids ABNORMAL LIPOPROTEINS LIPOPROTEIN X • • • • • • Abnormal lipoprotein found in obstructive jaundice and LCAT deficiency Specific and sensitive indicator of cholestasis Only lipoprotein migrating towards the cathode o All LPP migrates toward the anode Removed by reticuloendothelial system (spleen and liver) Major composition: Phospholipid and Free Cholesterol (90%) Protein fraction: Apo C and albumin ENDOGENOUS PATHWAY β-VLDL • Due to defective catabolism of VLDL o IDL is also present due to defective catabolism of VLDL to LDL • • Lipids produced from the liver are transported to peripheral cells for energy metabolism. Mediated by Apo B-100-containing lipoproteins (LDL, VLDL) • • • • VLDL contains Apo B-100 and Apo C-II o VLDL contains TAG and EC located in its core Apo-CII will activate Lipoprotein lipase on endothelial cells o Leading to hydrolysis of TAG to fatty acids o Free fatty acids - taken up by cell for energy production. Lipolysis of TAG in the core of VLDL transforms it to IDL and eventually to LDL Cholesterol Ester Transfer Protein (CETP) o Removes TAG from LDL and replace it with cholesterol esters from HDL o LDL (with CE) will return to the liver. o The cholesterol in the liver from LDL: ▪ Reused for secretion of lipoprotein ▪ Used in production of bile salts ▪ Excreted into the bile REVERSE CHOLESTEROL TRANSPORT PATHWAY • • • • • • Removal of excess cholesterol from the peripheral cells to the liver for excretion Cholesterol are pumped out from the cell by ABCA1 then bind to HDL LCAT will esterify cholesterol on HDL. Cholesterol ester will then be removed from HDL via binding to SR-BI receptor HDL with removed CE is returned to the circulation CETP transfers CE from HDL to LDL then eventually removed from the circulation by hepatic LDL receptor ENZYMES IN LIPOPROTEIN METABOLISM • INTRACELLULAR CHOLESTEROL TRANSPORT PATHWAY • • • • • • • Maintains cellular homeostasis of cholesterol Cholesterol - though important cell membrane component. Excess shall be removed as it is toxic to the cell. o Excess cholesterol may be deposited in blood vessels causing atherosclerosis Most lipoprotein receptors delivers lipoprotein particles to the lysosome for degradation. CE are unesterified to FC by lysosomal acid lipase The free cholesterol: o Used for membrane biogenesis o Stored after reesterification by ACAT o Removed from cell by the reverse cholesterol transport pathway • • Lipoprotein Lipase (LPL) o Hydrolyzes TAG and CE in lipoproteins Hepatic Lipase o Hydrolyzes TAG and CE in HDL o Hydrolyzes lipids on VLDL and IDL Lecithin Cholesterol Acyl Transferase (LCAT) o Catalyzes the esterification of cholesterol from HDL o Enables HDL to accumulate cholesterol as cholesterol ester Endothelial Lipase o Hydrolyzes phospholipids and TAG in HDL ATP-binding Cassette Protein A1 (ABCA1) o For efflux of cholesterol from peripheral cells into HDL DISORDER ASSOCIATED WITH LIPIDS AND LIPOPROTEINS FAMILIAL HYPERCHOLESTEROLEMIA (TYPE 2a) • • • • Autosomal dominant disorder Defective or deficient LDL receptors o Cannot bind and clear LDL Laboratory findings: TC and LDL-C (2-3x above normal) Clinical findings: o Xanthelasma o Planar (tendon) xanthomas FAMILIAL DYSBETALIPOPROTEINEMIA • • • • • Type 3 Hyperlipoproteinemia Accumulation of β-VLDL and chylomicron remnants (+) Apo E2/2 (rare form of Apo E) Laboratory findings: o Equal elevation of cholesterol and TAG o (+) β-VLDL Clinical findings: xanthomas & premature vascular disease • Screening test: measurement of VLDL-C/Cholesterol ratio o Reference value (VLDL-C/Cholesterol Ratio): 0.2 o Type 3 hyperlipoproteinemia: >0.3 • • ABETALIPOPROTEINEMIA • • • • Bassen-Kornzweig Syndrome Autosomal recessive disorder Defective Apo-B synthesis o VLDL, LDL, CM are absent o Decrease cholesterol and TAG levels o Defects in absorption of vitamins A, E, K ▪ Vitamin D absorption - not chylomicron dependent Characterized by cerebellar ataxia, acanthocytosis, fat malabsorption HYPOBETALIPOPROTEINEMIA • • • Defect in Apo-B gene (encodes for production of Apo-B) Decreased: LDL, Total Cholesterol Decreased or normal: VLDL, TAG NIEMANN-PICK DISEASE • • • Lipid storage disorder Associated with accumulation of sphingomyelin in the bone marrow, spleen and lymph node. Deficiency of Sphingomyelinase enzyme (removes phosphoryl choline from sphingomyelin) TANGIER DISEASE • • • • Autosomal recessive disorder Mutation in ABCA1 gene on Chromosome #9 resulting to deficiency of ABCA1 o ABCA1 - pumping excess cholesterol from cell to HDL o ABCA1 transfers cholesterol and phospholipid from the cell into Apo A1 proteins in plasma o HDL is significantly reduced from increased catabolism ▪ HDL 1-2 mg/dL Laboratory findings: low blood cholesterol (50-80 mg/dL) Clinical findings: orange or yellow discoloration of the tonsils and pharynx LIPOPROTEIN LIPASE (LPL) DEFICIENCY • • • • • • Rare autosomal recessive trait characterized by hyperchylomicronemia (Type I) Mutations in LPL gene (encode production of LPL) Inability to clear chylomicrons due to absent Lipoprotein Lipase Laboratory findings: TAG of 10,000 mg/dL (postprandial) Patients do not develop premature coronary heart disease Symptomatology: o Eruptive xanthomas – fat build-up under skin surface o Lipemia retinalis – occurs when TAG exceeds 20004000 mg/dL o Abdominal pain, pancreatitis - high TAG TAY SACHS DISEASE • • Mutation in LCAT gene (encode production of LCAT) o Complete LCAT deficiency Laboratory findings: o HDL-C: <10 mg/dL (due to increased HDL catabolism) o Total Cholesterol: normal or high A neurodegenerative disorder of lipid metabolism characterized by a deficiency of enzyme hexosaminidase A, which results in accumulation of sphingolipids in brain ANDERSON’S DISEASE • • • • Chylomicron Retention Disease Distinct from abetalipoproteinemia – only affects Apo-B48 Laboratory findings: hypocholesterolemia Clinical findings: fat malabsorption & low plasma lipid lvls SITOSTEROLEMIA • • • • Autosomal recessive disorder Mutations in ABCG8 or ABCG5 genes (Chromosome 2p21) Phytosterols (plant sterols) are absorbed and accumulate in the plasma and peripheral tissues; cholesterol in plants Laboratory findings: high serum LDL (mostly during childhood) FREDRICKSON-LEVY CLASSIFICATION OF HYPERLIPOPROTEINEMIA TYPE 1 HYPERLIPOPROTEINEMIA • • • • • Type 1 hyperchylomicronemia Familial LPL deficiency Inability to convert chylomicron to chylomicron remnant by Lipoprotein lipase Increased: chylomicron, TAG, Apo B-48 o Serum with creamy layer on top over clear serum Normal or increased cholesterol TYPE 2a HYPERLIPOPROTEINEMIA • • • A block in LDL catabolism and defective Apo-B protein that do not bind to LDL receptor. Increased: LDL, Cholesterol, Apo-B 100 o Serum: Clear Normal: Triglyceride TYPE 2b HYPERLIPOPROTEINEMIA • • • Familial combined hyperlipidemia Most common primary hyperlipidemia Increased: LDL, VLDL, Cholesterol, TAG, Apo B-100 o Serum: Clear to slightly turbid TYPE 3 HYPERLIPOPROTEINEMIA • • • LCAT DEFICIENCY • Clinical findings: Corneal opacity, normocytic anemia, renal failure (young adults) Fish-eye disease – Milder form of LCAT o partial LCAT deficiency • Type 3 Dysbetalipoproteinemia Presence of floating β-VLDL and IDL Increased: IDL, β-VLDL, Total Cholesterol, Triglyceride, Apo E-II o Serum: Creamy top layer sometimes present over a turbid layer Decreased: Apo E-III TYPE 4 HYPERLIPOPROTEINEMIA • • • Hypertriglyceridemia Inability to convert VLDL to IDL and LDL Increased: VLDL, TAG, Apo B-100 o Serum: turbid TYPE 5 HYPERLIPOPROTEINEMIA • • • Associated with LPL deficiency Inability to breakdown TAG Increased: VLDL, TAG, Chylomicrons, Apo B-100, Apo B-48. o Cholesterol: slightly to moderately increased o Serum: turbid with creamy layer on top SUMMARY OF FREDRICKSON-LEVEY CLASSIFICATION OF HYPERLIPOPROTEINEMIA Types TAG CHOLE LDL VLDL CM ↑ APO Type 1 ↑ N N N ↑ Type 2a Type 2b N ↑ ↑ ↑ ↑ ↑ N ↑ N Apo B-100 N Apo B- 100 Type 3 ↑ ↑ N ↑* N Type 4 Type 5 ↑ ↑ N ↑ N N ↑ ↑ N Apo B-100 ↑ Apo B-100, Apo B-48 • • * β-VLDL Apo B-48 Apo E-II Serum Appearance Creamy layer on top of clear serum Clear Clear or slightly turbid Creamy layer sometimes on top of turbid serum Turbid Turbid with creamy layer on top