Primary hyperlipidemias

Primary hyperlipidemias Dr Shreetal Rajan , Senior Resident, Cardiology,MCH,Calicut

Primary hyperlipidemiasClassification of hyperlipidemiasOverview on lipid metabolismPrimary hyperlipidemiasManagement

Terminology Hyperlipidemia

Concentration of lipid in the blood exceeds the upper range of normal in a 12 hr fasting blood sampleIncludes both hypercholesterolemia and hypertriglyceridemia

Dyslipidemia

Dyslipidemia derangement in blood lipid concentration or compositionAlmost always due to hyperlipidemiaDyslipidemia major role in atherosclerosis and CAD

Lipemic serum or plasma separated from blood that contains an excess concentration oftriglycerides (>200 mg/dL) Lactescence opaque milk like appearance of serum or plasma that contains an even higherconcentration of triglycerides (>1000 mg/dL) than lipemic serumEither increase or decrease in lipoprotein fractionsSometimes the total cholesterol may be normal but other underlying abnormalities are present(i) increase in small dense LDL particles (ii) increase in lipoprotein (a)

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Lipoprotein structure

hydrophobic coretriglyceride and/orcholesterol ester

surface coatphospholipid monolayerinterspersed free cholesterol and apolipoproteins

Here is a diagramatic representation of a lipoprotein. Plasma lipoproteins are spherical particles containing a hydrophobic core composed predominately of triglyceride and / or cholesterol esters and a surface coat whose primary component is a phopholipid monolayer. Interspersed in the phopholipid coat are free cholesterol and apolipoproteins.

(Apoproteins are the protein portion of the lipoproteins)

The lipoprotein fractions

ChylomicronsVery Low density lipoproteins (VLDL)Intermediate density Lipoproteins (IDL)Low density Lipoproteins (LDL)High density Lipoproteins (HDL)

Apolipoprotein classes

Lipoproteins physiological functions absorption of- dietary cholesterol- long-chain fatty acids- fat-soluble vitaminstransport of - triglycerides - cholesterol - fat-soluble vitamins - from the liver to peripheral tissues transport of cholesterol- from peripheral tissues to the liverApolipoproteins - functions proteins associated with lipoproteins.lipoprotein assembly and function.activate enzymes in lipoprotein metabolism. ligands for cell surface receptors.The story of lipids the normal physiology Chylomicrons transport fats from the intestinal mucosa to the liverIn the liver, the chylomicrons release triglycerides and some cholesterol and become low-density lipoproteins (LDL).LDL then carries fat and cholesterol to the bodys cells.High-density lipoproteins (HDL) carry fat and cholesterol back to the liver for excretion.

Why study of lipoproteins and apolipoproteins are important?Atherosclerosis and dyslipoproteinemias have a very close associationAll the cardiovascular risk models advocate lipoprotein studies in risk stratification and prognosticationRecently, non HDL fraction, apo B , ratio of apo B to apo A 1, number and size of small, dense LDL particles are all emerging as risk markers for CAD.Subendothelial retention of LDL -initiating factor for atherosclerotic plaque formation

Source: Yusuf S et al. Lancet. 2004;364:937-95236127102033020406080100SmokingFruits/VegExerciseAlcoholPsycho-socialLipidsAll 9 risk factorsPAR (%)141890DiabetesAbdominalobesityHyper-tensionLifestyle factors50INTERHEART Studyn=15,152 patients and 14,820 controls in 52 countriesMI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors)Attributable Risk Factorsfor a First Myocardial Infarction11In this study of 15,152 patients, lipids had the highest population attributable risk for a first myocardial infarction among 9 risk factors for cardiovascular disease.

Classification - hyperlipidemiaPrimary Secondary defect in genes and /or enzymes involved in lipoprotein metabolism1st case report of Familial hypercholesterolemiaIn 1938 Carl Muller, a Norwegian clinician, described FH as an inborn error of metabolism that produces high blood cholesterol and myocardial infarctions (heart attacks) in young people

Primary hyperlipidemia Fredrickson classification

Fredrickson and Levy classified hyperlipoproteinemias according to the type of lipoprotein particles that accumulate in the blood (Type I to Type V)13Alternative classificationI . Primary Primary Disorders of Elevated ApoB -Containing LipoproteinsInherited Causes of Low Levels of ApoB -Containing LipoproteinsGenetic Disorders of HDL MetabolismMiscellaneous- Elevated Plasma Levels of Lipoprotein(a) Elevated small dense LDL particlesII . Secondary forms of hyperlipidemia

Important from treatment point of view Effective patient management

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Primary Disorders of Elevated Apo B -Containing Lipoproteins

Lipid disorders associated with elevated LDL and normal triglyceridesLipid disorders associated with elevated triglycerides

Lipid disorders associated with elevated LDL and normal triglycerides

Familial Hypercholesterolemia (FH)Familial Defective ApoB-100 (FDB)Autosomal Dominant Hypercholesterolemia Due to Mutations in Pcsk9 (ADH-Pcsk9 or ADH3)Autosomal Recessive Hypercholesterolemia (ARH)SitosterolemiaPolygenic HypercholesterolemiaFamilial hypercholesterolemiaAutosomal codominant disorder Elevated plasma levels of LDL-C Triglyceride level-normalPremature coronary atherosclerosis

Pathophysiology Defect in LDL receptorHomozygous and heterozygousReceptor negative : < 2% LDL receptor activity Receptor defective: 2-25% receptor activity

Familial hypercholesterolemiatendon xanthomas hands, wrists, elbows, knees, heels or buttocksTotal cholesterol levels > 500 mg/DlAccelerated atherosclerosis begins in aortic root and extends into coronary ostiaReceptor negative-untreated patients dont survive beyond 2nd decadeReceptor defective- better prognosis

Familial Defective Apob-100 (FDB)Dominantly inherited disorderElevated plasma LDL levels with normal triglycerides, tendon xanthomas, increased incidence of premature ASCVDmutations in the LDL receptorbinding domain of apoB-100 LDL binds the receptor with reduced affinity -> removed from the circulation at a reduced rateClinically identical to heterozygous FH but have lower plasma levels of LDL

19Autosomal Dominant Hypercholesterolemia - physiologyAD disorder ; gain-of-function mutations in PCSK9PCSK9 is a secreted protein that binds to the LDL receptor causing its degradationLDL is internalized along with the receptor after bindingIn the low pH of the endosome LDL dissociates from the receptor and the receptor returns to the cell surfaceThe LDL is delivered to the lysosome

20Autosomal Dominant Hypercholesterolemia- pathologyWhen PCSK9 binds to the receptor, the complex is internalized and the receptor is redirected to the lysosome rather than to the cell surfaceThe missense mutations enhance the activity of PCSK9The number of hepatic LDL receptors is reducedindistinguishable clinically from patients with FH

21Autosomal Recessive Hypercholesterolemia (ARH)LDL Receptor Adaptor Protein (LDLRAP) is involved in LDL receptormediated endocytosis in the liver.In the absence of LDLRAP, lipoprotein-receptor complex fails to be internalizedHypercholesterolemia, tendon xanthomas, premature CADHyperlipidemia responds partially to treatment with HMG-CoA reductase inhibitorsUsually require LDL apheresis to lower plasma LDL-C

LDL Receptor adaptor protein (LDLRAP)22SitosterolemiaAutosomal recessive disease severe hypercholesterolemia, tendon xanthomas, premature ASCVD (Atherosclerotic CardioVascular Disease)mutations in either of two members of the ATP-binding cassette (ABC) half transporter family, ABCG5 and ABCG8genes are expressed in enterocytes and hepatocytes23Sitosterolemiaintestinal absorption of sterols is increased and biliary excretion of the sterols is reduced increased plasma and tissue levels of both plant sterols and cholesterolDysmorphic red blood cells and megathrombocyteshemolysis - distinctive clinical feature of this diseaserespond to reductions in dietary cholesterol content do not respond to statins.Bile acid sequestrants and cholesterol absorption inhibitors - effective

24Polygenic HypercholesterolemiaElevated LDL with a normal plasma level of triglyceride in the absence of secondary causes of hypercholesterolemiaPlasma LDL levels are generally not as elevated as they are in other primary hypercholesterolemiasFamily studies to differentiate polygenic hypercholesterolemia from single-gene disordersOne-half of the first-degree relatives of patients with FH and FDB are hypercholesterolemic, whereas