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Massive Hypertriglyceridaemia: A complete white-out, O. B OxLDL IDL B E CIII VLDL B E CIII -100 LPL B LDL HL FC AI AII INTESTINE B Chylomicrons CII -48.

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Presentation on theme: "Massive Hypertriglyceridaemia: A complete white-out, O. B OxLDL IDL B E CIII VLDL B E CIII -100 LPL B LDL HL FC AI AII INTESTINE B Chylomicrons CII -48."— Presentation transcript:

1 Massive Hypertriglyceridaemia: A complete white-out, O. B OxLDL IDL B E CIII VLDL B E CIII -100 LPL B LDL HL FC AI AII INTESTINE B Chylomicrons CII -48 AI LIVER LDL-R LRP Macrophage Lox-1 CD-36 SR-A SR-PSOX ABCA1 SR- B1 CE+FC CE TG CETP AI AII E HDL LCAT FCFC CE Othertissues LPL R E B CII FC LCAT FC CE DAVIGNON 2006

2 Metabolic Relationships Among Lipoproteins LDL 1. 3. 2. Lipoprotein Lipase` TG HDL VLDL  TRIGLYCERIDES  HDL SMALL DENSE LDL

3 Chylomicrons and their remnants may be less likely to cause atherosclerosis (smaller numbers and larger size)

4 FATTY ACIDS (ALBUMIN) TG (VLDL) TG (CHYLO-MICRONS) LIPO- PROTEIN LIPASE Fatty Acid and Triglyceride Flux

5 Pancreatic Lipase Movement Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries. Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

6 Chylomicron Role in Pancreatitis Pancreatic lipase acts on chylomicrons adherent to capillary endothelium, producing fatty acid anions, or soaps. By detergent action, cell membranes are disrupted, releasing more lipase, and additional fatty acid anions are produced in a vicious cycle. Pancreatic lipase acts on chylomicrons adherent to capillary endothelium, producing fatty acid anions, or soaps. By detergent action, cell membranes are disrupted, releasing more lipase, and additional fatty acid anions are produced in a vicious cycle.

7 Dietary management of lipoprotein lipase deficiency: Avoid dietary fat, except MCT’s and marine oil n-3 fatty acids

8 Other treatment options in lipoprotein lipase deficiency Fibrates and marine oil n-3 fatty acids: limitation of gene response Avoid insulin deficiency: Cofactor for lipoprotein lipase Temporary effect of plasmapheresis Temporary effect of plasma transfusion in apo C2 (cofactor) deficiency ? Xenical Future: DGAT1 inhibitors ?Gene therapy

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10 ■ Normal ■ Hypoalpha- lipoproteinemia ■ Complete (FHC) or partial LPL deficiency associated with a secondary factor ■ Complete LPL deficiency (FHC) ■ Primary apoC- II deficiency ■ Familial dysbeta- lipoproteinemia (type III) ■ Hepatic lipase deficiency ■ (Primary cause associated with a secondary factor) Apo B > 0.75 g/L Apo B < 0.75 g/L TC:Apo B > 6.2 TC:Apo B < 6.2 ■ Familial hyperTG ■ Partial LPL deficiency ■ FH ■ Polygenic ■ FDB ■ PCSK9 deficiency ■ ARH deficiency ■ CYP7A1 deficiency ■ Hypoalphalipo- proteinemia ■ FCH ■ β- Sitosterolemia NormalChylo + VLDLChylo Chylo + VLDL Remnants VLDLLDLVLDL + LDL NormoTG < 1.5 mmol/L TG:Apo B > 0.12 NormoApo B < 1.2 g/L TG:Apo B < 0.12 HyperTG > 1.5 mmol/L NomoTG > 1.5 mmol/L HyperApo B > 1.2 g/L Hyper TG > 1.5 mmol/L Primary Causes Algorithm for Diagnosis of Apo B Dyslipoproteinemias Abbreviations: apo, apolipoprotein; ARH, autosomal recessive hypercholesterolemia; CAPD, continuous ambulatory peritoneal dialysis; Chylo, chylomicrons; CP7A1, cytochrome P450 7A1; DM2, diabetes mellitus type 2; dysbeta; dysbetalipoproteinemia; FCH, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHC, familial hyperchylomicronemia; HAART, highly active antiretroviral therapy; LPL, lipoprotein lipase; PCOS, polycystic ovary syndrome; SLE, systemic lupus erythematosus; TC, total cholesterol; TG, triglyceride. de Graaf J et al. Nat Clin Pract Endocrinol Metab 2008;4:608- 18. Lipoproteins

11 Nordestgaard BG, et al. JAMA. 2007;298(3):299-308 Relationship of Non-Fasting Triglycerides and Cardiovascular Risk Copenhagen City Heart Study(7587 women and 6394 men)

12 Bansal S, et al. JAMA. 2007;298(3):309-316 Relationship of Non-Fasting Triglycerides and Cardiovascular Risk Womens Health Study (n= 26,509)

13 Nordestgaard BG, et al. JAMA. 2007;298(3):299-308 Relationship of Non-Fasting Triglycerides and Cardiovascular Risk Copenhagen City Heart Study(7587 women and 6394 men)

14 Rx and response Fibrates and marine oil n-3 fatty acids: greater prospect of gene upregulation Niacin: greater prospect of gene upregulation Avoid insulin deficiency: Cofactor for lipoprotein lipase Temporary effect of plasmapheresis ? Xenical Future: DGAT1 inhibitors

15 COOH C20:5 ω -3 Eicosapentaenoic (EPA) H3CH3C Essential Fatty Acid Families C18:3 ω -3 ω -3 family -Linolenic Flaxseed Oil Canola Oil Soybean Oil C22:6 ω -3 Docosahexaenoic (DHA) COOH H3CH3C Oily Fish Fish Oil Capsules H3CH3C COOH ω -6 family C20:4 ω -6 C18:2 ω -6 Linoleic Arachidonic H3CH3C COOH More thrombotic and inflammatory metabolites Corn Oil Safflower Oil Sunflower Oil Less thrombotic and inflammatory metabolites H3CH3C COOH

16 What happens in the food chain?:  Starting materials  Modification by herbivores  Accumulation by carnivores

17 Essential Fatty Acid Contrasts: Position of 1st double bond N-6 : Greater availability in diet Greater availability in membranes. Main substrate for PG & LT Typical inflammatory response N-3: Lower availability, so lesser substrate for PG & LT Highest potential number of double bonds. Less inflammatory response

18 Essential Fatty Acid Contrasts: Chain length N-3 < 20C (Plant): Too short for membrane Phosphlipid Full effect as anti- arrhythmic No effect on TG No effect on platelet adhesion Effective precursor N-3 > C20 (Marine) Suitable for membrane Phospholipid Strongly anti- arrhythmic Reduce TG synthesis and decrease TG by about 50% Reduce platelet adhesion.

19 Postprandial Lipoproteins affect FMD after Oral Fat Load Franco M et al. J Clin Endo & Metab 2004;89:2946-2950 0h 2h 4h 6h8h 0h 2h 4h 6h8h 0h 2h 4h 6h8h 2 3 4 5 6 7 10 12 14 16 18 0.4 0.7 0.8 0.9 1.0 0.6 0.5 mmol/L % Dilation mmol/L FMD Remnant-C Triglycerides TG & RLP-C increased significantly and continuously up to 4 & 6 hours respectively FMD revealed decreased vasodilation at 4-6 hours Results vary, but postprandial events, including secretion of chylomicrons, exert strong effects on vascular function

20 Summary and link to cases

21 Mrs N.S. This 36 year old woman has not been able to conceive. She gained a large amount of weight (BMI 38) when she stopped smoking in her mid 20’s. Unfortunately she resumed smoking in her early 30’s without any change in weight. Alcohol intake is less that 30 gms / week. Two years ago she became diabetic and now requires insulin to maintain HB A1C < 7.5%. Even then, associated lipid levels include triglyceride of 38 mmol/l, but she has not suffered pancreatitis.

22 Questions concerning Mrs N.S. What priority do you place on cessation of smoking in this case? High / Low Your preferred strategy to achieve weight loss involves the use of A) XenicalB) Meal replacementC) gastric bypassD) Metformin If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate intervention would include: A) Nil by mouth B) Consideration of plasmapheresis, C) Commencement of statin therapy D) Reduction in Insulin dose E) All of the above

23 What priority do you place on cessation of smoking in this case? High / Low Your preferred strategy to achieve weight loss involves the use of A) XenicalB) Meal replacementC) gastric bypass D) Metformin If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate intervention would include: A) Nil by mouth B) Consideration of plasmapheresis, C) Commencement of statin therapy D) Reduction in Insulin dose E) All of the above This 36 year old woman has not been able to conceive. She gained a large amount of weight (BMI 38) when she stopped smoking in her mid 20’s. Unfortunately she resumed smoking in her early 30’s without any change in weight. Alcohol intake is less that 30 gms / week. Two years ago she became diabetic and now requires insulin to maintain HB A1C < 7.5%. Even then, associated lipid levels include triglyceride of 38 mmol/l, but she has not suffered pancreatitis.

24 What priority do you place on cessation of smoking in this case? High Low

25 What priority do you place on cessation of smoking in this case? A vexed problem. Theoretical reasons for “high”

26 Your preferred strategy to achieve weight loss involves the use of... A) Xenical B) Meal replacement C) gastric bypass D) Metformin

27 Your preferred strategy to achieve weight loss involves the use of... Pro’s and con’s of each

28 If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate intervention would include A) Nil by mouth B) Consideration of plasmapheresis, C) Commencement of statin therapy D) Reduction in Insulin dose E) All of the above

29 If symptoms suggested the onset of an attack of pancreatitis, appropriate immediate intervention would include... Pattern of the problem (a case for “A”)

30 Mrs N.S. Although advice about diet and smoking fails to alter weight or glycaemic control, your introduction of fenofibrate and fish oil reduces TG to 17 mmol/l. Mrs N.S. desperate to start a family and is actively pursuing IVF. Is the decline in TG to 17 mmol/l sufficient to eliminate the risk of acute pancreatitis? Yes / No Do reproductive hormones like oestrogen and progesterone, IVF therapies or pregnancy itself affect triglyceride levels or risk of pancreatitis? Yes / No Would you continue fenofibrate? Yes / No Your estimate on Mrs N.S’s risk of a cardiovascular event is: A) Low now and in the future B) Low now, but high in the future C) High, even now.

31 Is the decline in TG to 17 mmol/l sufficient to eliminate the risk of acute pancreatitis? Yes No

32 Is the decline in TG to 17 mmol/l sufficient to eliminate the risk of acute pancreatitis? The case for “no” TG in mg% For mmol/l Divide by 90

33 Do reproductive hormones like oestrogen and progesterone, IVF therapies or pregnancy itself affect triglyceride levels or the risk of pancreatitis? Yes No

34 Do reproductive hormones like oestrogen and progesterone, IVF therapies or pregnancy itself affect triglyceride levels? The case for “yes” Obstet Gynecol.Obstet Gynecol. 1993 May;81(5 ( Pt 2)):890-2. Recurrent pancreatitis associated with in vitro fertilization. Steinmetz OKSteinmetz OK, Hashim E, Falcone T, Hemmings R, Bourque J.Hashim EFalcone THemmings RBourque J BACKGROUND: We report the possible association between in vitro fertilization (IVF) and recurrent acute pancreatitis. CASE: A patient developed acute pancreatitis during each of two cycles of IVF. On a spontaneous cycle, serum triglycerides were as follows: early follicular phase 2.34 mmol/L, mid-follicular phase 4.17 mmol/L, and late follicular phase 6.6 mmol/L. During an episode of acute pancreatitis, the serum triglyceride level was 38.45 mmol/L. CONCLUSION: Acute pancreatitis may occur in patients with a family or personal history of hypertriglyceridemia who are candidates for IVF.

35 Would you continue fenofibrate? Yes No

36 Would you continue fenofibrate? Uncertain teratogenicity versus manifest risk. Pregnancy: Teratogenic Effects, Pregnancy Category C Safety in pregant women has not been established. Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose (MRHD) and embryocidal in rabbits when given at 9 times the MRHD (on the basis of mg/meter2 surface area). There are no adequate and well-controlled studies in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

37 Your estimate on Mrs N.S’s risk of a cardiovascular event is: A) Low now and in the future B) Low now, but high in the future C) High, even now.

38 Your estimate on Mrs N.S’s risk of a cardiovascular event is: The tentative case for “C”

39 Mr G.T. Mr G.T. is 32 years old. He is Chinese and he consumes an Asian diet. He is not overweight, but his business and social obligations involve occasional Asian banquets. He rarely drinks more than 20 gms alcohol per week. He suffered occasional episodes of abdominal pain in adolescence and early adulthood, and recently he was admitted to an intensive care unit with his first episode of acute pancreatitis. Fasting plasma lipids included plasma triglyceride level of 56 mmol/l but plasma glucose is within normal limits.

40 Questions concerning Mr G.T. What physical findings might accompany an episode of this severity?(More than 1 possible) A) Tendon XanthomasB) Lipaemia Retinalis C) Tuberous XanthomasD) Eruptive Xanthomas E) Corneal Arcus How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? A) Plasma LPL massB) Plasma LPL activityC) Plasma LPL activity after a heparin bolusD) Protein iso-electric focussing for Apo C3E) Genetic testing What diet advice would you give on discharge? A) Low fat diet 15 gms) D) All of the aboveE) Low fat diet < 25% energy

41 Mr G.T. is 32 years old. He is Chinese and he consumes an Asian diet. He is not overweight, but his business and social obligations involve occasional Asian banquets. He rarely drinks more than 20 gms alcohol per week. He suffered occasional episodes of abdominal pain in adolescence and early adulthood, and recently he was admitted to an intensive care unit with his first episode of acute pancreatitis. Fasting plasma lipids included plasma triglyceride level of 56 mmol/l but plasma glucose is within normal limits. What physical findings might accompany an episode of this severity?(More than 1 possible) A) Tendon XanthomasB) Lipaemia Retinalis C) Tuberous XanthomasD) Eruptive Xanthomas E) Corneal Arcus How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? A) Plasma LPL massB) Plasma LPL activityC) Plasma LPL activity after a heparin bolusD) Protein iso-electric focussing for Apo C3E) Genetic testing What diet advice would you give on discharge? A) Low fat diet 15 gms) D) All of the aboveE) Low fat diet < 25% energy

42 What physical findings might accompany an episode of this severity? (More than 1 possible) A) Tendon Xanthomas B) Lipaemia Retinalis C) Tuberous Xanthomas D) Eruptive Xanthomas E) Corneal Arcus

43 What physical findings might accompany an episode of this severity? (More than 1 possible) The case for “B” and “D”

44 How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? A) Plasma LPL mass B) Plasma LPL activity C) Plasma LPL activity after a heparin bolus D) Protein iso-electric focussing for Apo C3 E) Genetic testing

45 How would you investigate the possibility of lipoprotein lipase (LPL) deficiency? The case for “C”, but “E” is becoming possible

46 What diet advice would you give Mr G.T. on discharge? A) Low fat diet < 10% energy B) Medium chain triglycerides to minimize carbohydrate C) Extra fish oil (>10 gms/day) D) All of the above E) Low fat diet < 25% energy

47 What diet advice would you give Mr G.T. on discharge? The case for “D”, but the dilemma re CHO

48 More questions about Mr G.T. Despite your dietary advice, Mr G.T. suffers a recurrence of pancreatitis 5 months later. When massive hypertriglyceridaemia is present, which of the following symptoms may occur?A) Risk of pancreatitis, Abdominal pain, hepatosplenomegalyB) ConfusionC) Peripheral paresthesias D) Dyspnea E) All of the above If lipoprotein lipase deficiency is confirmed, what treatment options would you suggest?A) Continuation of current dietB) Gene therapy C) Total pancreatectomy plus pancreatic transplant D) Biliary diversion E) Plasmapheresis

49 When massive hypertriglyceridaemia is present, which of the following symptoms may occur? A) Risk of pancreatitis, Abdominal pain, hepatosplenomegaly B) Confusion C) Peripheral paresthesias D) Dyspnea E) All of the above

50 When massive hypertriglyceridaemia is present, which of the following symptoms may occur? The case for “E”. Accumulated case reports, eg “He reported recurrent headaches and dizziness with lightheaddedness and vertigo independently of alcohol consumption. These symptoms were accompanied by mood disturbances including dysphoria and depression. Neurologic examination was normal.

51 If lipoprotein lipase deficiency is confirmed, what treatment options would you suggest? A) Continuation of current diet B) Gene therapy C) Total pancreatectomy plus pancreatic transplant D) Biliary diversion E) Plasmapheresis

52 If lipoprotein lipase deficiency is confirmed, what treatment options would you suggest? The case for “A”


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