Download Major risk factors (exclusive of LDL cholesterol)

Yasar Kucukardali
Professor
Yeditepe University
Department of Internel Medicine
Objectives
 To learn correct management of hyperlipidemia
 Review NCEP ATP III Guidelines
 Discuss laboratory monitoring
Relation between plasma cholesterol concentration and six-year coronary
heart disease risk in 361,662 men (ages 35 to 57) screened during the
MRFIT study.
There is a continuous, positive, graded correlation between the plasma
cholesterol concentration and coronary risk.
Data from Stamler, J, Wentworth, D, Neaton, JD, JAMA 1986; 256:2823.
Cholesterol
 Essential component of the cell membrane
 Precursor molecule from which steroid
hormones, bile salts, and vitamin D are
synthesized

Derived from
the diet
synthesized within
the body,mainly in the liver.
Dietary sources of Cholesterol
Type of Fat
Main Source
Effect on
Cholesterol
levels
Monounsaturated
Olives, olive oil, canola oil, peanut oil, cashews,
almonds, peanuts and most other nuts; avocados
Lowers LDL, Raises
HDL
Polyunsaturated
Corn, soybean, safflower and cottonseed oil; fish
Lowers LDL, Raises
HDL
Saturated
Whole milk, butter, cheese, and ice cream; red
meat; chocolate; coconuts, coconut milk, coconut
oil , egg yolks, chicken skin
Raises both LDL and
HDL
Trans
Most margarines; vegetable shortening; partially
hydrogenated vegetable oil; deep-fried chips; many
fast foods; most commercial baked goods
Raises LDL
Çoklu doymamış YAğlar: Mısır, ayçiçek, soya, susam, fındık, keten tohumu
Tekli doymamış yağlar: zeytinyağı
Doymuş yağlar: Tereyağ, sade yağ, krema, kaymak, süt, peynir ve etlerin bileşiminde bulunan yağlar
 Cholesterol circulates as a component of
lipoproteins
The principal plasma lipoproteins
chylomicrons (CMs)
very low density lipoproteins (VLDL)
low-density lipoproteins (LDL)
high-density lipoproteins (HDL)
 The principal fat in the diet is the
triglycerides (TG), which are absorbed in
the intestine
 The lipoproteins are transported in
combination with apoproteins (apo), like
apo-A, apo-B, and apo-C
Clasification
Hyperlipidemias are classified as primary or secondary
Primary hyperlipidemia have been classified into
5 major groups according to plasma lipoprotein patterns
Causes of Sec. Hyperlipidemia
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Diet
Hypothyroidism
Nephrotic syndrome
Anorexia nervosa
Obstructive liver disease
Obesity
Diabetes mellitus
Pregnancy
Acute hepatitis
 AIDS (protease inhibitors)
 Pancreatitis
 Hematopoietic diseases
(myeloma, Waldenstrom's
macroglobulinemia, cryoglobulinemia,
hemochromatosis
 Systemic lupus
erythematousus
 drugs like estrogens,
corticosteroids, and retinoids
Genetic primary hyperlipidemias
Symptoms of Hyperlipidemia
 Hyperlipidemia usually has no noticeable
symptoms and tends to be discovered during
routine examination or evaluation for
atherosclerotic cardiovascular disease.
 Deposits of cholesterol (known as xanthomas)
may form under the skin
 Individuals with hypertriglyceridemia may develop
numerous pimple-like lesions across their body. **
 Extremely high levels of triglycerides may also
result in pancreatitis, a severe inflammation of the
pancreas that may be life-threatening.
Dermatologic Markers of Lipid Derangement
 Abnormalities of lipid metabolism may favor lipid
deposition in the skin and present as xanthomas
 Xanthelasma palpebrarum is the commonest type
of cutaneous xanthoma
 The major lipid stored in xanthomas is esterified
cholesterol
 However, only about half of the patients with
xanthelasma are hyperlipidemic
 The most frequent hyperlipidemia associated with
xanthelasma is type IIa
 Isolated xanthelasmata are often treated with
destructive modalities, like trichloroacetic acid,
electrocautery, surgical excision, carbon dioxide
laser, pulsed dye laser, and erbium:YAG laser
Disorders of lipid storage
Individuals with hypertriglyceridemia may
develop numerous pimple-like lesions across their body
NCEP Guidelines
 The NCEP Adult Treatment
Panel (ATP) first published
guidelines for managing
hypercholesterolemia in 1988
(ATP I)
 Revised them in 1993 (ATP 2)
 The latest NCEP report (ATP
III) has been published in 2001.
managing hypercholesterolemia
 The first step is to determine lipoprotein levels after a 9- to 12-hour fast
 Next, coronary heart disease (CHD) risk equivalents and major risk factors
should be established.
CHD risk equivalents include
clinical CHD
symptomatic carotid artery disease
peripheral arterial disease
abdominal aortic aneurysm
diabetes
Major risk factors (exclusive of LDL cholesterol)
cigarette smoking
hypertension
low HDL cholesterol (<40 mg/dL)
family history of premature CHD
age (men >45 years; women >55 years)
 CHD risk equivalents and risk factors are then used to determine the risk
category of the patient
 Coronary Equivalents
 Risk Factors
Abdominal Aortic Aneurysm
Hypertension
Peripheral Artery Disease
HDL <40 mg/dl
(>60 mg/dl “negative” risk
factor)
Renal Artery Stenosis
Carotid Artery Stenosis
Cerebral Vascular Disease
Diabetes Mellitus
Family history of premature
CAD (male <55 female <65)
Male >45, Women >55
Cigarette Smoking
Checking lipids
 Nonfasting lipid panel

measures HDL and total cholesterol
 Fasting lipid panel
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Measures HDL, total cholesterol and triglycerides
LDL cholesterol is calculated:

LDL cholesterol = total cholesterol – (HDL + triglycerides/5)
When to check lipid panel
 Two different Recommendations
 Adult Treatment Panel (ATP III) of the National
Cholesterol Education Program (NCEP)
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Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile
consisting of total cholesterol, LDL, HDL and triglycerides
Repeat testing every 5 years for acceptable values
 United States Preventative Services Task Force
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Women aged 45 years and older, and men ages 35 years and older
undergo screening with a total and HDL cholesterol every 5 years.
If total cholesterol > 200 or HDL <40, then a fasting panel should be
obtained
Cholesterol screening should begin at 20 years in patients with a history
of multiple cardiovascular risk factors, diabetes, or family history of
either elevated cholesteral levels or premature cardiovascular disease.
Screening may be appropriate in older people who have never been
screened, although screening a second or third time is less important in
older people because lipid levels are less likely to increase after age 65.
NCEP/ATP III
 Identify if patient has CAD or equivalent (PAD, DM,
AAA, Carotid)
 Risk factor assessment (HTN, FHx, Tob, Age & Sex,
HDL<40 or >60)
 If 2 or more risk factors; do Framingham 10-yr risk
assessment.
NCEP/ATP III
Therapeutic lifestyle changes (TLC)
 TLC are considered first-line therapy in the
management of high cholesterol
 A 3-month trial of TLC should precede the use
of drug therapy
The essential features of TLC
(a) reduced intake of saturated fats [less than 7%
of total calories] and cholesterol [less than 200
mg/d]
(b) therapeutic options for enhancing LDL
lowering - such as plant stanols/sterols [2 g/d]
and increased soluble fiber [10-25 g/d;
(c) weight reduction
(d) increased physical activity
According to ATP III, the most cost-effective approach
to prevention of CHD
diet modification
exercise
weight control
cessation of smoking
 Cigarette smoking, leads to elevated
triglycerides and low HDL levels
 Smoking cessation should receive prime
emphasis in the clinical strategy to reduce
CHD risk.
 While moderate intakes of alcohol in middleaged and older adults may reduce risk for
CHD, high intakes of alcohol produce
multiple adverse effects.
 Persons who do not drink should not be
encouraged to initiate regular alcohol
consumption.
 Physical activity as a component of TLC
includes enough moderate exercise to expend
at least 200 kcal per day.
The NCEP recommends
 The use of statins as first-line therapy
 BASA's LDL-lowering effects may be enhanced in
combination with other cholesterol-lowering
medications, particularly statins.
 Nicotinic acid is recommended for high-risk
patients with low levels of LDL cholesterol, high
triglycerides, and low HDL cholesterol - a triad
known as atherogenic dyslipidemia.
 Fibrates are primarily used for persons with very
high triglycerides to reduce risk for acute
pancreatitis and for those with
dysbetalipoproteinemia.
Drug treatment/ Statins
 The statins are competitive inhibitors of
3-hydroxy-3-methyl-glutaryl-CoA
(HMG-CoA) reductase, the rate-limiting
enzyme
 Inhibition of HMG-CoA reductase leads
to a decrease in intrahepatic cholesterol
concentration ,leading to an increase in
receptor-mediated LDL catabolism.
 The statins also decrease the activity of
CETP Thus the overall effect is a small
increment in HDL
 Statins decrease serum triglycerides.
 Statin-induced increased LDL-receptor
activity also leads to the enhanced
removal of the TG-rich lipoproteins
VLDL and IDL. Similarly, increased
activity of LDL receptor leads to
enhanced uptake of CM remnants,
thereby increasing postprandial TG
clearance.
Drug treatment/
Bile-acid sequestrating agents (BASA)
 BASA are anion exchange resins, BASA bind the bile acids,
thus impeding their reabsorption and significantly
increasing their fecal excretion.
 This leads to the depletion of intrahepatic cholesterol,
which causes increased expression of LDL receptors.
 BASA promote apo-A1 synthesis by an unknown
mechanism and tend to raise HDL levels.
 BASA nonspecifically bind anions and interfere with
absorption of a number of drugs which are anionic at
intestinal pH (statins, fenofibrate, corticosteroids,
diuretics, tricyclic antidepressants, nonsteroidal antiinflammatory drugs, thyroxine, and digoxin).
Drug treatment/ Nicotinic acid (NA)
 Plasma FFA are immediate precursors of
hepatic and subsequently plasma triglycerides
transported in VLDL.
 NA is immediately taken up by adipose tissue
via a specific high-affinity G-protein-coupled
receptor. It then inhibits lipolysis in adipose
tissue, resulting in a decrease in plasma FFA
 NA, in a dose-dependent way, lowers
triglyceride-rich VLDL and cholesterol-rich
LDL.
 NA is the most potent HDL-raising drug. But
the unpleasant side effect of flushing precludes
many patients from taking this drug.
Drug treatment Fibric acid derivatives
(fibrates)
 Fibrates reduce triglycerides through PPARa-mediated reduced
expression of apo-CIII, which serves as an inhibitor of lipolytic
processing and receptor-mediated clearance. This leads to
increased LPL synthesis and enhanced clearance of triglyceriderich lipoproteins.
 Fibrate-mediated increases in HDL are due to PPARa stimulation
of apo-AI and apo-AII expression.
 Three fibric acid derivatives are currently available Fibrates are
primarily used for lowering elevated triglycerides because the LDL
cholesterol-lowering effects of fibrates are generally only 10% or
less in persons with hypercholesterolemia.
Other therapeutic targets in lipid metabolism
 Ezetimibe blocks uptake of cholesterol into
jejunal enterocytes, hence selectively blocking
dietary and biliary cholesterol absorption from
the gut. It acts by decreasing the intestinal
cholesterol supply to the liver, lowering
hepatic cholesterol levels and thus inducing
LDL receptor expression. Unlike the bile-acid
sequestrants, it does not interfere with
absorption of fat-soluble drugs. Moreover,
ezetimibe does not increase serum TG.
Lipid-lowering agents
NCEP/ATP III
 Treat elevated TG (>150mg/dl)
 First lower LDL; if TG still >200 consider
adding/increasing drug therapy
 But, if TG >500mg/dl, first lower triglycerides to prevent
pancreatitis. When they are <500 then return to LDL
lowering
 Treat HDL <40 after lowering LDL.