Serum Lipid Abnormalities

M Chadi Alraies, MD
Chief Medical Resident Case Western Reserve University / St. Vincent Hospital Cleveland, Ohio Saturday, December 20, 2007

A quick look at the differential diagnosis of Heart Murmurs

Intervention Valsalva
or

HOCM

Aortic Stenosis

Mitral Regurgitation

Increased Increased Decreased Decreased Increased Markedly increased Markedly increased

Decreased Increased Decreased Increased Increased Increased Increased

Standing Handgrip or squatting Supine position with legs elevated Exercise Amyl nitrite

Decreased or same Decreased Increased No change Decreased Decreased Decreased

IsoProterenol

Lipid abnormalities

Terminology 
  

Primary prevention Secondary prevention Lipoproteins. Apoproteins.

General consideration  

The two main lipids in blood are cholesterol and triglyceride. Why lipids are deposited into the walls of large and medium-sized arteries is not known. medium-

Lipoproteins   

Particles that have a hydrophobic core (TG/Cholesterol), Surrounded by a hydrophilic phospholipid outer layers which allows transport through the blood. LDL, VLDL, IDL, CHYLOMICRONS, HDL

Apoproteins 
 

Small proteins. Surrounding Lipoproteins. Helps lipoproteins:
Binding to receptors.  Activating enzymes. 

LIPOPROTEINS & ATHEROGENESIS 
 

The higher the LDL, the greater the risk of CHD. The higher the HDL, the lower the risk of (CHD). The mechanism of formation of atherosclerotic plaques is not known.

Lipid Fractions 

In fasting serum« 

Most triglyceride is found in VLDL particles, which contain five times as much triglyceride by weight as cholesterol.

Lipid Fractions 

the LDL should always be estimated as the mean of at least two determinations« 

Valid only if TG < 400 mg/dl

Lipoproteins

Chylomicrons (I) 
    

Large globules. Apo (B48, CII, E) CII activates LPL (lipoprotein lipase). LPL removes TG from chylomicrons. Familial LPL deficiency Familial CII deficiency.

VLDL (IV) 
     

Apo (B100, CII, E) Smaller than chylomicrons Contain more cholesterol than chylomicrons. Metabolized by LPL by means of CII. Familial LPL deficiency Familial CII deficiency. FCHL

IDL (III) 
   

Apo B100, E VLDL remnant. ½ taken by liver. Strong affinity to B100 & E ½ stays in plasma and convert to LDL. Familial betadyslipoproteinemia.

LDL (IIA) 
    

Apo B100«ONLY! Formed from IDL 2/3 binds to receptors & 1/3 scavenged. Liver receptors have a weak affinity to B100. Familial hypercholesterolemia. FCHL

LDL receptors 

DownDown-regulated or decreased: 
 

High dietary cholesterol or saturated fat. Age Familial hypercholesterolemia. Low dietary cholesterol Estrogen Thyroxine Acute illness Meds: statins and bile acid resins. 

UpUp-regulated or increased: 
   

HDL 
   

Apo (A1, A2, C) Protein and phospholipids. Very little cholesterol and TG Scavenges the unesterified cholesterol. Low HDL low apo C (including CII) increased VLDL and Chylomicrons.

Familial hyperlipidemia syndromes
Type What is elevated? Defect Name

I IIA IIB III IV V

TG (chylomicrons) Cholesterol (LDL) TG + Cholesterol (LDL & VLDL) TG + Cholesterol (IDL) TG (VLDL) TG Chylomicrons & VLDL

LPL deficiency CII deficiency Decreased LDL receptors Apo B + VLDL overproduction Apo B + VLDL overproduction Abnormal apo E (E2/E2) LPL deficiency CII deficiency Apo B + VLDL overproduction LPL deficiency CII deficiency Apo B + VLDL overproduction

Familial LPL deficiency Familial CII deficiency Familial hypercholesterolemia FCHL FCHL Familial dysbetalipoproteinemia Familial hyper TG FCHL Familial CII deficiency Familial LPL deficiency FCHL Familial CII deficiency 

 

I + IV = V have isolated hypertriglyceridemia IIa = cholesterol alone IIb and III = both cholesterol and TG.

Clinical findings

Tendinous xanthomas: Achilles xanthomas

Tendinous xanthomas: elbow xanthomas

Tendinous xanthomas: knuckle xanthomas

Lipemia retinalis

CLINICAL PRESENTATIONS 


No specific symptoms or signs. Triglyceride level (>1000 mg/dL) 

eruptive xanthomas Tendinous xanthomas on tendons of (Achilles, patella, back of the hand). Lipemia retinalis. 

High LDL concentrations  

Triglyceride levels (above 2000 mg/dL): 

SECONDARY CONDITIONS THAT AFFECT LIPID METABOLISM

Cause

Associated Lipid Abnormality
Increased triglycerides, decreased HDL cholesterol Decreased HDL cholesterol Increased triglycerides, increased total cholesterol Increased triglycerides, increased HDL cholesterol Increased total cholesterol Decreased total cholesterol Increased total cholesterol Increased total cholesterol, increased triglycerides Decreased total cholesterol Increased total cholesterol Decreased total cholesterol Increased total cholesterol Increased triglycerides, increased total cholesterol Increased total cholesterol, increased triglycerides Increased total cholesterol, decreased HDL

Obesity Sedentary lifestyle Diabetes mellitus Alcohol use Hypothyroidism Hyperthyroidism Nephrotic syndrome Chronic renal insufficiency Hepatic disease (cirrhosis) Obstructive liver disease Malignancy Cushing's disease (or corticosteroid use) Oral contraceptives Diuretics Beta Blockers

Therapeutic Effects of Lowering Cholesterol 

Primary prevention is statistically significant and showed clinically important reductions in:
Rates of myocardial infarctions,  New cases of angina,  Need for coronary artery bypass procedures.  

In general, decrease in morbidity. morbidity. 

Primary prevention
Pravastatin: West of Scotland Study.  Lovastatin: AFCAPS/TexCAPS study.  Atorvastatin: (ASCOT) study. 

Secondary prevention
1. 2.

3.

Regression of atherosclerotic plaques. Reduces the progression of atherosclerosis in saphenous vein grafts. Slow or reverse carotid artery atherosclerosis.

SECONDARY CONDITIONS THAT AFFECT LIPID METABOLISM These are important for two reasons:
Abnormal lipid levels may be the presenting sign of some of these conditions.  correction of the underlying condition may obviate the need to treat an apparent lipid disorder.  

SCREENING FOR HIGH BLOOD CHOLESTEROL

Who should be screened for high lipids? 


CHD CHD risk equivalents:
1. 2. 3. 4. 5.

Peripheral artery disease. AAA Symptomatic carotid artery disease Diabetes mellitus Multiple risk factors that confer a greater than 20% 10-year risk for developing CHD! 10- 

National Cholesterol Education Program (NCEP): 

Screen all adults aged 20 years or older. 

USPSTF: 

Screen every 35 years in men and age 45 years in women unless there are other risk factors for CHD.

Risk factors of coronary artery disease 

Age and gender 


Men aged 45 years or older. Women aged 55 years or older MI or sudden cardiac death
1. 2. 

A family history of premature CHD:
1.

<55 years in a 1st degree male relative. <65 years in a 1st degree female relative.

2. 3. 4.

Hypertension (whether treated or not.) Current cigarette smoking (10 or more cigarettes per day). HDL cholesterol (< 40 mg/dL).

10-year risk of developing CHD using 10Framingham projections of 10-year risk 10

Because risk factors alone are an imprecise measure of CHD risk, estimating the 10-year 10risk using Framingham data is likely to be helpful even in patients with one or no risk factors.

Screening in Women   

Low HDL is more important risk factor than a high LDL cholesterol in women. Using estimates of 10-year CHD risk may be 10particularly helpful in women. Women are less likely to benefit from therapy unless their LDL cholesterol is extremely high (greater than 190 mg/dL).

Screening in Older Patients 

Patients age 75 years or older:
+ CHD: LDL-lowering therapy can be continued. LDL No CHD: recommend screening and treatment.  

Decisions to discontinue therapy:
Overall functional status.  Life expectancy.  Comorbidities.  Patient preference. 

Treatment

Goal of treatment

Risk Category

LDL Goal (mg/dL)

LDL Level at Which to Initiate Lifestyle Changes (mg/dL)
100

LDL Level at Which to Consider Drug Therapy (mg/dL)
100

High risk: CHD or CHD risk equivalents (10-year risk > 20%) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) Moderate risk: 2+ risk factors (10-year risk < 10%) Low risk: 0±1 risk factors

< 100

< 130

130

130

< 130

130

160

< 160

160

190

Treatment of High LDL Cholesterol 

General measures:
Quitting smoking: increase HDL & lower LDL.  Exercise (and weight loss) reduce the LDL increase the HDL.  Modest alcohol use (1²2 ounces a day): raises HDL (1² 

Diet

Diet Therapy 
 

5²10% decrease in LDL cholesterol. Should be assessed 4 weeks after initiation. Reduce« 


Total daily fat to 25²30% 25² Saturated fat to less than 7% of daily calories. 

 

Dietary cholesterol less than 200 mg/d. Polyunsaturated fats decrease LDL and HDL Monounsaturated fats: 


Decrease LDL Increase HDL« GOOD!

Diet Therapy  

 

"Mediterranean diet´, monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. Soluble fiber, reduce LDL cholesterol by 5² 5² 10%. Garlic, soy protein, vitamin C, pecans, and plant sterols. Antioxidants, found primarily in fruits and vegetables.

Pharmacologic treatment

General measures 


Aspirin prophylaxis at a dose of 81 mg/d. The therapeutic goal is:
Approached slowly  Watching for side effects.  Encouraging adherence to nonpharmacologic Rx.  

 

Achieve a 30²40% reduction in LDL. 30² Combinations of drugs may be necessary. Monitor periodically (every 6²8 weeks) after 6² starting therapy.

NIACIN (NICOTINIC ACID) 
    

Decrease the production of VLDL. FullFull-dose niacin therapy, 3²4.5 g/d 3² 15²25% reduction in LDL cholesterol. 15² 25²35% increase in HDL cholesterol. 25² Reduce triglycerides by half. Side effects: 
 

Flushing and pruritus. Less with aspirin 325 mg. Increase blood sugar. Exacerbate gout and peptic ulcer disease.

BILE ACID-BINDING RESINS ACID    

Cholestyramine and Colestipol. Decrease plasma LDL levels 15²25%. 15² Increase Triglyceride level. Don·t affects HDL. Side effects:
constipation and gas  Nausea and vomiting.  Absorption of fat-soluble vitamins. fat

(HMG(HMG-COA) REDUCTASE INHIBITORS (STATINS) 
      

atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Reduce MI and total mortality in secondary prevention. Significant reduction in risk of stroke. Decrease LDL level by up to 35%. Increases HDL levels Decreases triglyceride levels. Myositis and hepatitis. Monitor LFT·s Q 2-3 months then 2x/year if stable. 2-

Fibric Acid Derivatives 
    

Gemfibrozil, Fenofibrate and Clofibrate. Increase the activity of LPL on VLDL. Reduce triglyceride levels by about 40% Reduce LDL levels by about 10²15%. 10² Raise HDL levels by about 15²20%. 15² Side effects (mainly Clofibrate): 

cholelithiasis, hepatitis and hepatic cancer and myositis.

EZETIMIBE   

Inhibits the intestinal absorption of dietary and biliary cholesterol. Reduces LDL 15% - 20% when used as monotherapy. The usual dose of ezetimibe is 10 mg/d orally.

HDL

What increase HDL?

HDL increases 
     

Nicotinic acid Statins. Moderate alcohol intake Gemfibrozil Exercise Stopping smoking Losing weight.

HDL decreases in « 
 

Beta blockers (except Labetalol). Smoking High polyunsaturated diet.

High Blood Triglycerides 


Risk for pancreatitis. Treat fasting levels above 500 mg/dL.

High Blood Triglycerides 

The primary therapy is dietary: 
   

Avoiding alcohol Avoiding simple sugars Avoiding refined starches Avoiding saturated trans fatty acids. Restricting total calories. 



Medications: niacin, a fibric acid derivative, or an HMGHMG-CoA reductase inhibitor. Elevated TG increase CHD risk in men by 14% and in women by 37%.

Metabolic syndrome 


25% of Americans 3 or more of the following:
1. 2. 3. 4. 5.

Waist circumference > 102 cm in men or > 88 cm in women Serum triglyceride level of at least 150 mg/dL HDL level of < 40 mg/dL in men or < 50 mg/dL in women. Blood pressure of at least 130/85 mm Hg Serum glucose level of at least 110 mg/dL.

NCEP ATP III
1.

2. 

TG (150²199 mg/dL): calorie restriction and (150² exercise. TG (> 200 mg/dL): Diet and medications to make non-HDL cholesterol 30 mg/dL higher nonthan the LDL goal. Should be used for high risk patients.

References 
  

CMDT 2007. Harrison·s principles of internal medicine. MedStudy 2007/2008. Executive Summary of the 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). 


JAMA. 2001 May 16;285(19):2486²97. 16;285(19):2486² http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm

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