lipid disorders ms2 cardiovascular lecture #62 november 7, 2006 richard j. baltaro, m.d., ph.d.,...

Lipid Disorders MS2 Cardiovascular Lecture #62

November 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

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

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

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.

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.

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.

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

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

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

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.

Progress? 1955 -1992

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

From Cecil Essentials of Medicine, 2001

Note: Updated table 6-1 in 7th edition essentially unchanged

Lipoprotein (An Artist’s view)

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%

Fredrickson’s Classification of

Hyperlipoproteinemias - Robbins page 508

Type I

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

Type II

• High cholesterol• Clear serum• Xanthelasma• Corneal Arcus• Atheroscler. +++• 4 genetic

Conditions

Autosomal Dominant

Type II

• Tendon &

Tuberous Xanthomas

• 10% IIA

Only cholesterol

• 40% IIB (!!!)

Both chol & TG

• Rx Diet, drugs

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?

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

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

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.

TypeV

• Pancreatitis• Eruptive

Xanthomas• Adults• ? atherosclerosis• 5% of total• DM,Alcohol• Rx Diet,drugs

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

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)

Familial alpha-Lipoprotein Deficiency Tangier’s disease

Rare familial, genetics ?

Plasma cholesterol very low

Marked decreased HDL

Triglycerides normal

Polyneuropathy,

lymphadenopathy

Orange-yellow tonsils

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

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.

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)

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: SMOKINGHIGH CHOLESTEROL

HIGH BLOOD PRESSURE

DIABETES

FraminghamBottom Line

• Four Potentially

Controllable:

• SMOKING

• CHOLESTEROL

• Systemic HBP

• DIABETES

Same asFig 11-10 p. 520 7th edRobbins

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!)

Serum Homocysteine

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

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

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).

High ("Healthy") Density Lipoprotein (HDL-C) = The “Good” Cholesterol

It prevents cholesterol from building up in the arteries. It is mostly protein and contains only a small amount of fat. HDL-C clears the bad cholesterol from the body by picking up cholesterol from the walls of the arteries and carrying it back to the liver for disposal.

Exercise increases the production of HDL-C. A higher HDL-C is linked with a lower risk of heart disease, stroke and atherosclerosis. Exercise can also help control weight, diabetes and high blood pressure. Exercise that uses oxygen to provide energy to large muscles (aerobic exercise) raises your heart and breathing rates. Stopping smoking will also improve HDL-C levels.

Estrogen and moderate alcohol intake can also raise HDL-C. Women have higher levels of HDL-C as compared to men. Women are just as likely as men to die for heart disease but the onset tends to be later in life.

Chapter 5GeneticDisordersp. 157Robbbins7th ed.

LDL Receptor Pathway Fig 5-9. P. 158, Robbins 7th ed

As previously discussed!

• About 2 in 3 has a total cholesterol < 240 mg/dl

• About 2 in 3 is a non smoker

• About 2 in 3 has a normal diastolic blood Pressure

• Over 90% is a non diabetic

1988 NIH Consensus NCEP

• Expert Panel of the National Education Cholesterol Program, Arch Inter Med 1988; 148: 36-69. Establishes for Adults:

• < 200 mg / dl is desirable for TC cholesterol

• 200 - 239 mg /dl is borderline

• Over 240 mg / dl is HIGH

• Either a fasting or non fasting specimen OK

NIH 3rd Report of NCEP May 2001

J curve Controversy Total vs. CV mortality - Cholesterol & BP

• Cardiovascular Mortality increases directly with Total cholesterol values (or Systemic blood pressure) in the population

• Mortality from all causes is about steady from 150-240 cholesterol

• Mortality from all causes actually increases with low cholesterol and blood pressure

J curve Controversy Total vs. CV mortality - Alcohol consumption

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Some of the Major Antioxidant and Phenolics in Wines

Antioxidant Capacities and Phenolics Levels of French Wines from Different Varieties and Vintages,

Landrault, N, et al, J. Agric. Food Chem. 49, 3341-3348, 2001.

Prevalence distribution (bars) of serum cholesterol concentration related to age-adjusted mortality from coronary heart disease (CHD) (broken curve) in men aged 40-59 years. The number above each bar is the percentage of death "attributable" to the cholesterol effect and arising at that level. Data from Martin et al [96].

CIS- OILS

CIS

“ONLY”

IS

NATURAL

NOT

TRANS

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Here are some examples:French fries (fast food)7.8gDoughnut5.0gMicrowave popcorn4.5gPound cake4.3gShortening4.2gWheat crackers4.0gPotato chips3.2gStick margarine2.8gTub margarine0.6g

2005 Genetics …

• About 15% of people have ApoE-4, which has been linked to heart disease, stroke and Alzheimer’s disease. (“Unlucky gene”)

• About 8% of population have ApoE-2, “the lucky gene”, which is associated with longer life and a lower risk of degenerative diseases.

• Most people carry ApoE-3, which does not affect health risks.

• Testing people for ApoE genes as a clinical tool is NOT recommended except to further investigate an independent Alzheimer’s diagnosis.

2004 Genetics from CECIL p. 568

• Polygenic Hypercholesterolemia• About 60 to 70% of a patient's cholesterol or LDL

level is genetically determined, with the remaining contribution from age, sex, diet, and other factors. The nature of these genetic effects is incompletely defined. Subjects in the upper range of the normal distribution have an increased CHD risk, and the upper 50% contribute about 80% of CHD cases.

2005 Conclusions

SUPERSIZE IT!

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

2005 Avant-garde or Profit ?

Experimental

??? Other types of

commercial

Tests available

for pay.

Stay tuned …

To be continued

Lipoprotein (Another view)

Questions?Questions?