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37 Year Old Female with Dyslipidemia and Abnormal Sterol Testing

This case study follows a 37-year-old female with a history of dyslipidemia, abnormal sterol testing, and familial hypercholesterolemia, managing her condition with medication and lifestyle changes.

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37 Year Old Female with Dyslipidemia and Abnormal Sterol Testing

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  1. 37 Year Old Female with Dyslipidemia and Abnormal Sterol Testing Case Categories Primary Prevention Secondary Prevention Pediatric Case Familial Hypertriglyceridemia Diabetes Metabolic Syndrome Low HDL Familial Combined Hyperlipidemia Familial Hypercholesterolemia Elevated Lipoprotein (a) Statin Intolerance Case category: Familial Hyperlipidemia History of present illness: 37 year old female with history of dyslipidemia and abnormal sterol testing. She also has a family history of heart disease. She is currently on Pravachol 40 mg and also taking Lovaza 4 g/day for arthritis. Previously on Niaspan for dyslipidemia prior to childbearing. Prior to this visit her LDL-P was high at 1326 as well as her Apo B at 120. She is here for follow-up.

  2. Patient Information

  3. Patient History

  4. Current Medications

  5. Labs Worth Noting on Pravachol 40 and Lovaza 4

  6. Questions to Consider • Question 1: Is she currently taking any hormone therapy supplements? This impacts lipoproteins. She is on a statin which would be contraindicated if planning to become pregnant. • Question 2: Always address diet and exercise and motivation to make more changes. Her HbA1C is very low which may suggest underlying insulin resistance to which a low carb diet may be more beneficial.

  7. Labs on Pravachol 40 and Lovaza 4 (1 of 6) HDL-C is high but we don’t know if it is functional or not. This should not be considered an automatic “negative” risk factor. Myeloperoxidase (MPO) may provide a window into dysfunctional HDL. HDL-P (measured by NMR) is more predictive of risk than HDL-Cholesterol and HDL-P was below optimal (next slide).

  8. Labs on Pravachol 40 and Lovaza 4 (2 of 6) Elevated CRP is an independent predictor of risk however it is nonspecific. It’s reassuring LpPLA2 which is a more vascular specific inflammatory marker is normal.

  9. Labs on Pravachol 40 and Lovaza 4 (3 of 6) Hypoglycemia may be autoimmune or insulin resistance. Ask about symptoms.

  10. Labs on Pravachol 40 and Lovaza 4 (4 of 6) On statin, she is showing evidence of hyperabsorption which is a common occurrence when on statins for a long time. She may be a candidate for Zetia, Bile acid sequestrant or Benecol (stanol) supplement.

  11. Labs on Pravachol 40 and Lovaza 4 (5 of 6) Ask about alcohol use with elevated AST. Typically ALT is more elevated in fatty liver disease.

  12. Labs on Pravachol 40 and Lovaza 4 (6 of 6) Good marker of compliance with Lovaza 4/day. Appears as though she is taking therapy as prescribed as omega 3 index is optimal.

  13. NMR LipoProfile • Insert NMR Lipoprofile 010312 SM74 Insert

  14. Initial Treatment & Management • Continue taking Pravachol 40 mg/day to lower LDL-P. • Start Zetia 10 mg/day to address hyperabsorption as noted on sterol testing. • AVOID all PHYTOSTEROL supplements. • Continue Lovaza 4 g/day for anti-inflammatory benefit. • Increase vitamin D3 to 3000-4000 IU/day for low vitamin D.

  15. Discussion (1 of 2)

  16. Discussion (2 of 2)

  17. Follow Up on Pravachol 40, Zetia 10 and Lovaza 4 • Familial Hyperlipidemia – Improved. • Currently taking Pravachol 40 and Lovaza 4. Added Zetia 10 last visit due to evidence of hyperabsorption. • LDL-P lowered from 1452 to 1091. Apo B lowered from 91 to 72, but still high. Total cholesterol lowered from 223 to 163. LDL-C reduced to 79 from 127. HDL decreased from 75 to 62. Triglycerides are normal at 52. • Sterol testing remains abnormal, but improved. • Continue therapy. • Elevated CRP – Improved • Currently taking Lovaza 4. • CRP lowered from 5.6 to 2.4. • Continue therapy. • Vitamin D Deficiency – Improved. • Currently taking vitamin D3 2000. • Levels increased from 43 to 56. • Continue supplements.

  18. Labs on Pravachol 40, Zetia 10 and Lovaza 4 (1 of 5)

  19. Labs on Pravachol 40, Zetia 10 and Lovaza 4 (2 of 5)

  20. Labs on Pravachol 40, Zetia 10 and Lovaza 4 (3 of 5) Sterol absorption has decreased from previously, when not on Zetia, but still high. It’s very important to avoid supplemental PHYTOSTEROLS. Check all labels for this. Phytosterols can be found in some Co Q 10 supplements, some orange juice or vitamins etc. She over absorbs sterols which may be much more toxic than her own endogenously produced cholesterol.

  21. Labs on Pravachol 40, Zetia 10 and Lovaza 4 (4 of 5)

  22. Labs on Pravachol 40, Zetia 10 and Lovaza 4 (5 of 5)

  23. NMR LipoProfile • Insert NMR Lipoprofile 022812 SM74 Insert

  24. Case Summary

  25. Clinical Pearls • Understand the significance of inverse relationship between synthesis and absorption markers. Understand the effects of medications on absorption. Statins and niacin both can lead to hyperabsorption. • If there is no evidence of hyperabsorption Zetia may have less of a role in treatment. • Clinically it may be most appropriate to use these intestinally acting agents in those patients that are shown to be hyperabsorbers as we saw here.

  26. Principles of Sterol Testing (1 of 3) • Markers of absorption and synthesis are reported as absolute values and as ratios adjusted for cholesterol. They have the same meaning. Some believe the ratios are best used if the patient is on a cholesterol lowering drug. • Absorption markers are sitosteroland campesterolwhich are phytosterols and cholestanol, a metabolite of cholesterol found in some dietary products. • The synthesis marker is desmosterol. • As a very general rule, typically hyperabsorbers tend to be hyposynthesizers and vice versa. Hypoabsorption is desirable and requires no treatment per se. • The pattern associated with the most risk is hyperabsorption with hyposynthesis. • Statins decrease synthesis and may increase absorption. • Ezetimibe, fibrates and sitostanol (Benecol) reduce absorption.

  27. Reporting Plasma Sterol Concentrations Normal Hyper Absorption Marker Hypo 2.1 - 4.4 Campesterol (µg/mL) > 4.43 < 2.11 Campesterol ratio 102 mmol/mol cholesterol 114.5 - 239.7 > 239.7 < 114.5 1.43- 3.17 Sitosterol (µg/mL) > 3.17 < 1.43 Sitosterol ratio 102 mmol/mol cholesterol < 75.8 > 167.8 75.8 - 167.8 STEROLS > 3.4 2.0 - 3.4 Cholestanol (µg/mL) < 2.0 Cholestanol ratio 102 mmol/mol cholesterol > 194.2 116.8 - 194.2 < 116.8 Hypo Hyper Normal Synthesis Marker 0.5 - 1.27 < 0.5 Desmosterol (µg/mL) > 1.27 Desmosterol ratio 102 mmol/mol cholesterol 31.0 - 64.4 < 31.2 > 64.4 Based on quintile cut-points from 500 patients Unless campesterol or sitosterol are in the ranges seen with phytosterolemic patients (100-300 µg/mL) one cannot state with assurance the phytosterols are causal of atherosclerosis

  28. Principles of Sterol Testing (2 of 3) • The disease phytosterolemia is very rare and the sitosterol, campesterol levels will be in the 100-300 µg/mL range. • Although elevations of phytosterols are associated with CV risk, one cannot state with assurance that phytosterols are causal of atherosclerosis. • Phytosterols used as nutritional supplements will increase phytosterol levels in hyperabsorbers and should be avoided in those situations. • Phytostanols such as sitostanol (Benecol) cannot be absorbed to any appreciable degree and can be used in patients with hyperabsorption of sterols. • When LDL-P (apo B) are elevated in the face of normal sterol values, there is a problem with overproduction (typically related to TG abnormalities) or decreased clearance of apo B particles (LDL receptor issues, defective apo B, PCSK9 gain of function issues)

  29. Principles of Sterol Testing (3 of 3) • With respect to treatment decisions in persons with sterol synthesis/absorption abnormalities, pay attention to the following: • Unless phytosterolemia is present or the patient is in the very high risk category, LDL-P (Apo B) is the goal of therapy, not the sterol level per se. • The overall risk of the patient: The higher the risk, the more aggressive LDL-P (Apo B) goal of therapy. • After lifestyle, unless TGs are > 500 mg/dL, statins are always the first line of LDL-P lowering therapy. If hyperabsorption is present in the face of elevated LDL-P, statin/ezetimibe is the preferred therapy. • Follow the algorithm on therapeutic considerations with abnormal sterol levels who have normal LDL-P.

  30. Absorption Markers Increased Adds to CV risk Synthesis Markers Normal LDL-P ↑ LDL-P WNL High or Moderate Risk Patient Low Risk Patient On Lipid Medication? Yes No Yes No On Statin ? On Statin* ? Consider sitostanol Start low or moderate dose statin plus ezetimibe Maintain or reduce statin dose or switch to a less potent statin and add ezetimibe Reduce statin and add Ezetimibe *High dose atorvastatin seems to be have the most potential to increase sterol hyprabsortpion

  31. References (1 of 2) Familial Hyperlipidemia • Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008 Apr;31(4):811-22. • Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham offspring study – implications for LDL management. J ClinLipidol. 2007 Dec;1(6):583-92. • Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007 May;192(1):211-7. • El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am CollCardiol. 2007 Feb 6;49(5):547-53. • Khera AV, Cuchel M, de la Llera-MoyaM,et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011 Jan 13;364(2):127-35. • Besler C, Heinrich K, Rohrer L, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest. 2011 Jul;121(7):2693-708. • Ansell BJ, Fonarow GC, Fogelman AM. The paradox of dysfunctional high-density lipoprotein. CurrOpinLipidol. 2007 Aug;18(4):427-34. • Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999 Aug 7;354(9177):447-55. • Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002 Oct 8;106(15):1943-8.

  32. References (2 of 2) Elevated CRP • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421. • Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000 Mar 23;342(12):836-43. Vitamin D Deficiency • Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168(12):1340-1349. • Giovannucci E, Liu Y, Hollis B, Rimm E. 25-hydroxyvitamin d and risk of myocardial infarction in men. Arch Intern Med. 2008;168(11):1174-1180. • Michos E and Blumenthal R. Vitamin D Supplementation and Cardiovascular Disease Risk. Circulation. 2007;115(7):827-828. • Hathcock J, Shao A, Vieth R, et al. Risk assessment for vitamin D. Am J ClinNutr. 2007;85:6-18. • Holick M. Vitamin D Deficiency. N Engl J Med. 2007;357:266-81. Hyperabsorption • Miettinen TA, Gylling H, et al. Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 1998;316(7138):1127-30. • Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002 Oct 8;106(15):1943-8.

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