Dr Shreetal Rajan, Senior Resident, Cardiology,MCH,Calicut.

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

Primary hyperlipidemias Classification of hyperlipidemias Overview on lipid metabolism Primary hyperlipidemias Management

Terminology Hyperlipidemia Concentration of lipid in the blood exceeds the upper range of normal in a 12 hr fasting blood sample Includes both hypercholesterolemia and hypertriglyceridemia Dyslipidemia Dyslipidemia derangement in blood lipid concentration or composition Almost always due to hyperlipidemia Dyslipidemia major role in atherosclerosis and CAD

Lipoprotein structure hydrophobic core triglyceride and/or cholesterol ester surface coat phospholipid monolayer interspersed free cholesterol and apolipoproteins

The lipoprotein fractions Chylomicrons Very 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 vitamins transport of - triglycerides - cholesterol - fat-soluble vitamins - from the liver to peripheral tissues transport of cholesterol - from peripheral tissues to the liver

Apolipoproteins - 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 liver In 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 association All the cardiovascular risk models advocate lipoprotein studies in risk stratification and prognostication Recently, 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;364:937-952 36 12 7 10 20 33 0 20 40 60 80 100 SmokingFruits/ Veg ExerciseAlcoholPsycho- social LipidsAll 9 risk factors PAR (%) 14 18 90 Diabetes Abdominal obesity Hyper- tension Lifestyle factors 50 INTERHEART Study n=15,152 patients and 14,820 controls in 52 countries MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors) Attributable Risk Factors for a First Myocardial Infarction

Classification - hyperlipidemia Primary Secondary defect in genes and /or enzymes involved in lipoprotein metabolism 1 st case report of Familial hypercholesterolemia In 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

Alternative classification I. Primary Primary Disorders of Elevated ApoB -Containing Lipoproteins Inherited Causes of Low Levels of ApoB -Containing Lipoproteins Genetic Disorders of HDL Metabolism Miscellaneous- Elevated Plasma Levels of Lipoprotein(a) Elevated small dense LDL particles II. Secondary forms of hyperlipidemia

Primary Disorders of Elevated Apo B -Containing Lipoproteins Lipid disorders associated with elevated LDL and normal triglycerides Lipid disorders associated with elevated triglycerides

Lipid disorders associated with elevated LDL and normal triglycerides 1. Familial Hypercholesterolemia (FH) 2. Familial Defective ApoB-100 (FDB) 3. Autosomal Dominant Hypercholesterolemia Due to Mutations in Pcsk9 (ADH-Pcsk9 or ADH3) 4. Autosomal Recessive Hypercholesterolemia (ARH) 5. Sitosterolemia 6. Polygenic Hypercholesterolemia

Familial hypercholesterolemia Autosomal codominant disorder Elevated plasma levels of LDL-C Triglyceride level-normal Premature coronary atherosclerosis Pathophysiology Defect in LDL receptor Homozygous and heterozygous Receptor negative : < 2% LDL receptor activity Receptor defective: 2- 25% receptor activity

Familial hypercholesterolemia tendon xanthomas hands, wrists, elbows, knees, heels or buttocks Total cholesterol levels > 500 mg/Dl Accelerated atherosclerosis begins in aortic root and extends into coronary ostia Receptor negative-untreated patients dont survive beyond 2 nd decade Receptor defective- better prognosis

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

Autosomal Dominant Hypercholesterolemia - physiology AD disorder ; gain-of-function mutations in PCSK9 PCSK9 is a secreted protein that binds to the LDL receptor causing its degradation LDL is internalized along with the receptor after binding In the low pH of the endosome LDL dissociates from the receptor and the receptor returns to the cell surface The LDL is delivered to the lysosome

Autosomal Dominant Hypercholesterolemia- pathology When PCSK9 binds to the receptor, the complex is internalized and the receptor is redirected to the lysosome rather than to the cell surface The missense mutations enhance the activity of PCSK9 The number of hepatic LDL receptors is reduced indistinguishable clinically from patients with FH

Autosomal 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 internalized Hypercholesterolemia, tendon xanthomas, premature CAD Hyperlipidemia responds partially to treatment with HMG-CoA reductase inhibitors Usually require LDL apheresis to lower plasma LDL-C

Sitosterolemia Autosomal 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 ABCG8 genes are expressed in enterocytes and hepatocytes

Sitosterolemia intestinal absorption of sterols is increased and biliary excretion of the sterols is reduced increased plasma and tissue levels of both plant sterols and cholesterol Dysmorphic red blood cells and megathrombocytes hemolysis - distinctive clinical feature of this disease respond to reductions in dietary cholesterol content do not respond to statins. Bile acid sequestrants and cholesterol absorption inhibitors - effective

Polygenic Hypercholesterolemia Elevated LDL with a normal plasma level of triglyceride in the absence of secondary causes of hypercholesterolemia Plasma LDL levels are generally not as elevated as they are in other primary hypercholesterolemias Family studies to differentiate polygenic hypercholesterolemia from single-gene disorders

Lipid Disorders Associated with Elevated Triglycerides 1. Familial Chylomicronemia Syndrome (Type I Hyperlipoproteinemia; Lipoprotein Lipase and ApoC-II Deficiency) 2. Familial Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) 3. Apo A-V Deficiency 4. GPIHBP1 Deficiency 5. Hepatic Lipase Deficiency 6. Familial Hypertriglyceridemia (FHTG) 7. Familial Combined Hyperlipidemia (FCHL)

Familial Chylomicronemia Syndrome LPL (Lipoprotein Lipase) is required for the hydrolysis of triglycerides in chylomicrons and VLDLs apoC-II is a cofactor for LPL Genetic deficiency or inactivity of LPL or apo C II results in impaired lipolysis and elevations in plasma chylomicrons The fasting plasma is turbid Very high triglyceride levels

Familial Chylomicronemia Syndrome Present in childhood with features suggestive of acute pancreatitis Lipemia retinalis Eruptive xanthomas Hepatosplenomegaly Premature CHD not a feature

Familial Chylomicronemia Syndrome- diagnosis IV heparin injection - endothelial-bound LPL is released LPL activity is profoundly reduced in both LPL and apo C-II deficiency normalizes after the addition of normal plasma (providing a source of apoC-II)

Familial Chylomicronemia Syndrome dietary fat restriction with fat-soluble vitamin supplementation medium-chain triglycerides Fish oils Fresh frozen plasma source of apo C Plasmapheresis in pregnancy

HYPERTRIGLYCERIDEMIA - OTHER CAUSES APO A V DEFICIENCY Apo A-V required for the association of VLDL and chylomicrons with LPL Deficiency presents as hyperchylomicronemia GPIHBP1 Deficiency LPL is attached to a protein on the endothelial surface of capillaries called GPIHBP1 mutations that interfere with GPIHBP1 synthesis or folding cause severe hypertriglyceridemia

Hepatic Lipase Deficiency autosomal recessive disorder elevated plasma levels of cholesterol and triglycerides (mixed hyperlipidemia) due to the accumulation of circulating lipoprotein remnants association of this genetic defect with ASCVD is not clearly known Lipid-lowering therapy with statins along with other drugs

Familial Dysbetalipoproteinemia FDBL (Type III Hyperlipoproteinemia) mixed hyperlipidemia; due to genetic variations in apoE Patients homozygous for the E2 allele (the E2/E2 genotype) comprise the most common subset of patients with FDBL precipitating factors usually present hyperlipidemia, xanthomas, premature coronary disease, peripheral vascular disease

Familial Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) The disease seldom presents in women before menopause Two distinctive types of xanthomas- tuberoeruptive and palmar Broad beta band on electrophoresis Premature CHD Dramatic response to weight reduction and dietary changes; statins Treatment of other metabolic conditions

Familial Hypertriglyceridemia (FHTG) The diagnosis of FHTG is suggested by the triad of Elevated levels of plasma triglycerides (2501000 mg/dL) Normal or only mildly increased cholesterol levels (

Familial Hypertriglyceridemia (FHTG) type IV and type V of Fredrickson classification autosomal dominant disorder of unknown etiology VLDL is elevated Precipitating factors not associated with increased risk of ASCVD secondary causes of hypertriglyceridemia to be ruled out Monitor pancreatitis

Familial Combined Hyperlipidemia (FCHL) autosomal dominant one of three phenotypes Elevated plasma levels of LDL-C Elevated plasma levels of triglycerides due to elevation in VLDL Elevated plasma levels of both LDL-C and triglyceride classical feature of FCHL - lipoprotein profile can switch among these three phenotypes in the same individual over time Associated with other metabolic risk factors Family history of hyperlipidemia and/or premature CHD

Familial Combined Hyperlipidemia (FCHL) significantly elevated plasma levels of apoB (Hyperapobetalipoproteinemia) Increased small, dense LDL particles are characteristic of this syndrome Overproduction of VLDL by liver cause not known

Inherited Causes of Low Levels of Apo B Containing Lipoproteins Familial Hypobetalipoproteinemia (FHB) MOST COMMON INHERITED FORM OF HYPOCHOLESTEROLEMIA low total cholesterol and LDL-C due to mutations in apoB LDL levels < 80 mg% Protection from CHD Parents have abnormal lipid fractions

Pcsk9 Deficiency Loss of function mutations PCSK9 normally promotes the degradation of the LDL receptor Absence cause increased activity of LDL receptor and low LDL levels ( 40% reduction) Protection from CHD increases as plasma LDL levels decrease

Abetalipoproteinemia autosomal recessive disease loss-of-function mutations in the gene encoding microsomal triglyceride transfer protein (MTP) transfers lipids to nascent chylomicrons and VLDLs in the intestine and liver Parents have normal lipid levels diarrhea and failure to thrive Neurologic manifestations Pigmented retinopathydefective absorption and transport of fat soluble vitamins vitamin E low-fat, high-caloric, vitamin-enriched diet

Genetic Disorders of HDL Metabolism Inherited causes of low levels of HDL-C 1. Gene Deletions in the Apo A V-AI-CIII-AIV Locus and Coding Mutations in ApoA-I 2. Tangier Disease (ABCA1 Deficiency) 3. LCAT Deficiency 4. Primary Hypoalphalipoproteinemia Inherited causes of high levels of HDL-C 1. CETP Deficiency 2. Familial Hyperalphalipoproteinemia

Gene Deletions in the ApoAV-AI-CIII-AIV Locus and Coding Mutations in ApoA-I Absence of mature HDL Free cholesterol increase in HDL and in tissues corneal opacities and planar xanthomas Premature CHD

Tangier Disease (ABCA1 Deficiency) autosomal recessive ABCA1, a cellular transporter that facilitates efflux of unesterified cholesterol and phospholipids from cells to apoA-I extremely low circulating plasma levels of HDL-C (

LCAT Deficiency Autosomal recessive defective formation of mature HDL 2 types complete and partial Progressive corneal opacification Low levels of HDL COMPLETE FORM hemolytic anemia, progressive renal insufficiency and ESRD PREMATURE CHD not seen

Primary Hypoalphalipoproteinemia (isolated low HDL Syndrome) defined as a plasma HDL-C level below the tenth percentile in the setting of relatively normal cholesterol and triglyceride level no apparent secondary causes of low plasma HDL-C no clinical signs of LCAT deficiency or Tangier disease. Premature CHD not a consistent feature

Inherited causes of high levels of HDL-C CETP DEFICIENCY Loss-of-function mutations CETP facilitates transfer of cholesteryl esters from HDL to apoB-containing lipoproteins CETP deficiency results in an increase in the cholesteryl ester content of HDL,decreased clearance of HDL and a reduction in plasma levels of LDL-C The relationship of CETP deficiency to ASCVD remains unresolved

defined as a plasma HDL-C level above the ninetieth percentile mutations in endothelial lipase Relation to reduced CHD risk and increased longevity not consistent Inherited causes of high levels of HDL-C Hyperalphalipoproteinemia

Secondary forms of lipoproteinemia

Management- What are the recommendations? Checking lipids Nonfasting lipid panel measures HDL and total cholesterol Fasting lipid panel Measures HDL, total cholesterol and triglycerides LDL cholesterol is calculated: LDL cholesterol = total cholesterol (HDL + triglycerides/5)

When to check lipid panel Two different Recommendations Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides Repeat testing every 5 years for acceptable values United States Preventative Services Task Force Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. If total cholesterol > 200 or HDL

Risk CategoryLDL-C GoalInitiate TLC Consider Drug Therapy High risk: CHD or CHD risk equivalents (10-year risk >20%) 100 mg/dL (130 mg/dL (100-129 mg/dL: consider drug options) Moderate risk: 2+ risk factors* (10 year risk 140/90 mmHg or on antihypertensive medication, HDL-C 60 mg/dl is a negative risk factor), family history of premature CHD, age >45 years in men or >55 years in women ATP III LDL-C Goals and Cut-points for Drug Therapy

Level (mg/dl)Classification 240High Level (mg/dl)Classification >40Minimum goal* 40-50Desired goal* >50High Level (mg/dl)Classification 500Very High Total CholesterolHDL-Cholesterol Triglyceride Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497 ATP III Classification of Other Lipoprotein Levels *These goals apply to men. For women, the minimum goal is >50 mg/dL HDL=High density lipoprotein

TREATMENT Lifestyle changes- diet, exercise and yoga mediterranean diet Drugs New therapies LDL apheresis, monoclonal antibodies,Apo A I mimetics

Soluble fiber Soy protein Stanol esters Dietary Adjuncts EzetimibeCholesterol absorption inhibitor Cholestyramine Colesevelam Colestipol Bile acid sequestrants Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG- CoA) reductase inhibitors [Statins] Drug(s)Class Nicotinic acidNiacin Drug therapies available Newer therapies CETP inhibitors, APO A analogues, monoclonal antibodies

LDL-C Mean % change from baseline to week 12 20 15 10 5 0 +5 16.9* +0.4 Triglycerides 5.7 HDL-C 1.6 +1.3 Placebo Ezetimibe 10 mg 892 patients with primary hypercholesterolemia randomized to ezetimibe (10 mg) or placebo for 12 weeks *p

Dr Shreetal Rajan, Senior Resident, Cardiology,MCH,Calicut.

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Transcript of Dr Shreetal Rajan, Senior Resident, Cardiology,MCH,Calicut.