Hypercholesterolemia, Pathophysiology, Clinical findings, Diagnosis and Treatment

1. HYPERCHOLESTEROLEMIA
DR.CARLOS E. SILVA

2. INTRODUCTION
 Lipoprotein disorders are clinically important due to the role in atherogenesis and
the associated risk of atherosclerotic cardiovascular disease (ASCVD).
 For patients WITH known ASCVD (secondary prevention), cholesterol-lowering
leads to a consistent reduction in cardiovascular mortality and cardiovascular
events.
 Among patients WHITOUT cardiovascular disease (primary prevention), the data
on reduction in atherosclerotic cardiovascular disease events with statin drugs is
also well documented.

3.  CHOLESTEROL IS THE MOST CLINACALLY RELEVANT LIPID
SUBSTANCES CONTRIBUTING TO ATHEROSCLEROSIS (LDL-C).
 Nearly 90% of patients with CHD have some form of dyslipidemia.
 Increased levels of LDL-C, remanent lipoproteins and Lp(a) and
decreased levels of HDL-C have all been associated with an
increased risk of premature vascular disease.

4. GENERAL PRINCIPLES
 Lipids are sparingly soluble macromolecules that include cholesterol, fatty acids and their derivates.
 Plasma lipids are transported by lipoproteins particles composed of apoliproteins, phospholipids, free
cholesterol, cholesterol esters and triglycerides.
 Human plasma lipoproteins are separated into five major classes based on density:
 Chylomicrons
 VLDL’s
 Intermidiate-density lipoproteins
 LDL’s
 HDL’s
 *A sixth class Lpa resembles LDL in lipid composition and has a density that overlaps LDL andb HDL.

5. Physical Properties of Plasma Lipoproteins
LIPOPROTEIN
LIPID
COMPOSITION ORIGIN
Chylomicron TG 85%,
Chol 3%
Intestine
VLDL TG 55%,
Chol 20%
Liver
IDL TG 25%,
Chol 35%
Metabolic
product of
VLDL
LDL TG 5%, Chol
60%
Metabolic
product of
IDL
HDL TG5%, Chol
20%
Liver,
Intestine
Lp(a) TG5%, Chol
60%
Liver

7. CHOLESTEROL
METABOLISM
Acetil-CoA Acetoacetyl-CoA
HMG-CoA
Mevalonate
FarnesylPPi
Squalene
Lanosterol
HMG-CoA Syntase
CHOLESTEROL
HMG-CoA Reductase
Cell membrane
Vitamin D
Bile salts
Steroids (Adrenal,Ovaries,
Testes
Insuline
Statins
Glucagon
cholesterol

8. Etiology
 Hypercholesterolemia can be defined as a LDL-cholesterol greater than 190 mg/dL, greater than 160
mg/dL with one major risk factor, or greater than 130 mg/dL with two cardiovascular risk factors.
 The important risk factors include:
 Age; male 45 years or older, female 55 years or older
 A positive family history of premature atherosclerotic cardiovascular disease (younger than 55 years
in a male and younger than 65yrs in a female)
 Hypertension
 Diabetes
 Smoking
 Low HDL-cholesterol levels (less than 40 mg/dl in male and less than 55 mg/dl in a female).

9.  Most common cause is Polygenic hypercholesterolemia which results from an
interaction of unidentified genetic factors compounded by a sedentary lifestyle
and an increased intake of saturated and trans-fatty acids.
 Secondary causes include:
 Hypothyroidism,
 Nephrotic syndrome,
 Cholestasis,
 Pregnancy,
 Certain drugs like
Cyclosporine,
Thiazide diuretics.

10. Lipid abnormality Primary disorders Secondary disorders
Hypercholesterolemia Polygenic, familial hypercholesterolemia,
familial defective apo B-100; PCSK9gain of
function mutation
Hypothyroidism, nephrotic
syndrome, anorexia nervosa.
Hypertriglyceridemia Lipoprotein lipase deficiency, apo C II
deficiency, familial hypertriglyceridemia,
dysbetalipoproteinemia
Diabetes mellitus, obesity,
syndrome, alcohol use, oral
estrogen,renal failure,
hypothyroidism, lipodystrophies.
Combined Familial comnined hyperlipodemia,
dysbetalipoproteinemia
Diabetes mellitus, obesity,
syndrome, nephrotic syndrome,
hypothyroidism, lipodystrophies
Low HDL Familia hypoalphalipoproteinemia, Tangier
disease (ABCA1 deficiency) apoA1mutations,
lecithin-cholesterol acyktransferase
deficiency.
Diabetes mellitus, obesity,
metaboloc syndrome,
hypertriglyceridemia, smoking,
anabolic steroids.

11. FAMILIAL HYPERCHOLESTEROLEMIA
 Classical genetic disorder due to mutations in the LDL-receptor gene resulting in LDL-C
greater than 190 mg/dl in heterozygotes and greater than 450 mg/dl in homozygotes. This
defect in the LDL receptor accounts for at least 85% of familial hypercholesterolemia.

12.  Defective apolipoprotein B (most common
with a mutation at position 3500) resulting
in a loss of ligand binding to the LDL
receptor
 A gain-of-function mutation in proprotein
convertase subtilisin/kexin type 9 (PCSK9) gene
leading to increased affinity of PCSK9 for the LDL-
receptor

13. Epidemiology
 According to the Center for Disease Control and Prevention (CDC), 73.5 million or 31.7% of adults in the United
States have high levels of LDL-C and are at twice the risk for heart disease than people with normal levels.
 Only 48.1% are receiving treatment to lower LDL-C levels.
 Familial hypercholesterolemia has a prevalence of estimate of 1/250,000 as homozygous and 1/200-250 as a
heterozygote.
 In certain populations such as the French Canadians, Lebanese, and Afrikaners it could be as high as 1/100.
 In the US, the highest level of LDL cholesterol occurs in Hispanic males, followed by African Americans and
white males.

14. DIAGNOSIS

15. CLINICAL CRITERIA
 Three sets of clinical criteria have been devised to identify
patients with heterozygous familial hypercholesterolemia. Each
is based on a combination of:
 Lipid levels, typically an LDL-C greater than 190 mg/dL
 Family history of premature coronary artery disease or
familial hypercholesterolemia
 Clinical history
 Physical signs such as xanthelasma (cholesterol deposits
in the skin of the eyelids); xanthoma (deposits in
connective tissue in and around extensor tendons—
pathognomonic for this disease) and arcus cornealis or
corneal arcus (deposits along the corneal border)

16. Criteria Points
Family history
First-degree relative with known premature atherosclerotic cardiovascular disease (age < 55 in men, age < 60 in women) or first-
degree relative with LDL-C > 95th percentile
1
First-degree relative with tendon xanthomas or arcus cornealis, or child under age 18 with LDL-C > 95th percentile 2
Clinical history
Premature coronary artery disease 2
Premature cerebral or peripheral vascular disease 1
Physical examination
Tendon xanthomas 6
Arcus cornealis before age 45 4
LDL-C levels, mg/dL
≥ 330 8
250–329 5
190–249 3
155–189 1
DNA analysis
Functional mutation in the LDLR, APOB, or PCSK9 gene 8
Interpretation Total
Definite familial hypercholesterolemia > 8
Probable familial hypercholesterolemia 6–8
Possible familial hypercholesterolemia 3–5
Unlikely familial hypercholesterolemia < 3
The Dutch Lipid Clinic Network diagnostic criteria for familial
hypercholesterolemia

17. Criterion Description
A Total cholesterol level > 290 mg/dL or LDL-C > 190 mg/dL in adults (age ≥
16)
Total cholesterol level > 260 mg/dL or LDL-C > 155 mg/dL in children (age
< 16)
B Tendon xanthomas in the patient or in a first- or second-degree relative
C DNA-based evidence of a mutation in LDLR, APOB, or PCSK9
D Family history of myocardial infarction before age 50 in a second-degree
relative, or before age 60 in a first- degree relative
E Total cholesterol > 290 mg/dL in a first- or second-degree relative
The Simon Broome diagnostic criteria for familial hypercholesterolemia
Interpretation:
“Definite” familial hypercholesterolemia requires criterion C by itself, or criterion A plus
B;
“probable” familial hypercholesterolemia requires either A plus D, or A plus E.

18. GENETIC TESTING IS THE
GOLD STANDARD
 Genetic testing is the gold standard for diagnosing familial
hypercholesterolemia. Most of the known mutations are
in LDLR, but APOB, PCSK9, and potentially other genes
involved in LDL-C catabolism can also have mutations.

19.  Patients hospitalized for an acute coronary syndrome or
coronary revascularization should have a lipid panel
obtained within 24 hours of admission if lipid levels are
unknown
 Individuals with hyperlipidemia should be evaluated for
potential secondary causes including hypothyroidism,
DM, obstructive liver disease, chronic renal disease
(nephrotic syndrome) and medications such as
estrogens, progestins, anabolic steroids/androgens,
corticosteroids, cyclosporine, retinoids, atypical
antipsychotics and antiretrovirals.

20. SCREENING
 Screening for Hypercholesterolemia should be done in all adults age 20 years or older
 Presence of diabetes
 Tobacco use
 Family history of cardiac disease
 Personal history of heart disease or peripheral vascular disease
 Obesity (BMI > 30)
 Hypertension

21. Screening is best performed with a lipid profile
Total cholesterol
LDL-C, HDL-C, and Triglycerides
OBTEINED AFTER 12 HOUR FASTING
If not fasting:
Total cholesterol and HDL cholesterol
be measured
Non-HDL Cholesterol > 220 mg/dL may indicative of genetic or
secondary cause.
A fasting lipid panel is required if non-HDL Cholesterol is > 220mg/dL
triglycerides > 500 mg/dL

22. LETS REMEMBER !!!

24. CHOLESTEROL
METABOLISM
Acetil-CoA Acetoacetyl-CoA
HMG-CoA
Mevalonate
FarnesylPPi
Squalene
Lanosterol
HMG-CoA Syntase
CHOLESTEROL
HMG-CoA Reductase
Cell membrane
Vitamin D
Bile salts
Steroids (Adrenal,Ovaries,
Testes
Insuline
Statins
Glucagon
cholesterol

25.  Defective apolipoprotein B (most common
with a mutation at position 3500) resulting
in a loss of ligand binding to the LDL
receptor
 A gain-of-function mutation in proprotein
convertase subtilisin/kexin type 9 (PCSK9) gene
leading to increased affinity of PCSK9 for the LDL-
receptor

26. Treatment

27. DIET
 Adopt a diet that is high in fruits and vegetables
 Whole grains
 Fish
 Lean meat
 Low-fat dairy
 Legumes
 Nuts
 Lower intake of red meat
 Low intake of saturated and trans fats, sweets and sugary beverages

28. EXERCISE
Aerobic and resistance exercise recommended in all
patients
For all obese patients (body mas index > 30) and for
overweight patients (body mass index > 25) who have
additional risk factors, sustained weight loss of 3% to
5% or greater reduces ASCVD risk.

29. MEDICATION THERAPY

30. Prior to the start of treatment discuss with your patient:
Potential for ASCVD risk reduction benefits
Potential for adverse effects and drug-drug interactions
Heart healthy lifestyle and management of other risk
factors
Patient preferences

31. Description of Lipid-Lowering Medications
Drug Class Agents Mechanism of Action Lipoprotein
Changes
Statin
•Atorvastatin
•Fluvastatin
•Lovastatin
•Pitavastatin
•Pravastatin
•Rosuvastatin
•Simvastatin
Competitively inhibits HMG-CoA reductase to inhibit cholesterol
synthesis in the liver, resulting in increased expression of LDL-
receptors that accelerates uptake of LDL from blood to liver
LDL-C: ↓ 18%–55%
HDL-C: ↑ 5–15%
TGs: ↓ 7–30%
Cholesterol
absorption
inhibitor
•Ezetimibe Blocks the Niemann-Pick C1-Like 1 receptor to inhibit absorption of
cholesterol, leading to decreased delivery of intestinal cholesterol
the liver reducing hepatic cholesterol stores and increasing
cholesterol clearance from the blood
LDL-C: ↓ 13%–20%
HDL-C: ↑ 3%–5%
TGs: ↓ 5%–11%
Bile acid
sequestrant
•Colesevelam
•Colestipol
•Cholestyramine
Binds intestinal bile acids, impeding reabsorption, upregulating
cholesterol 7-α-hydroxylase, which increases conversion of
cholesterol to bile acids with the increased cholesterol demand in
the liver increasing hepatic LDLRs and increasing cholesterol
clearance from the blood
LDL-C: ↓ 15%–30%
HDL-C: ↑ 3%–5%
TGs: ↓ 0%–10%
PCSK9
inhibitor
•Alirocumab
•Evolocumab
Binds PCSK9, which normally binds to LDLRs to promote LDLR
degradation (LDLR is the primary receptor that clears circulating
LDL); by inhibiting PCSK9 binding to LDLRs, there are increased
number of LDLRs and results in increased cholesterol removal
LDL-C: ↓ 40%–72%
HDL-C: ↑ 0%–10%
TGs: ↓ 0%–17%

34. NEED TO KNOW!!!
CLINICAL ASCVD
 CLINICAL ASCVD INCLUDES:
 Acute coronary syndromes
 History of MI
 Stable angina
 Arterial revascularization
 Stroke
 Transient Ischemic Attack
 Atherosclerotic peripheral arterial disease

35. HIGH INTENSITY
(LDL > 50%)
MEDIUM INTENSITY
(LDL 30%-49%)
LOW INTENSITY
(LDL <30%)
Atorvastatin 40-80 mg
Rosuvastatin 20-40 mg
Atorvastatin 10-20 mg
Fluvastatin 40 mg bid, 80 mg
XL
Lovastatin 40 mg
Pitavastatin 1-4mg
Pravastatin 40-80 mg
Rosuvastatin 5-10 mg
Simvastatin 20-40 mg
Fluvastatin 20-40 mg
Lovastatin 20 mg
Pravastatin 10-20 mg
Simvastatin10 mg
Statin Therapy Regimens by Intensity
• Secondary prevention is an indication for high intensity statin therapy.
• If high-dose statin therapy is contraindicated or poorly tolerated or there are significant risk to
high-intensity therapy (including age >75 years, the maximally tolerated statin therapy is an
option.
• In very-high-risk ASCVD, use LDL-C threshold of 70 mg/dL to consider addition of nonstatins to
statins therapy.
• If Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitor is considered add ezetimibe to
maximal statin before start PCSK9 inhibitor

36. GUIDELANIES FOR THE MANAGEMENT
OF HYPERCHOLESTEROLEMIA
AMERICAN HEART ASSOCIATION /
AMERICAN COLLEGE OF CARDIOLOGY
EUROPEAN SOCIETY OF CARDIOLOGY /
EUROPEAN ATHEROSCLEROTIC SOCIETY

37. Clinical ASCVD
Age 21-75 High-intensity Statin
Age > 75 Moderate-intensity statin
LDL-C > 190 High-Intensity statin
LDL-C 70-189 Age
40-75 Y
10 Y ASCVD
Risk > 7.5%
Moderate- intensity
Statin
DM
LDL-C 70-189
AGE 40-75 Y
10 Y ASCVD
RISK > 7.5%
High-intensity Statin
10 Y ASCVD RISK < 7.5% Moderate-intensity statin
ACC/A
HA

38. ESC/
EAS
Score <1%
LDL-C <100 NO Intervention
LDL-C 100-190 Lifestyle Intervention
LDL-C >190 Consider Drug Treatment
Score 1-5%
LDL-C <100 Lifestyle intervention
LDL-C >100 Consider Drug Treatment
Score 5-10%
Or high Risk
LDL-C <100 Consider Drug Treatment
LDL-C >100 Inmediate drug treatment
Score > 10% or very high
risk
LDL-C <70 Consider drug treatment
LDL-C >70 Inmediate drug treatment