Lipid Disorders MS2 Cardiovascular Lecture #62 November 7, 2006

1. Lipid Disorders MS2 Cardiovascular Lecture #62November 7, 2006 Richard J. Baltaro, M.D., Ph.D., FCAP Associate Professor Department of Pathology Creighton University Medical Center 601 N. 30th Street Omaha, NE 68131-2197 USA baltaro@creighton.edu

2. Reading Material • Robbins and Cotran Pathologic Basis of Disease, Seventh Edition, Elsevier Saunders, 2003 Vinay Kumar, MBBS, MD, FRCPath, Univ. of Chicago, Abdul Abbas, MBBS, Univ of Ca, SF & Nelson Fausto, MD Univ. Washington pp. 156-158 Chapter 5, Disorders Associated with Defects in Receptor Proteins, Familiar Hypercholesterolemia pp. 520-523, 525f Chapter 11, Hyperlipidemia & Atherosclerosis • CECIL Essentials of Medicine, 6th Edition, W.B. Saunders Co, 2004 pp. 563-570, Chapter 61, Disorders of Lipid Metabolism, Reed E. Pyeritz. M.D., Ph.D., Univ. of Pa

3. Women brave tribal elders, warlords to vote Kabul, Afghanistan September 20, 2005 Making history … a woman gestures while talking to voters in Kabul. Some women were forced to hand over their voting cards so others would vote for them.

4. The Lipid Fairy Tale: IN THE BEGINNING … a long time ago in1948, in a place near • FAT WAS GOOD ! • SATURATED FATS WERE GOOD ! • Cigarettes were recommended by doctors ! • High blood pressure happened ! • Thin was bad … possible sign of TB, pneumonia, infectious disease, infant or maternal mortality, malnutrition, etc.

8. Heart Attack Epidemic Begins in USA 1930-1948… • From 1900 to 1963 Cardiovascular and Renal mortality increased 53% • Infectious diseases decreased • After World war II there was a need to understand the pathogenesis of heart attacks.

9. 1948 … Prospective Studies Begin after World War II • 1) NIH funds Framingham study (Prospective Epidemiological Study of Healthy and Free of Disease) • 2) Johns Hopkins University, Baltimore, MD starts following prospectively their medical school graduates • 3) Richard Doll & Richard Peto study the British Physicians lifestyle and survival

11. Framingham, Massachusetts • About 18 miles west of Boston, 20K people • The study would follow a group of normal people for a period of years to see who among them got high blood pressure, heart attacks and stroke. • The town’s doctors were cooperative • 5000 residents between 30 and 59 years participated with regular check-ups 1950-74

12. Fatty streaks … 1950 • Pathologists describe fatty streaks in the aortas young men killed in action during the Korean War (1950-1951) see Robbins Fig. 12-9 page 502 • Cigarettes and Good Hearty American High Animal Fat Content Food is given freely to soldiers to improve morale and maintain health • High blood pressure not usually treated • Health “nuts” (non-physician groups) raise issues about safety of too much cholesterol in diet

14. Late September 1955…The President recovering from MI • On the Friday following the unfortunate heart attack, President Dwight D. Eisenhower, recovered in the Denver military hospital, “he asked and got, a stump of his favorite beef bacon.” The next breakfast he had soft boiled eggs, prunes, oatmeal, toast and milk. Later he had servings of steak, prime ribs of beef and so forth. • In the 1950s smoking was considered of such unimportance in heart disease that Ike’s long smoking history was not even mentioned.

16. Progress? 1955 -1992

17. NIH 1967 • Donald Fredrickson and his people in the NIH’s molecular diseases branch of the heart institute publish . • Fredrickson et al., “ Fat Transport in Lipoproteins -- an integrated Approach to Mechanisms and Disorders,” NEJM 276 (January 5, 1967):34-42 and the four following issues

18. From Cecil Essentials of Medicine, 2001 Note: Updated table 6-1 in 7th edition essentially unchanged

21. Lipoprotein (An Artist’s view)

22. Fredrickson’s Formula • LDL = TC - (TG/5 + HDL) • Memorize, still used today • TC= Total Cholesterol • TG = Triglycerides (divide by 5) • HDL = HDL Cholesterol • LDL is still calculated this way • LDL calculated vs.. LDL measured (direct) • LDL calculated may be significantly off in 10%

24. Fredrickson’s Classification ofHyperlipoproteinemias - Robbins page 508

25. Type I • Hyper TG • Chylomicrons • Serum milky • High cholesterol • High TG • < 1% • No Atherosclerosis • Rx:Diet, No alcohol

26. Type II • High cholesterol • Clear serum • Xanthelasma • Corneal Arcus • Atheroscler. +++ • 4 genetic Conditions Autosomal Dominant

27. Type II • Tendon & Tuberous Xanthomas • 10% IIA Only cholesterol • 40% IIB (!!!) Both chol & TG • Rx Diet, drugs

28. A 40 year-old man to the ER for evaluation of chest pain AND severe “heartburn”. The Achilles tendons bilaterally have painless, fleshy, faintly yellow lesions: DIAGNOSIS?

29. Primary vs. Secondary Hypercholesterolemias Cholesterol elevated in: • Cholestasis, intra- or extra-hepatic • Nephrotic Syndrome • Hypothyroidism • Oral Contraceptives • Normal Pregnancy • Acute Intermittent Porphyria (AIP) • Macroglobulememia … & other conditions

30. Type III • Rare electrophoretic pattern of abnormal LP • Atherosclerosis +++ (atherogenic) • Remnant chylomicrons & IDL Intermediate • Mutation in apolipoprotein E • TG & cholesterol both greatly elevated • Uncommon not rare < 1 % of primary LP • Rx : Diet & reduction in weight

31. Type IV (2 different genetic) • Increase in VLDL & TG • Possibly atherogenic • Common: 45% of cases (Rx diet & drugs) • Example: mutation in LP lipase gene • Secondary hypertriglyceridemias in: Non-fasting specimen (most common) Diabetes, Acute alcoholism,Oral contraceptives, Nephrotic syndrome, CRF, Steroids, Acute pancreatitis, Gout, Gram negative infections,etc.

32. TypeV • Pancreatitis • Eruptive Xanthomas • Adults • ? atherosclerosis • 5% of total • DM,Alcohol • Rx Diet,drugs

33. Hypolipidemia • Hypolipidemia (Hypoproteinemia) - rare familial disorders or secondary to hyperthyroidism, malabsorption, malnutrition e.g. AIDS, cancers • Hypo-alphalipoprotenemia (Low HDL) associated with increased CAD: genetic or secondary to obesity, sedentary, cigarettes, diabetes, nephrotic syndr., medications (beta-blockers, diuretics, steroids, progestationals,..) lack of red wine… In about 10 % of population - important

34. Hypolipidemias (continued) • Hypo-beta-lipoproteinemia, rare inherited reduced LDL gene mutation of apo B • Total cholesterol 70-120 mg/dl • Decreased CAD & so called together with familial hyper-alpha lipoprotenemia … “longevity syndr” • Familial alpha-Lipoprotein Deficiency or Tangier’s disease (see next slide) • A-beta-lipoproteinemia or Bassen-Kornzweig Syndrome (see slide after that)

35. Familial alpha-Lipoprotein DeficiencyTangier’s disease Rare familial, genetics ? Plasma cholesterol very low Marked decreased HDL Triglycerides normal Polyneuropathy, lymphadenopathy Orange-yellow tonsils

36. A-beta-lipoproteinemiaBassen-Kornzweig Syndr. • Robbins p. 815 • Rare congenital • Autosomal Recessive • Defect in intestine • No LDL, VLDL, & Chylomicrons • Low Cholesterol & TG • Burr cells (acanthocytes) • Failure to thrive • Diarrhea, steatorrhea

37. Lipidoses (Lipid Storage Diseases) Not covered here • Gaucher’s disease (glucocerebroside lipidosis) • Niemann-Pick disease • Fabry’s disease (alpha-galactosidase A deficiency) • Wolman disease (acid cholesteryl ester hydrolase deficiency) • Cholesteryl Ester Storage disease • Cerebrotendinous Xanthomatosis • Beta-Sitosterolemia & Xanthomatosis • Refsum’s disease (phytanic acid storage disease) • Tay-Sachs disease (GM2 gangliosidosis) • Etc., etc.

38. Bad news from Framingham, MA • Organizers are overwhelmed at how many of the Framingham’s adults free of disease in 1950 developed heart disease as time went on. • Fully 1/3 of the men who had been in their early 40s when the study begun had signs of heart disease by 1974 • 2/3 of the healthy 50-59 year old at the beginning of the study had heart disease by 1974 (1948-1974)

40. Framingham “Final” Results 1974 • LIPIDS ARE BAD, especially if your cholesterol is abnormally high (Normal in 1960-1970s up to 300 mg/dl) • Risk factors: SMOKING HIGH CHOLESTEROL HIGH BLOOD PRESSURE DIABETES

42. FraminghamBottom Line • Four Potentially Controllable: • SMOKING • CHOLESTEROL • Systemic HBP • DIABETES

44. Same as Fig 11-10 p. 520 7th ed Robbins

45. 2004 JAMA • Cholesterol, Smoking, Hypertension and Diabetes Account for about 80% of the Predictive value! • (Clinical pearl aka My editorial comment: Concentrate on these & … • Downplay the other thousands of Risk Factors!)

47. Serum Homocysteine

48. Hs-CRP = “high sensitivity” C- Reactive Protein

49. Familial Hypercholesterolemia • Robbins, 7th ed, see pages 156-158 • Is a “receptor disease” • Mutation in the gene encoding for the receptor for Low Density Lipoprotein (LDL), which is involved in the transport & metabolism of cholesterol • 1/500 individuals heterozygous, possibly the most frequent mendelian disorder • Tendinous xanthomas & premature atherosclerosis

50. Low ("Lousy") Density Lipoprotein (LDL-C) • This "BAD" cholesterol is carried into the blood and is the main cause of harmful fatty buildup in the arteries. • LDL-C is mostly fat with a small amount of protein. • The higher the LDL-C level in the blood, the greater the risk of heart disease. • LDL-C is strongly influenced by genetic factors. One of the other important causes of elevated LDL-C levels is a diet high in saturated fats (fats found in animal products), trans fatty acids (hydrogenated fats) and cholesterol (found only in animal products).