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Hyperlipidemia - etiology epidemiology clinical features

Hyperlipidemia refers to elevated levels of lipids in the blood, including triglycerides and cholesterol. There are several types of hyperlipidemia based on the elevated lipoprotein, including types I-V. Type I is caused by deficiencies of lipoprotein lipase or ApoC-II, resulting in an inability to remove chylomicrons from the blood. Type IIa, or familial hypercholesterolemia, is caused by mutations in the LDL receptor gene and results in markedly elevated LDL cholesterol. It can be either homozygous or heterozygous. Both forms increase the risk of premature cardiovascular disease if not properly treated.

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Hyperlipidemia Etiology, epidemiology and clinical features of hyperlipidemia
• lipoproteins • cholesterol • triglyceride Hyperlipidemia Hyperlipidemia: elevated levels of lipids, i.e. triglycerides and cholesterol in blood Hyperlipoproteinemia: elevated levels of lipoproteins, especially VLDL, IDL and LDL Hypercholesterolemia: elevated levels of cholesterol in blood Hypertriglyceridemia: elevated levels of triglycerides in blood Bays HE, et al. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-S43. Source: GUIDELINES FOR ADOLESCENT NUTRITION SERVICES. Stang J and story M. Chapter 10. Hyperlipidemia. Page 109-124. Adams LB. Http://www.Epi.Umn.Edu/let/pubs/adol_book.Shtm VLDL: very low density lipoprotein IDL: intermediate density lipoprotein LDL: low density lipoprotein
Jacobson TA, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1—Full Report. J Clin Lipidol. 2015 Mar-Apr;9(2):129-69. Normal serum levels of cholesterol and triglycerides
Hyper- lipoproteinemia Name of the disease Increased lipoprotein Increased lipid fraction Type I Hyperchylomicronemia Chylomicrons Triglycerides Type IIa Familial hypercholesterolemia LDL Cholesterol Type IIb Familial combined hypercholesterolemia LDL and VLDL Cholesterol and triglycerides Type III Dysbetalipoprotenemia IDL Triglycerides and cholesterol Type IV Familial hypertriglyceridemia VLDL Triglycerides Type V Familial lipoprotein lipase deficiency VLDL and Chylomicrons Triglycerides and cholesterol Fredrickson classification is still followed Chandra KS, et al. Consensus statement on management of dyslipidemia in Indian subjects. Indian Heart J. 2014 Dec;66 Suppl 3:S1-51. Levy RI, Fredrickson DS. Diagnosis and management of hyperlipoproteinemia. Am J Cardiol 1968;22:576-583. Source: Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull World Health Organ. 1970; 43(6): 891–915.
Main cause of hypercholesterolemia Primary disorders Familial hypercholesterolemia Familial combined hyperlipidemia Polygenic hypercholesterolemia Secondary disorders Hyperthyroidism Nephrotic syndrome Dysproteinemias Obstructive liver disease Thiazide diuretics Main cause of hypertriglyceridemia Primary disorders Familial hypertriglyceridemia Familial combined hyperlipidemia Congenital deficiency of lipoprotein lipase Familial dysbetalipoproteinemia Secondary disorders Nephrotic syndrome Dysproteinemias Oral contraceptives Thiazide diuretics Beta-adrenergic blocking agents Alcohol Uncontrolled diabetes mellitus Source: Clinical Methods: The history, physical, and laboratory examination. Chapter 31, Cholesterol, Triglycerides and Associated Lipoproteins. http://www.ncbi.nlm.nih.gov/books/NBK351/#!po=20.8333 Accessed on 04/22/2016 Looking at it at a different angle
White B. Dietary fatty acids. Am fam physician. 2009 aug 15;80(4):345-350. Source: harrigan gg, et al. Metabolomics in alcohol research and drug development. Http://pubs.Niaaa.Nih.Gov/publications/arh311/26-35.Htm. Accessed on 04/22/2016 Source: cholesterol esterase. Http://www.Worthington-biochem.Com/cepm/default.Html accessed on 04/22/2016 Source: Overweight & obesity. Http://www.Indiana.Edu/~k562/ob.Html accessed on 04/22/2016 Triglyceride Fatty acid Building blocks Phospholipid Cholesteryl esterCholesterol + Fatty acid =
Karasinska JM and Hayden MR. Cholesterol metabolism in Huntington disease. Nature Reviews Neurology 7, 561-572 (October 2011) Cholesterol synthesis Glucose Pyruvate Amino acid Acetyl CoA Fatty acids Ketone bodies Source of Acetyl CoA Acetyl CoA Acetyl CoA + Source of Acetoacetyl CoA
Reaches back into liver Small percent excreted Walters JR. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol. 2014 Jul;11(7):426-34 Ioannou YA.. Multidrug permeases and subcellular cholesterol transport. Nature Reviews Molecular Cell Biology 2, 657-668 (September 2001) Bile acid synthesis, recirculation and excretion Bile acid circulation
Chaves VE, et al. Glyceroneogenesis is reduced and glucose uptake is increased in adipose tissue from cafeteria diet-fed rats independently of tissue sympathetic innervation. J Nutr. 2006 Oct;136(10):2475-80. Chen HC and Farese RV Jr. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):482-6. Fung MA and Frohlich JJ. Common problems in the management of hypertriglyceridemia. CMAJ. 2002 November 26; 167(11): 1261–1266. Triglyceride synthesis
Lipoproteins Ridker PM. LDL cholesterol: controversies and future therapeutic directions. Lancet. 2014 Aug 16;384(9943):607-17.
Lipoprotein synthesis, transport and recycling Source: Clinical Methods: The history, physical, and laboratory examination. Chapter 31, Cholesterol, Triglycerides and Associated Lipoproteins. http://www.ncbi.nlm.nih.gov/books/NBK351/#!po=20.8333 Accessed on 04/22/2016
VLDL synthesis D Gruffat, D Durand, B Graulet, D Bauchart. Regulation of VLDL synthesis and secretion in the liver. Reproduction Nutrition Development, EDP Sciences, 1996, 36 (4), pp.375-389. LDL
Source: Feingold KR, Grunfeld C. Introduction to Lipids and Lipoproteins. [Updated 2015 Jun 10]. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. http://www.ncbi.nlm.nih.gov/books/NBK305896/?report=reader#_NBK305896_pubdet_ Accessed on 04/22/2016 Source: Lipids and lipoproteins: metabolism and its violations. http://intranet.tdmu.edu.ua/data/kafedra/internal/distance/classes_stud/English/2%20course/Elective%20course%20(Modern%20Methods%20of%20Diagnosis)/08.%20Lipids%20and%20lipoproteins%20metabolis%20and%20its%20violatios.htm Accessed on 04/22/2016 Vaverkova H. LDL-C or apoB as the Best Target for Reducing Coronary Heart Disease. Should Apob be Implemented into Clinical Practice? Clin Lipidology. 2011;6(1):35-48. Composition of Lipoproteins
Rader DJ, Hoeg JM and Brewer HB Jr. Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med. 1994 Jun 15;120(12):1012-25. Lipoprotein Associated apolipoproteins Chylomicron apoB-48, apoA, apoC, apoE, apoH VLDL apoE, apoB-100, apoC IDL apoE, apoB-100, apoC LDL apoB-100, apoC, apoE HDL apoA-1, apoC, apoD, apoE The apolipoproteins that are in bold are the major apolipoprotein on the particular lipoprotein Lipoprotein synthesis, transport and recycling Major apolipoprotein Function of the apolipoprotein apoA-1 Structural protein - HDL apoB-48 Structural protein - Chylomicron apoB-100 Ligand for binding to LDL receptors Structural protein in VLDL and LDL apoE Ligand for binding to remnant apoE-receptor
Chylomicron 5% 90% 3% 2% Protein Phospholipid Triglycerides Cholesterol and esters VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters HDL 25% 5% 30% 40% Protein Phospholipid Triglycerides Cholesterol and esters Composition of Lipoproteins Free fatty acids not included in the above diagrams
Hyper- lipoproteinemia Name of the disease Increased lipoprotein Increased lipid fraction Type I Hyperchylomicronemia Chylomicrons Triglycerides Type IIa Familial hypercholesterolemia LDL Cholesterol Type IIb Familial combined hypercholesterolemia LDL and VLDL Cholesterol and triglycerides Type III Dysbetalipoprotenemia IDL, chylomicron remnants Triglycerides and cholesterol Type IV Familial hypertriglyceridemia VLDL Triglycerides Type V Familial lipoprotein lipase deficiency VLDL and Chylomicrons Triglycerides and cholesterol Fredrickson classification is still followed Chandra KS, et al. Consensus statement on management of dyslipidemia in Indian subjects. Indian Heart J. 2014 Dec;66 Suppl 3:S1-51. Levy RI, Fredrickson DS. Diagnosis and management of hyperlipoproteinemia. Am J Cardiol 1968;22:576-583. Source: Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull World Health Organ. 1970; 43(6): 891–915.
Tall AR and Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nature Reviews Immunology 15, 104–116 (2015) Source: LIPOPROTEINS – ROLE IN HEALTH AND DISEASES. Edited by sasa frank and gerhard kostner. Chapter 5. The apob/apoa-i ratio is a strong predictor of cardiovascular risk. Göran walldius. Http://www.Intechopen.Com/books/lipoproteins-role-in-health- and-diseases/the-apob-apoa-i-ratio-is-a-strong-predictor-of-cardiovascular-risk accessed on 04/23/2016 LDL vs HDL
Jacobson TA, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1—Full Report. J Clin Lipidol. 2015 Mar-Apr;9(2):129-69. Normal serum levels of cholesterol and triglycerides
Type I Hyperlipoproteinemia or Hyperchylomicronemia Chylomicron 5% 90% 3% 2% Protein Phospholipid Triglycerides Cholesterol and esters • Inherited condition (1 in 1 million) • Deficiency of lipoprotein lipase or apolipoprotien C-II (a lipase- activating protein) • Thus, inability to remove chylomicrons and triglycerides from blood (i.e. hyperchilomicronemia and hypertriglyceridemia) • Usually presents in childhood with eruptive xanthomata and abdominal colic • Development of lipemia retinalis • Complications include retinal vein occlusion, acute pancreatitis, steatosis and organomegaly (hepatosplenomegaly) Ladizinski B, and Lee KC. Clinical Images: Eruptive xanthomas in a patient with severe hypertriglyceridemia and type 2 diabetes CMAJ 2013;185:1600 George Yuan et al.. Hypertriglyceridemia: its etiology, effects and treatment CMAJ 2007;176:1113-1120 Eruptive xanthomata Lipemic plasma Lipemia retinalis Tuberous xanthomas Palmar crease xanthomas Eruptive xanthomata Merkel M, Eckel RH and Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J. Lipid Res. 2002 43:(12) 1997-2006. Forte TM, Shu X and Ryan RO. The ins (cell) and outs (plasma) of apolipoprotein A-V. J Lipid Res. 2009 Apr;50 Suppl:S150-5.
Type IIa Hyperlipoproteinemia or Familial hypercholesterolemia (increased LDL) LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters Homozygous familial hypercholesterolaemia • 1 in 1 000 000 • Life-threatening condition (first decade of life) • Mutations in LDL receptor (LDLR) gene • Parents are heterozygous for the mutations • Markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) Source: Namrata C. Biochemistry for medics. Cholesterol metabolism (Subjective questions Set-4). http://www.namrata.co/cholesterol-metabolism-subjective-questions-set-4/ Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512 Modified from: Harisa GI and Alanazi FK. Low density lipoprotein bionanoparticles: From cholesterol transport to delivery of anti-cancer drugs. Saudi Pharm J. 2014 Dec; 22(6): 504–515. Cont. next slide
Type IIa Hyperlipoproteinemia or Familial hypercholesterolemia (increased LDL) • Leading to accelerated and premature atherosclerotic cardiovascular disease • Usually presents as cutaneous xanthomas in feet, hands, elbows, Achilles tendons. • Arcus senilis corneae • Complications are mainly cardiovascular Homozygous familial hypercholesterolaemia Source: Corneal arcus (arcus senilis). Ophthalmic Atlas Images by EyeRounds.org, The University of Iowa http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Arcus/in dex.htm Accessed on 04/25/2016 Goldstein JL, and Brown MS. The LDL Receptor. Arterioscler Thromb Vasc Biol. 2009;29:431-438 Cuch el M, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;eurheartj.ehu274 Source: PEIR Digital Library. HISTOLOGY: CARDIOVASCULAR: VASCULATURE: coronary artery: atherosclerosis: micro low mag hemorrhage into plaque and thrombosis. http://peir.path.uab.edu/library/picture.php?/1964
Type IIa Hyperlipoproteinemia or Familial hypercholesterolemia (increased LDL) Heterozygous familial hypercholesterolaemia • 1 in 500 • Treatable life-threatening condition (beyond adolescence) • Heterozygous mutations in the LDLR gene • Autosomal dominant inheritance • Markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) • Clinical features similar to Homozygous condition Yuan G, Wang J and Hegele RA. Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. CMAJ. 2006 Apr 11; 174(8): 1124–1129. Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512 LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters
Type IIb Hyperlipoproteinemia or combined hyperlipidemia (increased VLDL and LDL) • 1 in 40 • Autosomal dominant inheritance • But molecular basis is yet to be deciphered • Leads to increased serum Triglycerides and LDL cholesterol • No/rare cutaneous xanthomas • Usually recognized during investigation of cardiovascular or ceribrovascular accident VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters Yuan G, and Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007 Apr 10; 176(8): 1113–1120. Brahm A and Hegele RA. Hypertriglyceridemia. Nutrients. 2013 Mar; 5(3): 981–1001. Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512
IDL 22% 36% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters Type III Hyperlipoproteinemia or Dysbetalipoproteinemia (increased IDL) • 1 in 1 million • Mutation in apoE apoprotein has been identified but not in all patients • Autosomal recessive • Not all with the mutation have symptoms • Elevated plasma triglycerides and cholesterol • Manifests earlier in males and usually after menopause in women • When severe: symptoms in first year of life or in young childhood • growth delay, malabsorption, hepatomegaly, and neurological and neuromuscular manifestations, diarrhea with steatorrhea HSPG/LPR: Heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor- related protein (LRP) Mahley WR, Huang Y and Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res. 1999 Nov;40(11):1933-49. Kei A, et al. Dysbetalipoproteinemia: Two cases report and a diagnostic algorithm. World J Clin Cases. 2015 Apr 16;3(4):371-6. Source: Abetalipoproteinemia. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=14 Accessed on 04/25/2016 Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512
VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters Type IV Hyperlipoproteinemia or Familial hypertriglyceridemia (increased VLDL) Levy RI, Fredrickson DS. Diagnosis and management of hyperlipoproteinemia. Am J Cardiol 1968;22:576-583. Fung MA and Frohlich JJ. Common problems in the management of hypertriglyceridemia. CMAJ. 2002 November 26; 167(11): 1261–1266. Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512 • 1 in 100 • Autosomal dominant inheritance • Mutations have been identified in Apolipoprotein C and Lecithin:cholesterol acyltransferase • Clinical features include eruptive xanthomas, lipemia retinalis and hepatosplenomegaly. • May present as acute pancreatitis • Patients are at increased risk of coronary artery disease
Type V Hyperlipoproteinemia or Familial lipoprotein lipase deficiency (increased VLDL and Chylomicron) Chylomicron 5% 90% 3% 2% Protein Phospholipid Triglycerides Cholesterol and esters VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters Brahm A and Hegele RA. Hypertriglyceridemia. Nutrients. 2013 Mar; 5(3): 981–1001 Ghiselli G, et al. Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia. J Clin Invest. 1982 Aug; 70(2): 474–477 Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512. • 1 in 600 • Mutation in the apoE apolipoprotein • Patients overproduce triglycerides and defective clearance of VLDL • A fat free diet will convert the patients to express a Type IV Hyperlipoproteinemia features • Presents with hepatosplenomegaly, occasional eruptive xanthomas, increased incidence of pancreatitis
Secondary hyperlipidemia • Usually a “two hit phenomenon” is noticed o “First hit” is the genetic predisposition o “Second hit” are the secondary factors, which worsen lipid levels Bays HE, et al. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-S43. Source: GUIDELINES FOR ADOLESCENT NUTRITION SERVICES. Stang J and story M. Chapter 10. Hyperlipidemia. Page 109-124. Adams LB. Http://www.Epi.Umn.Edu/let/pubs/adol_book.Shtm
• Secondary causes of hyperlipidemia: metabolic syndrome, insulin resistance, limited physical activity, cigarette smoking, substantial alcohol consumption, pregnancy, anorexia narvosa, corticosteroid therapy. • Endocrine diseases: inadequately controlled diabetes mellitus, untreated hypothyroidism, polycystic ovarian syndrome. • Kidney disease: chronic kidney disease, nephrotic syndrome. • Liver disease: hepatitis with fatty liver, cholestasis, biliary cirrhosis, primary sclerosing cholangitis. • Pancreatic disease: acute pancreatitis. • Infections: HIV infection especially when on highly active anti-retroviral therapy. • Inflammatory diseases: systemic lupus erythematosus, rheumatoid arthritis. • Storage diseases: glycogen storage disease, Gaucher’s disease, juvenile Tay-Sachs disease, Niemann-Pick disease. • Others: idiopathic hypercalcemia, Klinefelter syndrome, Kawasakis disease, acute intermittent prophyria. Secondary hyperlipidemia Source: GUIDELINES FOR ADOLESCENT NUTRITION SERVICES. Stang J and story M. Chapter 10. Hyperlipidemia. Page 109-124. Adams LB. Http://www.Epi.Umn.Edu/let/pubs/adol_book.Shtm Bays HE, et al. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-S43.
Hyperlipidemia in pregnancy In normal pregnancy • Maternal hyperlipidemia is normal during pregnancy • Especially in the third trimester • Mainly triglycerides (TAG) and to a lesser extent cholesterol and phospholipids • Increased VLDL production and decreased removal • Increased levels of TAG in LDL and HDL • The above is assisted by the insulin-resistant state in pregnancy Source: Metabolism in normal pregnancy. Herrera E and Ortega H. In Textbook of Diabetes and Pregnancy”, second ed. , M.Hod, L.Jovanovich, G.C.Di Renzo, A. De Leiva, O. Langer, eds., Informa healthcare, London, pgs. 25-34, 2008. http://dspace.ceu.es/bitstream/10637/2873/1/pag25_34.pdf Accessed on 04/27/2016 Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016
Lipid and lipoprotein (mg/dl) Third trimester Non-pregnant controls HDL-C 81±17 69±10 LDL-C 136±33 99±23 TGs 245±73 77±34 TC 267±30 183±23 VLDL 109 (38-710) 23 (5-85) IDL 124(79-157) 35(18-62) LDL 353(244-534) 207(150-363) In normal pregnancy Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016 Hyperlipidemia in pregnancy
Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016 Medical complications of pregnancy Pre-eclampsia, Pregnancy-induced hypertension Gestational diabetes mellitus, Prelipaemia Intra-uterine growth restriction(retardation) Co-existing medical conditions Obesity, Types 1 and 2 diabetes mellitus Hypothyroidism, Hypertension Renal diseases, particularly nephritic syndrome Others Alcoholism, Medications, eg LMWt-heparin and glucocorticoid Other maternal factors Obesity, Maternal weight gain, Maternal nutrition, Pre-pregnancy lipid levels Hyperlipidemia in pregnancy
Consequences Consequences of hyperlipidemia in pregnancy on the mother • Cholesterol gallstones • Intrahepatic cholestasis • Acute pancreatitis • Endothelial dysfunction • Preeclampsia Consequences of hyperlipidemia in pregnancy on the child • Intra-uterine growth retardation • Future development of metabolic syndrome in affected fetus • increased risk of cardiovascular disease later in life • Preterm birth • Large for gestational age Vrijkotte TG, et al. Maternal lipid profile during early pregnancy and pregnancy complications and outcomes: the ABCD study. J Clin Endocrinol Metab. 2012 Nov;97(11):3917-25. Clausen T, Djurovic S and Henriksen T. Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia. BJOG. 2001 Oct;108(10):1081-7. Source: Mukherjee M. Dyslipidemia in Pregnancy. http://www.acc.org/latest-in-cardiology/articles/2014/07/18/16/08/dyslipidemia-in-pregnancy. Accessed on 04/27/2016 Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016 Hyperlipidemia in pregnancy
Hyperlipidemia Conclusions • Increased levels of lipids or lipoproteins • Primary/Familial and secondary causes • Fredrickson classification of familial causes of 1968 is still mainly followed • Mainly concerned with cholesterol and triglyceride levels in blood • Genetic mutations in the genes of apolipoprotein or its receptors or lipoprotein lipase is the cause of familial diseases • Secondary causes uncover the primary causes • Pregnancy is, even normally, a hyperlipidemic condition • Primary causes can get uncovered during pregnancy • Hyperlipidemia can complicate pregnancy

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Hyperlipidemia - etiology epidemiology clinical features

  • 1.
    Hyperlipidemia Etiology, epidemiology andclinical features of hyperlipidemia
  • 2.
    • lipoproteins • cholesterol •triglyceride Hyperlipidemia Hyperlipidemia: elevated levels of lipids, i.e. triglycerides and cholesterol in blood Hyperlipoproteinemia: elevated levels of lipoproteins, especially VLDL, IDL and LDL Hypercholesterolemia: elevated levels of cholesterol in blood Hypertriglyceridemia: elevated levels of triglycerides in blood Bays HE, et al. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-S43. Source: GUIDELINES FOR ADOLESCENT NUTRITION SERVICES. Stang J and story M. Chapter 10. Hyperlipidemia. Page 109-124. Adams LB. Http://www.Epi.Umn.Edu/let/pubs/adol_book.Shtm VLDL: very low density lipoprotein IDL: intermediate density lipoprotein LDL: low density lipoprotein
  • 3.
    Jacobson TA, etal. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1—Full Report. J Clin Lipidol. 2015 Mar-Apr;9(2):129-69. Normal serum levels of cholesterol and triglycerides
  • 4.
    Hyper- lipoproteinemia Name of thedisease Increased lipoprotein Increased lipid fraction Type I Hyperchylomicronemia Chylomicrons Triglycerides Type IIa Familial hypercholesterolemia LDL Cholesterol Type IIb Familial combined hypercholesterolemia LDL and VLDL Cholesterol and triglycerides Type III Dysbetalipoprotenemia IDL Triglycerides and cholesterol Type IV Familial hypertriglyceridemia VLDL Triglycerides Type V Familial lipoprotein lipase deficiency VLDL and Chylomicrons Triglycerides and cholesterol Fredrickson classification is still followed Chandra KS, et al. Consensus statement on management of dyslipidemia in Indian subjects. Indian Heart J. 2014 Dec;66 Suppl 3:S1-51. Levy RI, Fredrickson DS. Diagnosis and management of hyperlipoproteinemia. Am J Cardiol 1968;22:576-583. Source: Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull World Health Organ. 1970; 43(6): 891–915.
  • 5.
    Main cause of hypercholesterolemia Primarydisorders Familial hypercholesterolemia Familial combined hyperlipidemia Polygenic hypercholesterolemia Secondary disorders Hyperthyroidism Nephrotic syndrome Dysproteinemias Obstructive liver disease Thiazide diuretics Main cause of hypertriglyceridemia Primary disorders Familial hypertriglyceridemia Familial combined hyperlipidemia Congenital deficiency of lipoprotein lipase Familial dysbetalipoproteinemia Secondary disorders Nephrotic syndrome Dysproteinemias Oral contraceptives Thiazide diuretics Beta-adrenergic blocking agents Alcohol Uncontrolled diabetes mellitus Source: Clinical Methods: The history, physical, and laboratory examination. Chapter 31, Cholesterol, Triglycerides and Associated Lipoproteins. http://www.ncbi.nlm.nih.gov/books/NBK351/#!po=20.8333 Accessed on 04/22/2016 Looking at it at a different angle
  • 6.
    White B. Dietaryfatty acids. Am fam physician. 2009 aug 15;80(4):345-350. Source: harrigan gg, et al. Metabolomics in alcohol research and drug development. Http://pubs.Niaaa.Nih.Gov/publications/arh311/26-35.Htm. Accessed on 04/22/2016 Source: cholesterol esterase. Http://www.Worthington-biochem.Com/cepm/default.Html accessed on 04/22/2016 Source: Overweight & obesity. Http://www.Indiana.Edu/~k562/ob.Html accessed on 04/22/2016 Triglyceride Fatty acid Building blocks Phospholipid Cholesteryl esterCholesterol + Fatty acid =
  • 7.
    Karasinska JM andHayden MR. Cholesterol metabolism in Huntington disease. Nature Reviews Neurology 7, 561-572 (October 2011) Cholesterol synthesis Glucose Pyruvate Amino acid Acetyl CoA Fatty acids Ketone bodies Source of Acetyl CoA Acetyl CoA Acetyl CoA + Source of Acetoacetyl CoA
  • 8.
    Reaches back into liver Smallpercent excreted Walters JR. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol. 2014 Jul;11(7):426-34 Ioannou YA.. Multidrug permeases and subcellular cholesterol transport. Nature Reviews Molecular Cell Biology 2, 657-668 (September 2001) Bile acid synthesis, recirculation and excretion Bile acid circulation
  • 9.
    Chaves VE, etal. Glyceroneogenesis is reduced and glucose uptake is increased in adipose tissue from cafeteria diet-fed rats independently of tissue sympathetic innervation. J Nutr. 2006 Oct;136(10):2475-80. Chen HC and Farese RV Jr. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):482-6. Fung MA and Frohlich JJ. Common problems in the management of hypertriglyceridemia. CMAJ. 2002 November 26; 167(11): 1261–1266. Triglyceride synthesis
  • 10.
    Lipoproteins Ridker PM. LDLcholesterol: controversies and future therapeutic directions. Lancet. 2014 Aug 16;384(9943):607-17.
  • 11.
    Lipoprotein synthesis, transportand recycling Source: Clinical Methods: The history, physical, and laboratory examination. Chapter 31, Cholesterol, Triglycerides and Associated Lipoproteins. http://www.ncbi.nlm.nih.gov/books/NBK351/#!po=20.8333 Accessed on 04/22/2016
  • 12.
    VLDL synthesis D Gruffat,D Durand, B Graulet, D Bauchart. Regulation of VLDL synthesis and secretion in the liver. Reproduction Nutrition Development, EDP Sciences, 1996, 36 (4), pp.375-389. LDL
  • 13.
    Source: Feingold KR,Grunfeld C. Introduction to Lipids and Lipoproteins. [Updated 2015 Jun 10]. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. http://www.ncbi.nlm.nih.gov/books/NBK305896/?report=reader#_NBK305896_pubdet_ Accessed on 04/22/2016 Source: Lipids and lipoproteins: metabolism and its violations. http://intranet.tdmu.edu.ua/data/kafedra/internal/distance/classes_stud/English/2%20course/Elective%20course%20(Modern%20Methods%20of%20Diagnosis)/08.%20Lipids%20and%20lipoproteins%20metabolis%20and%20its%20violatios.htm Accessed on 04/22/2016 Vaverkova H. LDL-C or apoB as the Best Target for Reducing Coronary Heart Disease. Should Apob be Implemented into Clinical Practice? Clin Lipidology. 2011;6(1):35-48. Composition of Lipoproteins
  • 14.
    Rader DJ, HoegJM and Brewer HB Jr. Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med. 1994 Jun 15;120(12):1012-25. Lipoprotein Associated apolipoproteins Chylomicron apoB-48, apoA, apoC, apoE, apoH VLDL apoE, apoB-100, apoC IDL apoE, apoB-100, apoC LDL apoB-100, apoC, apoE HDL apoA-1, apoC, apoD, apoE The apolipoproteins that are in bold are the major apolipoprotein on the particular lipoprotein Lipoprotein synthesis, transport and recycling Major apolipoprotein Function of the apolipoprotein apoA-1 Structural protein - HDL apoB-48 Structural protein - Chylomicron apoB-100 Ligand for binding to LDL receptors Structural protein in VLDL and LDL apoE Ligand for binding to remnant apoE-receptor
  • 15.
    Chylomicron 5% 90% 3% 2% Protein Phospholipid Triglycerides Cholesteroland esters VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters HDL 25% 5% 30% 40% Protein Phospholipid Triglycerides Cholesterol and esters Composition of Lipoproteins Free fatty acids not included in the above diagrams
  • 16.
    Hyper- lipoproteinemia Name of thedisease Increased lipoprotein Increased lipid fraction Type I Hyperchylomicronemia Chylomicrons Triglycerides Type IIa Familial hypercholesterolemia LDL Cholesterol Type IIb Familial combined hypercholesterolemia LDL and VLDL Cholesterol and triglycerides Type III Dysbetalipoprotenemia IDL, chylomicron remnants Triglycerides and cholesterol Type IV Familial hypertriglyceridemia VLDL Triglycerides Type V Familial lipoprotein lipase deficiency VLDL and Chylomicrons Triglycerides and cholesterol Fredrickson classification is still followed Chandra KS, et al. Consensus statement on management of dyslipidemia in Indian subjects. Indian Heart J. 2014 Dec;66 Suppl 3:S1-51. Levy RI, Fredrickson DS. Diagnosis and management of hyperlipoproteinemia. Am J Cardiol 1968;22:576-583. Source: Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull World Health Organ. 1970; 43(6): 891–915.
  • 17.
    Tall AR andYvan-Charvet L. Cholesterol, inflammation and innate immunity. Nature Reviews Immunology 15, 104–116 (2015) Source: LIPOPROTEINS – ROLE IN HEALTH AND DISEASES. Edited by sasa frank and gerhard kostner. Chapter 5. The apob/apoa-i ratio is a strong predictor of cardiovascular risk. Göran walldius. Http://www.Intechopen.Com/books/lipoproteins-role-in-health- and-diseases/the-apob-apoa-i-ratio-is-a-strong-predictor-of-cardiovascular-risk accessed on 04/23/2016 LDL vs HDL
  • 18.
    Jacobson TA, etal. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1—Full Report. J Clin Lipidol. 2015 Mar-Apr;9(2):129-69. Normal serum levels of cholesterol and triglycerides
  • 19.
    Type I Hyperlipoproteinemiaor Hyperchylomicronemia Chylomicron 5% 90% 3% 2% Protein Phospholipid Triglycerides Cholesterol and esters • Inherited condition (1 in 1 million) • Deficiency of lipoprotein lipase or apolipoprotien C-II (a lipase- activating protein) • Thus, inability to remove chylomicrons and triglycerides from blood (i.e. hyperchilomicronemia and hypertriglyceridemia) • Usually presents in childhood with eruptive xanthomata and abdominal colic • Development of lipemia retinalis • Complications include retinal vein occlusion, acute pancreatitis, steatosis and organomegaly (hepatosplenomegaly) Ladizinski B, and Lee KC. Clinical Images: Eruptive xanthomas in a patient with severe hypertriglyceridemia and type 2 diabetes CMAJ 2013;185:1600 George Yuan et al.. Hypertriglyceridemia: its etiology, effects and treatment CMAJ 2007;176:1113-1120 Eruptive xanthomata Lipemic plasma Lipemia retinalis Tuberous xanthomas Palmar crease xanthomas Eruptive xanthomata Merkel M, Eckel RH and Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J. Lipid Res. 2002 43:(12) 1997-2006. Forte TM, Shu X and Ryan RO. The ins (cell) and outs (plasma) of apolipoprotein A-V. J Lipid Res. 2009 Apr;50 Suppl:S150-5.
  • 20.
    Type IIa Hyperlipoproteinemiaor Familial hypercholesterolemia (increased LDL) LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters Homozygous familial hypercholesterolaemia • 1 in 1 000 000 • Life-threatening condition (first decade of life) • Mutations in LDL receptor (LDLR) gene • Parents are heterozygous for the mutations • Markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) Source: Namrata C. Biochemistry for medics. Cholesterol metabolism (Subjective questions Set-4). http://www.namrata.co/cholesterol-metabolism-subjective-questions-set-4/ Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512 Modified from: Harisa GI and Alanazi FK. Low density lipoprotein bionanoparticles: From cholesterol transport to delivery of anti-cancer drugs. Saudi Pharm J. 2014 Dec; 22(6): 504–515. Cont. next slide
  • 21.
    Type IIa Hyperlipoproteinemiaor Familial hypercholesterolemia (increased LDL) • Leading to accelerated and premature atherosclerotic cardiovascular disease • Usually presents as cutaneous xanthomas in feet, hands, elbows, Achilles tendons. • Arcus senilis corneae • Complications are mainly cardiovascular Homozygous familial hypercholesterolaemia Source: Corneal arcus (arcus senilis). Ophthalmic Atlas Images by EyeRounds.org, The University of Iowa http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Arcus/in dex.htm Accessed on 04/25/2016 Goldstein JL, and Brown MS. The LDL Receptor. Arterioscler Thromb Vasc Biol. 2009;29:431-438 Cuch el M, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;eurheartj.ehu274 Source: PEIR Digital Library. HISTOLOGY: CARDIOVASCULAR: VASCULATURE: coronary artery: atherosclerosis: micro low mag hemorrhage into plaque and thrombosis. http://peir.path.uab.edu/library/picture.php?/1964
  • 22.
    Type IIa Hyperlipoproteinemiaor Familial hypercholesterolemia (increased LDL) Heterozygous familial hypercholesterolaemia • 1 in 500 • Treatable life-threatening condition (beyond adolescence) • Heterozygous mutations in the LDLR gene • Autosomal dominant inheritance • Markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) • Clinical features similar to Homozygous condition Yuan G, Wang J and Hegele RA. Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. CMAJ. 2006 Apr 11; 174(8): 1124–1129. Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512 LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters
  • 23.
    Type IIb Hyperlipoproteinemiaor combined hyperlipidemia (increased VLDL and LDL) • 1 in 40 • Autosomal dominant inheritance • But molecular basis is yet to be deciphered • Leads to increased serum Triglycerides and LDL cholesterol • No/rare cutaneous xanthomas • Usually recognized during investigation of cardiovascular or ceribrovascular accident VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters LDL 50% 8% 22% 20% Protein Phospholipid Triglycerides Cholesterol and esters Yuan G, and Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007 Apr 10; 176(8): 1113–1120. Brahm A and Hegele RA. Hypertriglyceridemia. Nutrients. 2013 Mar; 5(3): 981–1001. Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512
  • 24.
    IDL 22% 36% 22% 20% Protein Phospholipid Triglycerides Cholesteroland esters Type III Hyperlipoproteinemia or Dysbetalipoproteinemia (increased IDL) • 1 in 1 million • Mutation in apoE apoprotein has been identified but not in all patients • Autosomal recessive • Not all with the mutation have symptoms • Elevated plasma triglycerides and cholesterol • Manifests earlier in males and usually after menopause in women • When severe: symptoms in first year of life or in young childhood • growth delay, malabsorption, hepatomegaly, and neurological and neuromuscular manifestations, diarrhea with steatorrhea HSPG/LPR: Heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor- related protein (LRP) Mahley WR, Huang Y and Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res. 1999 Nov;40(11):1933-49. Kei A, et al. Dysbetalipoproteinemia: Two cases report and a diagnostic algorithm. World J Clin Cases. 2015 Apr 16;3(4):371-6. Source: Abetalipoproteinemia. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=14 Accessed on 04/25/2016 Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512
  • 25.
    VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesteroland esters Type IV Hyperlipoproteinemia or Familial hypertriglyceridemia (increased VLDL) Levy RI, Fredrickson DS. Diagnosis and management of hyperlipoproteinemia. Am J Cardiol 1968;22:576-583. Fung MA and Frohlich JJ. Common problems in the management of hypertriglyceridemia. CMAJ. 2002 November 26; 167(11): 1261–1266. Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512 • 1 in 100 • Autosomal dominant inheritance • Mutations have been identified in Apolipoprotein C and Lecithin:cholesterol acyltransferase • Clinical features include eruptive xanthomas, lipemia retinalis and hepatosplenomegaly. • May present as acute pancreatitis • Patients are at increased risk of coronary artery disease
  • 26.
    Type V Hyperlipoproteinemiaor Familial lipoprotein lipase deficiency (increased VLDL and Chylomicron) Chylomicron 5% 90% 3% 2% Protein Phospholipid Triglycerides Cholesterol and esters VLDL 20% 60% 15% 5% Protein Phospholipid Triglycerides Cholesterol and esters Brahm A and Hegele RA. Hypertriglyceridemia. Nutrients. 2013 Mar; 5(3): 981–1001 Ghiselli G, et al. Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia. J Clin Invest. 1982 Aug; 70(2): 474–477 Dammerman M and Breslow JL. Genetic Basis of Lipoprotein Disorders Circulation. 1995; 91: 505-512. • 1 in 600 • Mutation in the apoE apolipoprotein • Patients overproduce triglycerides and defective clearance of VLDL • A fat free diet will convert the patients to express a Type IV Hyperlipoproteinemia features • Presents with hepatosplenomegaly, occasional eruptive xanthomas, increased incidence of pancreatitis
  • 27.
    Secondary hyperlipidemia • Usuallya “two hit phenomenon” is noticed o “First hit” is the genetic predisposition o “Second hit” are the secondary factors, which worsen lipid levels Bays HE, et al. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-S43. Source: GUIDELINES FOR ADOLESCENT NUTRITION SERVICES. Stang J and story M. Chapter 10. Hyperlipidemia. Page 109-124. Adams LB. Http://www.Epi.Umn.Edu/let/pubs/adol_book.Shtm
  • 28.
    • Secondary causesof hyperlipidemia: metabolic syndrome, insulin resistance, limited physical activity, cigarette smoking, substantial alcohol consumption, pregnancy, anorexia narvosa, corticosteroid therapy. • Endocrine diseases: inadequately controlled diabetes mellitus, untreated hypothyroidism, polycystic ovarian syndrome. • Kidney disease: chronic kidney disease, nephrotic syndrome. • Liver disease: hepatitis with fatty liver, cholestasis, biliary cirrhosis, primary sclerosing cholangitis. • Pancreatic disease: acute pancreatitis. • Infections: HIV infection especially when on highly active anti-retroviral therapy. • Inflammatory diseases: systemic lupus erythematosus, rheumatoid arthritis. • Storage diseases: glycogen storage disease, Gaucher’s disease, juvenile Tay-Sachs disease, Niemann-Pick disease. • Others: idiopathic hypercalcemia, Klinefelter syndrome, Kawasakis disease, acute intermittent prophyria. Secondary hyperlipidemia Source: GUIDELINES FOR ADOLESCENT NUTRITION SERVICES. Stang J and story M. Chapter 10. Hyperlipidemia. Page 109-124. Adams LB. Http://www.Epi.Umn.Edu/let/pubs/adol_book.Shtm Bays HE, et al. National Lipid Association Annual Summary of Clinical Lipidology 2016. J Clin Lipidol. 2016 Jan-Feb;10(1 Suppl):S1-S43.
  • 29.
    Hyperlipidemia in pregnancy Innormal pregnancy • Maternal hyperlipidemia is normal during pregnancy • Especially in the third trimester • Mainly triglycerides (TAG) and to a lesser extent cholesterol and phospholipids • Increased VLDL production and decreased removal • Increased levels of TAG in LDL and HDL • The above is assisted by the insulin-resistant state in pregnancy Source: Metabolism in normal pregnancy. Herrera E and Ortega H. In Textbook of Diabetes and Pregnancy”, second ed. , M.Hod, L.Jovanovich, G.C.Di Renzo, A. De Leiva, O. Langer, eds., Informa healthcare, London, pgs. 25-34, 2008. http://dspace.ceu.es/bitstream/10637/2873/1/pag25_34.pdf Accessed on 04/27/2016 Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016
  • 30.
    Lipid and lipoprotein (mg/dl) Thirdtrimester Non-pregnant controls HDL-C 81±17 69±10 LDL-C 136±33 99±23 TGs 245±73 77±34 TC 267±30 183±23 VLDL 109 (38-710) 23 (5-85) IDL 124(79-157) 35(18-62) LDL 353(244-534) 207(150-363) In normal pregnancy Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016 Hyperlipidemia in pregnancy
  • 31.
    Source: Lipoproteins –The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016 Medical complications of pregnancy Pre-eclampsia, Pregnancy-induced hypertension Gestational diabetes mellitus, Prelipaemia Intra-uterine growth restriction(retardation) Co-existing medical conditions Obesity, Types 1 and 2 diabetes mellitus Hypothyroidism, Hypertension Renal diseases, particularly nephritic syndrome Others Alcoholism, Medications, eg LMWt-heparin and glucocorticoid Other maternal factors Obesity, Maternal weight gain, Maternal nutrition, Pre-pregnancy lipid levels Hyperlipidemia in pregnancy
  • 32.
    Consequences Consequences of hyperlipidemiain pregnancy on the mother • Cholesterol gallstones • Intrahepatic cholestasis • Acute pancreatitis • Endothelial dysfunction • Preeclampsia Consequences of hyperlipidemia in pregnancy on the child • Intra-uterine growth retardation • Future development of metabolic syndrome in affected fetus • increased risk of cardiovascular disease later in life • Preterm birth • Large for gestational age Vrijkotte TG, et al. Maternal lipid profile during early pregnancy and pregnancy complications and outcomes: the ABCD study. J Clin Endocrinol Metab. 2012 Nov;97(11):3917-25. Clausen T, Djurovic S and Henriksen T. Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia. BJOG. 2001 Oct;108(10):1081-7. Source: Mukherjee M. Dyslipidemia in Pregnancy. http://www.acc.org/latest-in-cardiology/articles/2014/07/18/16/08/dyslipidemia-in-pregnancy. Accessed on 04/27/2016 Source: Lipoproteins – The Importance of Lipid and Lipoprote in Ratios in Interpretetions of Hyperlipidaemia of Pregnancy. Meshelia DS and Kullima AA. Role in health and disease. Biochemistry, Genetics and Molecular Biology. Frank S and Kostner G. http://www.intechopen.com/books/lipoproteins-role-in-health-and-diseases/the-importance-of-lipid-and-lipoprote-in-ratios-in-interpretetions-of-hyperlipidaemia-of-pregnancy Accessed on 04/27/2016 Hyperlipidemia in pregnancy
  • 33.
    Hyperlipidemia Conclusions • Increased levelsof lipids or lipoproteins • Primary/Familial and secondary causes • Fredrickson classification of familial causes of 1968 is still mainly followed • Mainly concerned with cholesterol and triglyceride levels in blood • Genetic mutations in the genes of apolipoprotein or its receptors or lipoprotein lipase is the cause of familial diseases • Secondary causes uncover the primary causes • Pregnancy is, even normally, a hyperlipidemic condition • Primary causes can get uncovered during pregnancy • Hyperlipidemia can complicate pregnancy

Editor's Notes

  • #5 The above classification system has two main deficiencies. Firstly, it is incomplete since it does not include more recently discovered genetic disorders which are discussed later under the group captioned “Non-Fredrickson inherited lipid diseases”. Secondly, many patients with hypertrigly-ceridemia can be either Type I, IIb, IV or V. Thirdly, it does not include HDL-C and it does not differentiate severe monogenic disorders from more common polygenic disorders. The Fredrickson classification strictly applies to type I (Hyperchylomicronemia) and type IIa (Familial hypercholesterolemia) disorders. For other Fredrickson subtypes, serum profile of a single patient can move from one category to another depending on environmental factors or treatment, as the extent of enzymatic activity can increase or decrease depending on the clinical milieu.
  • #17 The above classification system has two main deficiencies. Firstly, it is incomplete since it does not include more recently discovered genetic disorders which are discussed later under the group captioned “Non-Fredrickson inherited lipid diseases”. Secondly, many patients with hypertrigly-ceridemia can be either Type I, IIb, IV or V. Thirdly, it does not include HDL-C and it does not differentiate severe monogenic disorders from more common polygenic disorders. The Fredrickson classification strictly applies to type I (Hyperchylomicronemia) and type IIa (Familial hypercholesterolemia) disorders. For other Fredrickson subtypes, serum profile of a single patient can move from one category to another depending on environmental factors or treatment, as the extent of enzymatic activity can increase or decrease depending on the clinical milieu.
  • #20 LPL: LPL-mediated tissue-uptake of lipids. LPL appears to mediate uptake of both lipolyzed lipids (fatty acids [FAs]) and core lipids, such as triglycerides (TGs), cholesteryl ester, and retinyl esters. A: Several pathways allow organ uptake of lipids. FA associated with albumin can cross the endothelial barrier. Lipolysis of VLDL or chylomicrons (CMs) releases FA. In addition, as is known to occur for transfer of lip- ids and apolipoproteins from TG-rich lipoprotein to HDL, surface lipid, apolipoproteins, and some core lipids may dissociate from the par- ticle as a complex (lipolysis product). B: Although lipolysis of nascent TG-rich lipoproteins probably requires initial hydrolysis within the cir- culation, lipolysis may continue within the subendothelial space either because the smaller lipoproteins are able to cross the capillar y endothelial barrier or because the barrier is “leaky.” Lipolysis itself will cause capillary leakage. LPL, present on the surface of parenchymal cells such as adipocytes and myocytes, could interact with these particles. Apolipoprotein C: Postulated extracellular effects of apoA-V on TG-rich lipoprotein metabolism. ApoA-V interaction with HSPGs can facilitate apoC-II activation of LPL, resulting in accelerated TG hydrolysis. Catabolism of TG-rich lipoproteins [VLDL and chylomicrons (CM)] to a remnant particle may result in apoA-V dissociation from TG-rich particles and transfer to plasma HDL, where it remains poised to exchange onto nascent plasma TG-rich lipoproteins. ApoA-V binding to GPIHBP1 could facilitate hydrolysis of TG in CM. It has been proposed that the GPIHBP1 protein forms a homodimer whose negatively charged domains bind LPL and apoA-V, leading to efficient lipolytic processing of CM (45). ApoA-V interaction with LDLR family mem- bers could facilitate endocytosis of remnant lipoproteins. Solid arrows represent the path of lipoprotein particles; dashed arrows represent the path of apoA-V. Adapted from Wong and Ryan (46) with permission.
  • #21 Cutaneous and tuberous xanthomas in homozygous familial hypercholesterolaemia. Interdigital xanthomas (see B, yellow arrows) in children are highly suggestive of homozygous familial hypercholesterolaemia diagnosis. Photograph (A) kindly provided by Prof. Eric Bruckert. Photograph (B) kindly supplied by Prof. Frederick Raal.