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Dyslipidemia

Rene J. Harper, M.D.


Georgia Health Sciences University
October 21, 2012

Dyslipidemia

Definition
Classification
Signs and symptoms
Primary causes
Secondary causes
Evaluation
Treatment

Dyslipidemia

Elevation of plasma cholesterol and/or


tryglycerides or a low HDL level that
contributes to the development of
atherosclerosis.
Causes may be primary (genetic) or
secondary (most common).
Diagnosis is by measuring plasma levels of
total cholesterol, TGs, and individual
lipoproteins.
Treatment is dietary changes, exercise, and
lipid-lowering drugs.

Dyslipidemia

There is no natural cutoff between normal and


abnormal lipid levels because lipid measurements
are continuous
A linear relation probably exists between lipid levels
and cardiovascular risk, so many people with
normal cholesterol levels benefit from achieving
still lower levels
Consequently, there are no numeric definitions of
dyslipidemia; the term is applied to lipid levels for
which treatment has proven beneficial
Proof of benefit is strongest for lowering elevated
LDL levels; it is less strong for lowering elevated TG
and increasing low HDL levels, in part because
elevated TG and low HDL levels are more predictive
of cardiovascular risk in women than in men

Dyslipidemia

Dyslipidemias have been traditionally


classified by patterns of elevation in
lipids and lipoproteins (Fredrickson
phenotype)

Fredrickson Classification
Lipoprotein Patterns (Fredrickson Phenotypes)
Phenotype
I
IIa
IIb
III
IV
V

Elevated Lipoprotein(s)
Chylomicrons
LDL
LDL and VLDL

Elevated Lipids
TGs
Cholesterol
TGs and
cholesterol
VLDL and chylomicron remnants TGs and
cholesterol
VLDL
TGs
Chylomicrons and VLDL
TGs and
cholesterol

Classification of
dyslipidemias

A more practical system classifies


dyslipidemias as primary or secondary
and characterizes these by:
increases in cholesterol only (pure or
isolated hypercholesterolemia)
increases in TGs only (pure or isolated
hypertriglyceridemia)
increases in both cholesterol and TGs
(mixed or combined hyperlipidemias)

Signs and symptoms

Dyslipidemias are usually asymptomatic but often


lead to atherosclerotic vascular disease
High levels of LDL can cause eyelid xanthelasma
and xanthomas found at the Achilles, elbow, and
knee tendons and over metacarpophalangeal joints
(tendinous) or pressure areas (tuberous)
Patients with the homozygous form of familial
hypercholesterolemia may have the above findings
and additionally planar or cutaneous xanthomas
Patients with hypertriglyceridemia may have
xanthelasma and eruptive or planar xanthomas

Signs and symptoms

Patients with the rare dysbetalipoproteinemia may


have palmar and tuberous xanthomas and
involvement of palmar creases
Patients with severe elevations of TGs can have
eruptive xanthomas over the trunk, back, elbows,
buttocks, knees, hands, and feet
Severe hypertriglyceridemia (> 2000 mg/dL) may
give retinal arteries and veins a creamy white
appearance (lipemia retinalis)
Extremely high lipid levels also give a lactescent
(milky) appearance to blood plasma.
High TGs (> 1000 mg/dL) may cause acute
pancreatitis

Planar xanthoma

Planar xanthoma

Tendinous xanthoma

Tendinous xanthoma

Tendinous xanthoma

Eruptive xanthoma

Eruptive xanthoma

Tuberous xanthoma

Palmar xanthoma

Tuberous xanthoma

Xanthelasma

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Xanthelasma

Lipemia retinalis

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Lipemia retinalis

Arcus corneae

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Lipoprotein

Size and Buoyancy


Characteristics of
Lipoproteins

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Primary (genetic) causes

Single or multiple genetic mutations that result in


either overproduction or defective clearance of TG
and LDL cholesterol, or in underproduction or
excessive clearance of HDL.
Primary lipid disorders are suspected when a
patient has physical signs of dyslipidemia, onset of
premature atherosclerotic disease (< 60 yr), a
family history of atherosclerotic disease, or serum
cholesterol > 240 mg/dL (> 6.2 mmol/L).
Primary disorders are the most common cause of
dyslipidemia in children, but dont cause a large
percentage of cases in adults.

Primary (genetic) causes

Familial hypercholesterolemia (FH)

Defect in LDL receptor that leads to diminished


LDL clearance
Autosomal dominant inheritance
Heterozygotes: 1/500; 5% of AMIs < 60 yr

Tendon xanthomas, xanthelasma, arcus corneae


and premature CAD (ages 3050)
TC 250500 mg/dL, normal TGL

Homozygotes: 1/1 million

Tendon xanthomas, xanthelasma, planar


xanthomas, and premature CAD (< age 18)
TC > 500 mg/dL, normal TGL

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Primary (genetic) causes

Familial defective apo B-100


Defect in Apo B (LDL receptor-binding
region) that leads to diminished LDL
clearance
Autosomal dominant inheritance
1/700
Xanthomas, xanthelasma, and premature
CAD (milder manifestations than FH)
TC 250500 mg/dL

Primary (genetic) causes

Polygenic hypercholesterolemia
Unknown genetic defect; likely multiple
defects and mechanisms
Variable inheritance
Common
Premature CAD
TC 250350 mg/dL

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Primary (genetic) causes

LPL deficiency (chylomicronemia)


Defect in endothelial LPL that leads to
diminished chylomicron clearance
Recessive inheritance
Rare
Failure to thrive (infants), eruptive
xanthomas, lipemia retinalis,
hepatosplenomegaly, and pancreatitis
TG > 750 mg/dL

Primary (genetic) causes

Apo C-II deficiency


Defect in Apo C-II (activating cofactor for
LPL) leading to functional LPL deficiency
Recessive inheritance
Very rare, frequency < 1/1 million
Pancreatitis in children and young adults,
may be associated with metabolic
syndrome
TG > 750 mg/dL

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Primary (genetic) causes

Familial hypertriglyceridemia

Unknown defect, possibly multiple defects and


mechanisms
Autosomal dominant
1/100 (affects 1/2 of first-degree relatives)
Usually no symptoms or findings; obesity and
insulin resistance; occasional eruptive
xanthomas or pancreatitis; low HDL,
hyperuricemia
TG 200500 mg/dL; levels increased by dietary
factors, estrogens, hypothyroidism and alcohol

Primary (genetic) causes

Familial combined hyperlipidemia

Unknown defect
Autosomal dominant
1/50 to 1/100
Premature CAD, 15% of AMIs < 60 yr; obesity
and insulin resistance; low HDL, hyperuricemia
Small, dense LDL; apo B elevated
TC 250500 mg/dL
TG 250750 mg/dL

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Primary (genetic) causes

Familial dysbetalipoproteinemia
Defect in Apo E (usually e2/e2 homozygotes);
diminished chylomicron and VLDL clearance
Recessive (more common) or dominant (less
common)
1/5000
Xanthomas (especially palmar), yellow palmar
creases, premature CAD
TC 250500 mg/dL
TG 250500 mg/dL

Secondary causes

Most cases of dyslipidemia in adults


The most important secondary cause in developed
countries is a sedentary lifestyle with excessive
dietary intake of saturated fat, cholesterol, and
trans fatty acids (TFAs)
Other common secondary causes:

diabetes mellitus
alcohol abuse
chronic renal insufficiency, nephrotic syndrome
hypothyroidism
primary biliary cirrhosis and other cholestatic liver
diseases,
Drugs: thiazides, -blockers, retinoids, highly-active
antiretroviral agents, estrogen and progestins, and
glucocorticoids

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Diabetic dyslipidemia

Diabetic patients, in particular DM-2, tend to have an


atherogenic combination of high TGs, high small/dense
LDL and low HDL.
This profile may be a consequence of obesity and/or
poor control of diabetes, which increases circulating
FFAs, leading to increased hepatic VLDL production.
TG-rich VLDL then transfers TG and cholesterol to LDL
and HDL, promoting formation of TG-rich, small, dense
LDL and clearance of TG-rich HDL.
Diabetic dyslipidemia is often exacerbated by the
increased caloric intake and physical inactivity that
characterize the lifestyles of some patients with DM-2.
Diabetic women may be at special risk for cardiac
disease.

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Diagnosis and Screening

Measure serum lipids (lipid profile)


TC, TG, and HDL are measured
directly
LDL is calculated or measured directly
TC and TG values reflect cholesterol
and TG in all circulating lipoproteins,
including chylomicrons, VLDL, IDL,
LDL, and HDL.

Diagnosis and Screening

LDL values are often calculated as the amount of


cholesterol not contained in HDL and VLDL, where
VLDL is estimated by TG 5: LDL = TC [HDL +
(TG 5)] (Friedewald formula); valid only when TG
are < 400 mg/dL and patients are fasting
The calculated LDL value incorporates measures of
all non-HDL, nonchylomicron cholesterol, including
that in IDL and Lp(a)
LDL can be measured directly using plasma
ultracentrifugation or by immunoassay
Direct measurement may be useful in patients with
elevated TG to determine if LDL levels are elevated

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Diagnosis and Screening

TC values may vary by 10% and TG by up


to 25% even in the absence of disease
Testing should be postponed until after
resolution of acute illness, because TG
increase and cholesterol levels decrease in
inflammatory states
Lipid profiles are generally reliable within
the first 24 h after an AMI but then change
afterwards

Diagnosis and Screening

A fasting lipid profile (TC, TG, HDL, and calculated


LDL) should be obtained in all adults 20 yr and
should be repeated q 5 yr
Assessment of other cardiovascular risk factors at
the time of initial screening:
DM
Smoking
HTN
FH of premature CAD - 1st-degree relative
male before age 55
female before age 65

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Diagnosis and Screening

Indications for screening patients < 20yr


Atherosclerotic risk factors
DM
HTN
Smoking
Obesity
Premature CAD in a parent, grandparent, or
sibling
Cholesterol level > 240 mg/dL or known
dyslipidemia in a parent

Additional testing

Blood tests for secondary causes of


dyslipidemia should be obtained in
patients with recently diagnosed
dyslipidemia, or when a component of
the lipid profile has changed for the
worse:
FBG, liver enzymes, creatinine, TSH,
urinary protein

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Evaluation
1. Measure fasting lipoproteins
2. Identify CAD or CAD equivalents

Other atherosclerotic disease: peripheral arterial disease,


abdominal aortic aneurysm, symptomatic carotid artery
disease
Diabetes mellitus

3. Identify major CAD risk factors

Cigarette smoking
Hypertension (BP 140/90 or on antihypertensive drug)
Low HDL ( 40 mg/dL
Family history of premature CAD - 1st-degree relative
male < 55 yr
female < 65 yr
Age (men 45 yr, women 55 yr)

Evaluation

If 2 major risk factors are present


without CAD or CAD equivalent, assess
10-yr risk of MI or CAD death using
Framingham risk tables or electronic
calculation tool

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Estimation of CHD risk*

*Use internet Framingham 10-year risk calculator

Online calculation tools

http://hp2010.nhlbihin.net/atpiii/calculat
or.asp
http://www.mdcalc.com/framinghamcoronary-heart-disease-risk-score-siunits/
http://www.medcalc.com/heartrisk.html
http://reference.medscape.com/calculato
r/framingham-coronary-risk-ldl

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Lipid profile references


TC (mg/dL)
< 200
200239
240
LDL (mg/dL)
< 100
100129
130159
160189
190

Desirable
Borderline high
High
Optimal
Near optimal/above optimal
Borderline high
High
Very high

Lipid profile references


HDL (mg/dL)
< 40
60
TG (mg/dL)
< 150
150199
200499
500

Low
High
Desirable
Borderline high
High
Very high

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Comparison of LDL Cholesterol and


Non-HDL Cholesterol Goals for
Three Risk Categories
LDL-C Goal
(mg/dL)

Non-HDL-C
Goal (mg/dL)

CHD and CHD Risk


Equivalent (10-year risk
for CHD >20%)

<100

<130

Multiple (2+) Risk Factors


And 10-year risk <20%

<130

<160

01 Risk Factor

<160

<190

Risk Category

CHD or CHD risk


equivalents

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ATP III update

The treatment goal for high-risk


patients is an LDL < 100 mg/dL
Update: There is a therapeutic option
to set the goal at an LDL <70 mg/dL
for very high-risk patients:
Recent heart attack
Cardiovascular disease combined with
either diabetes, or severe or poorly
controlled risk factors

Treatment

Guidelines focus primarily on reducing


elevated LDL levels and secondarily on
treating high TGs, low HDL, and
metabolic syndrome.
Start therapeutic lifestyle changes
(TLC) in all patients (diet modification,
physical activity, weight loss, smoking
cessation, BP control)

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Drug therapy

Drug treatment options depend on the specific lipid


abnormality, although different lipid abnormalities
often coexist.
In some patients, a single abnormality may require
several drug therapies
In others, a single drug treatment may be adequate
for several abnormalities.
Treatment should always include treatment of
hypertension and diabetes, smoking cessation, and
in those with a 10-yr risk of MI or death from CAD
of 10% (as determined from the Framingham
tables) low-dose daily aspirin.

Drug therapy - statins

Statins are the treatment of choice for LDL


reduction and demonstrably reduce
cardiovascular mortality
Statins inhibit hydroxymethylglutaryl CoA
reductase, a key enzyme in cholesterol
synthesis, leading to up-regulation of LDL
receptors and increased LDL clearance
They reduce LDL by up to 60% and produce
small increases in HDL and modest
decreases in TGs

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Drug therapy - statins

Statins also appear to decrease intra-arterial


and/or systemic inflammation by stimulating
production of endothelial nitric oxide
They may also decrease LDL deposition in
endothelial macrophages and decrease
cholesterol in inflammatory cell membranes
This anti-inflammatory effect is
antiatherogenic even in the absence of
elevated lipid levels

Drug therapy - statins

Adverse effects are uncommon but include liver


enzyme elevations, and myositis or rhabdomyolysis
Muscle toxicity without enzyme elevation has also
been reported
Adverse effects are more common in older patients,
those with multiple diseases, and those on multiple
drugs; changing from one statin to another or
lowering the dose may relieve the problem
Muscle toxicity seems to be most common when
some of the statins are used with drugs that inhibit
cytochrome P3A4 (eg, macrolide antibiotics, azole
antifungals, cyclosporine) and with fibrates
(especially gemfibrozil)

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Drug therapy - fibrates

Activate PPAR (peroxisome


proliferator-activated receptors)
especially PPAR
Stimulate endothelial LPL, leading to
increased fatty acid oxidation in the
liver and muscle and decreased
hepatic VLDL synthesis
Structurally and pharmacologically
related to the thiazolidinediones (TZD)

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Drug therapy - fibrates

Reduce TGs by up to 50%


Increase HDLs by up to 20%
May cause GI adverse effects,
including dyspepsia and abdominal
pain; rarely cause cholelithiasis
Potentiate muscle toxicity when used
with statins and potentiate the effects
of warfarin

PPAR -alpha and -gamma pathways.

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Drug therapy - bile acid


sequestrants

Block intestinal bile acid reabsorption,


forcing up-regulation of hepatic LDL
receptors to recruit circulating
cholesterol for bile synthesis.
Proven to reduce cardiovascular
mortality.
Usually used with statins or with
nicotinic acid to augment LDL
reduction

Drug therapy - bile acid


sequestrants

Drugs of choice for children and


women who are or are planning to
become pregnant
Safe, but their use is limited by
adverse effects of bloating, nausea,
cramping, and constipation
They may also increase TGs, so their
use is contraindicated in patients with
hypertriglyceridemia.

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Drug therapy - bile acid


sequestrants

Cholestyramine and colestipol, but not


colesevelam, interfere with absorption
of other drugsnotably thiazides, blockers, warfarin, digoxin, and
thyroxinean effect that can be
minimized by administration 4 h
before or 1 h after other drugs
Lower LDL 15-25%

Drug therapy - niacin

Most effective drug for increasing HDLs


Mechanism of action is unknown, but it
appears to both increase HDL production
and inhibit HDL clearance; it may also
mobilize cholesterol from macrophages.
Also decreases TGs and, in doses of 1500 to
2000 mg/day, reduces LDLs
Lower LDL 15-30%, lower TGs 30-40% amd
raise HDL 15-25%

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Drug therapy - niacin

Produces flushing, pruritus, and nausea;


premedication with low-dose aspirin may
prevent these adverse effects; slow-release
preparations cause these side effects less often
May cause liver enzyme elevations and
occasionally liver failure, insulin resistance, and
hyperuricemia and gout.
In patients with average LDL and belowaverage HDL levels, niacin combined with statin
treatment may be effective in preventing
cardiovascular disease

Drug therapy - ezetimibe

Inhibits intestinal absorption of cholesterol


and phytosterol
Usually lowers LDL by 15-20% and causes
small increases in HDL and a mild decrease
in TGs
Can be used as monotherapy in patients
intolerant to statins or added to statins for
patients on maximum doses with persistent
LDL elevation
Adverse effects are infrequent

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Drug therapy omega-3


fatty acids

Omega-3 fatty acids in high doses (1 to 6 g/day


of eicosapentaenoic acid [EPA] and
docosahexaenoic acid [DHA]) can be effective
in reducing TGs
The -3 fatty acids EPA and DHA are the active
ingredients in fish oil or -3 capsules
Adverse effects include eructation and diarrhea;
these may be decreased by giving the fish oil
capsules with meals in divided doses (eg, bid or
tid)
Omega-3 fatty acids can be a useful adjunct to
other therapies

Treatment of diabetic
dyslipidemia

Treatment of diabetic dyslipidemia should


always involve lifestyle changes, with statins
to reduce LDLs and/or fibrates to decrease
TGs
Metformin lowers TGs, which may be a
reason to choose it over other oral
antihyperglycemic drugs when treating
diabetics with dyslipidemia

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Treatment of diabetic
dyslipidemia

Thiazolidinediones (TZDs) may increase


both HDLs and LDLs (probably the less
atherogenic large, buoyant type of LDLs)
TZDs may decrease TGs; however, these
agents should not be chosen over lipidlowering drugs to treat lipid abnormalities in
diabetic patients but may be useful adjuncts
Patients with very high TG levels and less
than optimally controlled diabetes may have
better response to insulin than to oral
antihyperglycemic drugs

Targets for dyslipidemia


in diabetic patients

LDL <100 mg/dl


Triglycerides <150 mg/dl
HDL >40 mg/dl

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