lipoprotein metabolism.pptx

DISORDERS OF
LIPOPROTEIN
METABOLISM
IRENE C. CATAMBING-DAMPIL, MD, FPCP
,
DPSEDM
INTERNIST-ENDOCRINOLOGIST
Mukesh Sah, MD
Mukesh Sah, MD
Mukesh Sah, MD

outline:
what are lipoproteins
lipoprotein metabolism
dyslipidemias
treatment

lipoproteins
large macromolecular complexes composed of lipids and
proteins that transport poorly soluble lipids (primarily
triglycerides, cholesterol, and fat-soluble vitamins)
through body fluids (plasma, interstitial fluid, and lymph)
to and from tissues.
Major role in:
• absorption of dietary cholesterol, long- chain
fatty acids, and fat-soluble vitamins
• transport of triglycerides, cholesterol, and fat-
soluble vitamins from the liver to peripheral tissues;
• transport of cholesterol from peripheral
tissues to the liver and intestine.

LIPOPROTE
INS
PROJECT
DATE
DATE CLIENT
NAME

major classes based on their relative density.
• Plasma lipoproteins are divided into five
major classes based on their relative density.
• Each lipoprotein class comprises a family of
particles that vary in density, size, and
protein composition.
• The density of a lipoprotein particle is
primarily determined by the amount of lipid
per particle.
• Chylomicrons are the most lipid-rich and
therefore least dense lipoprotein particles,
HDLs have the least lipid and are therefore
the most dense lipoproteins.
•

apolipoproteins
The proteins associated with lipoproteins, called
apolipoproteins, are required for
• assembly
• structure
• function
• metabolism
Apolipoproteins
• activate enzymes important in lipoprotein
metabolism
• act as ligands for cell surface receptors.

DISORDERS OF ELEVATED
CHOLESTEROL AND
TRIGLYCERIDES

oly-
e,
dyslipidemias
Disorders of lipoprotein metabolism are collectively
referred to as “dyslipidemias.”
Characterized clinically by increased plasma levels of
cholesterol, triglycerides, or both, variably
accompanied by reduced levels of HDL cholesterol.
Combination of genetic predisposition (often p
genic) and environmental contribution (lifestyl
medical condition, or drug).

Patients with dyslipidemia are at increased risk for ASCVD,
Intervention may reduce this risk.
In addition, patients with substantially elevated levels of triglycerides may be at risk for
acute pancreatitis and require intervention to reduce this risk.

dyslipidemia caused by excessive
hepatic secretion of VLDL
•
One of the most common causes of dyslipidemia.
•Usually have elevated fasting triglycerides and low levels of HDL cholesterol (HDL-C),
with variable elevations in LDL cholesterol (LDL-C) but usually elevated plasma levels
of apoB.
•Cluster of other metabolic risk factors are often found in association with VLDL
overproduction, including obesity, glucose intolerance, insulin resistance, and
hypertension (the so-called metabolic syndrome).
Major factors that drive hepatic VLDL secretion include:
•obesity,
•insulin resistance,
•high-carbohydrate diet,
•alcohol use,
•exogenous estrogens,
•genetic predisposition.

secondary causes of VLDL
overproduction
high carbohydrate diet
alcohol
obesity and insulin resistance

overproduction
NEPHROTIC SYNDROME -
• Nephrotic syndrome is a classic cause of excessive VLDL production.
• mechanism remains poorly understood
• attributed to the effects of hypoalbuminemia leading to increased hepatic protein
synthesis.
• Effective treatment of the underly- ing renal disease often normalizes the lipid
profile, but most patients with chronic nephrotic syndrome require lipid-lowering
drug therapy.

overproduction
CUSHING’S SYNDROME
• Endogenous or exogenous glucocorticoid excess is associated with increased VLDL
synthesis and secretion and hypertriglyceridemia.
• characterized by hypertriglyceridemia and low HDL-C
• elevations in plasma levels of LDL-C can also be seen.

Familial Combined Hyperlipidemia
• The best recognized inherited condition associated with VLDL overproduction is
familial combined hyperlipidemia.
• Characterized by elevations in plasma levels of TGs (VLDL) and LDL-C
(including small dense LDL) and reduced plasma levels of HDL-C.
• Occurs in approximately 1 in 100–200 individuals
• An important cause of premature coronary heart disease (CHD)
Three possible phenotypes:
(1) elevated plasma levels of LDL-C,
(2) elevated plasma levels of TGs due to elevation in VLDL
(3) elevated plasma levels of both LDL-C and TG

Features Suggestive of Diagnosis
• plasma TG levels between 200 and 600 mg/dL
• total cholesterol levels between 200 and 400 mg/dL
• HDL-C levels <40 mg/dL
• Men and <50 mg/dL in women)
• Family history of mixed dyslipidemia
• premature CHD strongly

• Individuals with this phenotype should be treated aggressively due to significantly
increased risk of premature CHD.
• Decreased dietary intake of simple carbohydrates, aerobic exercise, and weight loss
can all have beneficial effects on the lipid profile.
• Patients with diabetes should be aggressively treated to maintain good glucose control.
• Lipid-lowering drug therapy, starting with statins, to reduce lipoprotein levels and
lower the risk of cardiovascular disease.

erally
ell as
ound
of
Generalized Lipodystrophy
• Acondition in which the generation of adipose tissue
gen or in certain fat depots is impaired.
•Often associated with insulin resistance and elevated
plasma levels of VLDL and chylomicrons due to
increased fatty acid synthesis and VLDL production, as w
reduced clearance of TG-rich particles.
•Difficult to control and very rare
• Nearly complete absence of subcutaneous fat, with prof
insulin resistance and leptin deficiency, and accumulation
TGs in multiple tissues including the liver.

Partial Lipodystrophy
• more common
• most notable gene mutation of lamin A.
• Characterized by increased truncal fat accompanied
by markedly reduced or absent subcutaneous fat in
the extremities and buttocks.
• Usually have severe insulin resistance accompanied
by type 2 diabetes, hepatos- teatosis, and
dyslipidemia.
• Characterized by elevated TGs and cholesterol
and can be difficult to manage clinically.
• Increased risk of atherosclerotic vascular disease and
are treated aggressively with statins

Dyslipidemia caused by
impaired lipolysis of TG rich
lipoproteins
LPL is the key enzyme responsible for hydrolyzing the TGs in chylomicrons and VLDL.
LPL is synthesized and secreted into the extracellular space from adipocytes, myocytes,
and cardiomyocytes. It is then transported from the subendothelial to the vascular
endothelial surfaces by GPIHPB1. LPL is also synthesized in macrophages.
Individuals with impaired LPL activity, whether secondary or due to a primary genetic
disorder, have elevated fasting TGs and low levels of HDL-C, usually without elevation
in LDL-C or apoB.
Insulin resistance, in addition to causing excessive VLDL production, can also cause
impaired LPL activity and lipolysis.

Dyslipidemia caused by
impaired lipolysis of TG rich
lipoproteins (TRLs)
Secondary Causes of Impaired Lipolysis of TRLs RESISTANCE
•obesity
•insulin resistance
•type 2 diabetes
Proposed mechanisms:
•tissue insulin resistance
•reduced transcription of LPL in skeletal muscle and adipose,
•increased production of the LPL inhibitor apoC-III by the liver.

Primary/Genetic Causes
Impairing Lipolysis of TRL’s
FAMILIAL CHYLOMICRONEMIA
LPL is required for the hydrolysis of TGs in chylomicrons and
VLDLs, and apoC-II is a cofactor for LPL.
Genetic deficiency or inactivity of either protein results in impaired
lipolysis and profound elevations in plasma chylomicrons.
Elevated plasma levels of VLDL, but chylomicronemia predominates.
The fasting plasma is turbid, and if left at 4°C (39.2°F) for a few
hours, the chylomicrons float to the top and form a creamy
supernatant.
fasting TG levels are almost invariably >1000 mg/dL.

Primary/Genetic Causes
Impairing Lipolysis of TRL’s
LPL Deficiency which is autosomal recessive inheritance
frequency of approximately 1 in 1 million in the population.
Multiple different mutations in the LPL andAPOC2 genes cause these
diseases.
Obligate LPL heterozygotes often have mild-to-moderate elevations in
plasma TG levels, whereas individuals heterozygous for mutation in
apoC-II do not have hypertriglyceridemia.

Both LPL and apoC-II deficiency usually present in childhood with recurrent
episodes of severe abdominal pain due to acute pancreatitis.
On funduscopic examination, the retinal blood vessels are opalescent (lipemia
retinalis).
Eruptive xanthomas, which are small, yellowish- white papules, often appear in
clusters on the back, buttocks, and extensor surfaces of the arms and legs.
Hepatosplenomegaly results from the uptake of circulating chylomicrons by
reticuloendothelial cells in the liver and spleen.
Premature CHD is not generally a feature of familial chylomicronemia syndromes.

The diagnoses of LPL and apoC-II deficiency are established enzy-
matically in specialized laboratories by assaying TG lipolytic activity
in postheparin plasma.
Molecular sequencing of the genes can be used to confirm the
diagnosis.

TREA
TMENT
The major therapeutic intervention in familial chylomicronemia
syndrome is dietary fat restriction (to as little as 15 g/d) with fat-
soluble vitamin supplementation. Fish oils have been effective in some
patients.
Gene therapy (alipogene tiparvovec) is approved for LPL deficiency in
Europe; it involves multiple intramuscular injections of an adeno-
associated viral vector encoding a gain-of-function LPL variant,
leading to skeletal myocyte expression of LPL.

APO-A
V DEFICIENCY
Apolipoprotein, ApoA-V
, facilitates the association of VLDL and
chylomicrons with LPL and promotes their hydrolysis.

GP1HBP1 deficiency
Homozygosity for mutations that interfere with
GPIHBP1 synthesis or folding cause severe
hypertriglyceridemia by compromising the transport
of LPL to the vascular endothelium. The frequency
of chylomicronemia due to mutations in GHIHBP1
has not been established but appears to be very rare.

familial hypertriglycedemia
Characterized by:
• elevated fasting TGs without a clear secondary cause,
• average to below average LDL-C levels,
• low HDL-C levels
• family history of hypertriglyceridemia.
Plasma LDL-C levels are often reduced due to defective conversion of
TG-rich particles to LDL.
Not generally associated with a significantly increased risk of CHD.
Significant pancreatitis risk

familial hypertriglycedemia
It is important to consider and rule out secondary causes of the
hypertriglyceridemia:
• Increased intake of simple carbohydrates,
• obesity
• insulin resistance
• alcohol use
• estrogen treatment
Patients who are at high risk for CHD due to other risk factors should be
treated with statin therapy.
Patients with plasma TG levels >500 mg/ dL after a trial of diet and
exercise should be considered for drug therapy with a fibrate or fish oil to
reduce TGs in order to prevent pancreatitis.

DYSLIPIDEMIACAUSED BY
IMPAIRED HEPA
TIC UPTAKE OF
APOB CONTAINING LIPOPROTEINS
Impaired uptake of LDL and remnant lipoproteins by the liver is another
common cause of dyslipidemia.
The LDL receptor is the major receptor responsible for uptake of LDL and
remnant particles by the liver.
Downregulation of LDL receptor activity or genetic variation that reduces the
activity of the LDL receptor pathway leads to elevations in LDL-C.
One major factor that reduces LDL receptor activity is a diet high in saturated
and trans fats.
Other medical conditions that reduce LDL receptor activity include
hypothyroidism and estrogen deficiency.

secondary causes of
impaired hepatic uptake
THYROIDISM
Hypothyroidism is associated with elevated plasma LDL-C levels due
primarily to a reduction in hepatic LDL receptor function and delayed
clearance of LDL.
Thyroid hormone increases hepatic expression of the LDL receptor.
Hypothyroid patients also frequently have increased levels of circulating IDL,
and some patients with hypothyroidism also have mild hypertriglyceridemia.
Thyroid replacement therapy usually ameliorates the hypercholesterolemia; if
not, the patient probably has a primary lipoprotein disorder and may require
lipid-lowering drug therapy with a statin.

chronic kidney disease
• Associated with mild hypertriglyceridemia (<300 mg/ dL) due
to the accumulation of VLDLs and remnant lipoproteins in the
circulation.
• TG lipolysis and remnant clearance are both reduced in
patients with renal failure.
• decreased LPL activity may also be a factor
• Because the risk of ASCVD is increased in end-stage renal
disease, subjects with hyperlipidemia, they should usually be
aggressively treated with lipid-lowering
•
Patients with solid organ transplants often have increased lipid
• levels due to the eﬀect of the drugs required for
immunosuppression.

primary causes of impaired
hepatic uptake of lipoproteins
• At least 50% of variation in LDL-C is genetically determined.
• M a ny p a t i en t s w i t h e le v a t e d LD L- C h a v e p o l
y g e ni c hypercholesterolemia characterized by hypercholesterolemia
in the absence of secondary causes of hypercholesterolemia
(other than dietary factors) or a primary Mendelian disorder.
• In patients who are genetically predisposed to higher LDL-C levels, diet
plays a key role; saturated and trans fats in the diet shifts the entire
distribution of LDL levels in the population to the right.
•

familial
hypercholesterolemi
a
• FH, also known as autosomal dominant hypercholesterolemia (ADH) type 1,
• autosomal co- dominant disorder
• characterized by elevated plasma levels of LDL-C in the absence of
hypertriglyceridemia.
• FH is caused by loss-of-function mutations in the gene encoding the LDL
receptor. The reduction in LDL receptor activity in the liver results in a reduced
rate of clearance of LDL from the circulation.
• The plasma level of LDL increases to a level such that the rate of LDL production
equals the rate of LDL clearance by residual LDL receptor as well as non-LDL
receptor mechanisms.

familial hypercholesterolemia
•approximately 1 in 250 individuals,
•one of themost common single-gene disorders in humans. Dominant inheritance
•FH has a higher prevalence in certain founder populations, such as South African
Afrikaners, Christian Lebanese, and French Canadians.
•Heterozygous FH is characterized by elevated plasma levels of LDL-C (usually
200– 400 mg/dL) and normal levels of TGs.
•Patients with heterozygous FH have hypercholesterolemia from birth, and disease
recognition is usually based on detection of hypercholesterolemia on routine
screening,

familial
hypercholesterolemi
a
Inheritance is dominant, (inherited from one parent and ~50% of the patient’s
siblings can be expected to have hypercholesterolemia). The family history is
frequently positive for premature CHD on the side of the family from which the
mutation was inherited.
Physical findings
•corneal arcus
•tendon xanthomas particularly involving the dorsum of the hands and the Achilles
tendons.

treatment
Untreated heterozygous FH is associated with a markedly increased risk of
cardiovascular disease. Untreated men with heterozygous FH have an ~50%
chance of having a myocardial infarction before age 60 years,
TREATMENT
low trans fat diet
potent, aggressive statin therapy
LDL apheresis

homozygous FH
receptor defective
receptor negative

homozygous FH
• Homozygous FH is caused by mutations in both alleles of the LDL receptor
• LDL-C levels in patients with homozygous FH range from about 400 to >1000 mg/
dL, with receptor-defective patients at the lower end and receptor-negative patients
at the higher end of the range.
• TGs are usually normal.
• present in childhood with cutaneous xanthomas on the hands, wrists, elbows,
knees, heels, or buttocks.
• The devastating consequence of homozygous FH is accelerated ASCVD, which
often presents in childhood or early adulthood.Atherosclerosis often develops first
in the aortic root, where it can cause aortic valvular or supravalvular stenosis,
• Untreated, receptor- negative patients with homozygous FH rarely survive beyond
the second decade;

familial defective apoB
•autosomal dominant hypercholesterolemia (ADH) type 2
•dominantly inherited disorder that clinically resembles heterozygous FH with
elevated LDL-C levels and normal TGs.
•FDB is caused by mutations in the gene encoding apoB-100, specifically in LDL
receptor–binding domain of apoB-100.
•The mutation results in a reduction in the affinity of LDL binding to the LDL
receptor, so LDL is removed from the circulation at a reduced rate.
•FDB is less common than FH but is more prevalent in individuals of central
European descent; the Lancaster County (United States)Amish are a founder
population in which the prevalence of FDB is as high as 1 in 10 individuals.

FDB
FDB is characterized by elevated plasma LDL-C levels with normal TGs; tendon
xanthomas can be seen, although not as frequently as in FH, and there is an
associated increase in risk of CHD.
Patients with FDB cannot be clinically distinguished from patients with
heterozygous FH, although patients with FDB tend to have somewhat lower
plasma levels of LDL-C than FH heterozygotes, presumably due to the fact that
IDL clearance is not impaired in this disorder.

autosomal dominant
hypercholesterolemia due
to mutations in PCSK9
very rare autosomal dominant disorder caused by gain-of-function mutations in proprotein
convertase subtilisin/kexin type 9 (PCSK9).
PCSK9 is a secreted protein that binds to the LDL receptor, targeting it for degradation.
Normally, after LDL binds to the LDL receptor, it is internalized along with the receptor,
and in the low pH of the endosome, the LDL receptor dissociates from the LDL and
recycles to the cell surface. When PCSK9 binds the receptor, the complex is internalized
and the receptor is directed to the lysosome, rather than to the cell surface.
The missense mutations in PCSK9 that cause hypercholesterolemia enhance the activity of
PCSK9.
As a consequence, the number of hepatic LDL receptors is reduced. Patients with ADH-
PCSK9 are similar clinically to patients with FH. They may be particularly responsive to
PCSK9 inhibitors in clinical development. Loss-of-function mutations in PCSK9 cause low
LDL-C levels

autosomal recessive
hypercholesterolemi
a
• very rare disorder that is mostly seen in individuals of Sardinian descent.
• The disease is caused by mutations in a protein, ARH (also called LDLR adaptor protein,
LDLRAP), which is required for LDL receptor–mediated endocytosis in the liver.
• ARH binds to the cytoplasmic domain of the LDL receptor and links the receptor to the
endocytic machinery. In the absence of LDLRAP
, LDL binds to the extracellular domain of
the LDL receptor, but the lipoprotein-receptor complex fails to be internalized.
• ARH, like homozygous FH, is characterized by hypercholesterolemia, tendon xanthomas, and
premature coronary artery disease (CAD).
• The levels of plasma LDL-C tend to be intermediate between the levels present in FH
homozygotes and FH heterozygotes, and CAD is not usually symptomatic until the third
decade.

sitosterolemia
rare autosomal recessive disease that can result in severe hypercholesterolemia, tendon xanthomas, and
prematureASCVD
caused by loss-of-function mutations in either of two members of theA
TP-binding cassette (ABC)
half transporter family,ABCG5 andABCG8. These genes are expressed in enterocytes and hepatocytes.
The proteins heterodimerize to form a functional complex that transports plant sterols such as sitosterol
and campesterol, and animal sterols, predominantly cholesterol, across the biliary membrane of
hepatocytes into the bile and across the intestinal luminal surface of enterocytes into the gut lumen.
In normal individuals, <5% of dietary plant sterols are absorbed by the proximal small intestine. The
small amounts of plant sterols that enter the circulation are preferentially excreted into the bile. Thus,
levels of plant sterols are kept very low in tissues.
sitosterolemia, the intestinal absorption of sterols is increased and biliary and fecal excretion of the
sterols is reduced, resulting in increased plasma and tissue levels of both plant sterols and cholesterol.
The increase in hepatic sterol levels results in transcriptional suppression of the expression of the LDL
receptor, resulting in reduced uptake of LDL and substantially increased LDL-C levels.
In addition to the usual clinical picture of hypercholesterolemia (i.e., tendon xanthomas and premature
ASCVD), these patients also have anisocytosis and poikilocytosis of erythrocytes and megathrom-
bocytes due to the incorporation of plant sterols into cell membranes. Episodes of hemolysis and
splenomegaly are a distinctive clinical feature of this disease compared to other genetic forms of
hypercholesterolemia and can be a clue to the diagnosis.

cholesterol ester
storage disease
• also known as lysosomal acid lipase deficiency, is an autosomal recessive disorder
characterized by elevated LDL-C, usually in association with low HDL- C,
• Plasma TG levels can also be mild to moderately increased in this disorder.
• The most severe form of this disorder, Wolman’s disease, presents in infancy and is
rapidly fatal. Both Wolman’s disease and CESD are caused by loss-of-function variants
in both alleles of the gene encoding lysosomal acid lipase (LAL; gene name LIPA).
• LAL is responsible for hydrolyzing neutral lipids, particularly TGs and cholesteryl esters,
after delivery to the lysosome by cell-surface receptors such as the LDL receptor.
• It is particularly important in the liver, which clears large amounts of lipoproteins from
the circulation. Genetic deficiency of LAL results in accumulation of neutral lipid in the
hepatocytes, leading to hepatosplenomegaly, microvesicular ste- atosis, and ultimately
fibrosis and end-stage liver disease.
• CESD should be particularly suspected in nonobese patients with elevated LDL-C, low
HDL-C, and evidence of fatty liver in the absence of overt insulin resistance.
• The diagnosis can be made with a dried blood spot assay of LAL activity and confirmed
by DNAgenotyping and liver biopsy

familia
l
dysbetalipoproteineimi
a
(also known as type III hyperlipoproteinemia) is usually a recessive
disorder characterized by a mixed hyperlipidemia (elevated
cholesterol and TGs) due to the accumulation of remnant
lipoprotein particles (chylomicron remnants and VLDL remnants,
or IDL).
FDBL is due to genetic variants of apoE, most commonly apoE2,
that result in an apoE protein with reduced ability to bind
lipoprotein receptors.
associated with slightly higher LDL-C levels and increased CHD
risk,
increased risk of Alzheimer’s disease. ApoE2 has a lower affinity
for the LDL receptor; therefore, chylomicron remnants and IDL
containing apoE2 are removed from plasma at a slower rate.

FDBL
The most common precipitating factors are a high-fat diet, diabetes mellitus, obesity,
hypothyroidism, renal disease, HIV infection, estrogen deficiency, alcohol use, or
certain drugs. The disease seldom presents in women before menopause.
Patients with FDBL usually present in adulthood with hyperlipidemia, xanthomas, or
premature coronary or peripheral vascular disease.
The plasma levels of cholesterol and TG are often elevated to a similar degree, and the
level of HDL-C is usually normal or reduced.
Two distinctive types of xanthomas (pathognomonic)
• Tuberoeruptive xanthomas begin as clusters of small papules on the elbows, knees,
or buttocks and can grow to the size of small grapes.
• Palmar xanthomas (alternatively called xanthomata striata palmaris) are orange-
yellow discolorations of the creases in the palms and wrists.

Goals of therapy
(1) prevention of acute pancreatitis
in patients with severe
hypertriglyceridemia
(2) prevention of CVD and related
cardiovascular events

prevention of pancreatitis
intervention for TG >500 mg/dl
lifestyle modification
reduction/elimination of alcohol
restriction of dietary fat and carbohydrates
aerobic exercise
weight loss for overweight/obese patients

• FIBRATES Fibric acid derivatives, or fibrates
• agonists of PPARα, a nuclear receptor involved in the regulation
of lipid metabolism.
• stimulate LPL activity (enhancing TG hydrolysis), reduce apoC-III
synthesis (enhancing lipoprotein remnant clearance), promote β-
oxidation of fatty acids, and may reduce VLDL TG production.
• first-line therapy for severe hypertriglyceridemia (>500 mg/dL).

• Fibrates
• Sometimes lowers but more often raises the plasma level of LDL-C
• associated with an increase in the incidence of gallstones
• can cause myopathy, when combined with other lipid-lowering
therapy (statins, niacin),
• used with caution in patients with CKD. (can increased creatinine)
• can potentiate the eﬀect of warfarin and certain oral hypoglycemic
agents,

omega 3-fatty acid
• OMEGA 3 FATTY ACIDS
Omega-3 fatty acids, or omega-3 polyunsaturated fatty acids (n-3 PUFAs),
• commonly known as fish oils, are present in high concentration in fish and in flaxseed.
• most widely used: eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA).
• concentrated into tablets and in doses of 3–4 g/d are eﬀective at
lowering fasting TG levels.

omega 3-fatty acid
• reasonable consideration for first- line therapy in patients
with severe hypertriglyceridemia (>500 mg/ dL) to prevent
pancreatitis.
• can increase in plasma LDL-C levels in some patients.
• well tolerated, with the major side eﬀect being dyspepsia.
• but can be associated with a prolongation in the bleeding
time. (3-4g/day)

Niacin
Nicotinic acid, or niacin, is a B-complex vitamin that has been used as a lipid-modifying
agent for more than five decades.
Suppresses lipolysis in the adipocyte through its effect on the niacin receptor GPR109A
and has other effects on hepatic lipid metabolism that are poorly understood.
Reduces plasma TG and LDL-C levels and also raises the plasma concentration of
HDL-C. B
Third-line agent for the management of severe hypertriglyceridemia due to side effects.
SIDE EFFECTS:
Cutaneous flushing
Esophageal refllux
Dyspepsia
Mild elevations in transaminases

prevention of cardiovascular disease
There are abundant and compelling data that intervention to
reduce LDL-C substantially reduces the risk of CVD, including
myocardial infarction and stroke, as well as total mortality.
Thus, it is imperative that patients with hypercholesterolemia
be assessed for cardiovascular risk and for the need for
intervention.

lifestyle
weight loss for overweight or obese patients
dietary counseling for reduction of transfer and
saturated fat intake
exercise

who do we treat?
10 year risk >7.5%
warrants
pharmacologic
treatment

HMG CoA Reductase Inhibitors
(Statins)
inhibits the key enzyme in cholesterol biosynthesis
increases hepatic LDL-receptor activity, leading to
increased LDL clearance = decreased LDL levels
decreases TG levels
Modest HDL increase
drug class of choice

Statins
well tolerated
side eﬀects: headache, muscle pains, fatigue,
joint pains, rarely hepatitis, and new onset DM
Myopathy - rare side eﬀects, more common in the
frail, elderly, combination with other meds (e.g.
fibric acids, erythromycin, immunosuppressives
etc
may cause transient transaminase increase

cholesterol absorption inhibitors
Ezetimibe is a cholesterol absorption inhibitor that binds directly to and
inhibits NPC1L1 and blocks the intestinal absorption of cholesterol.
Inhibits cholesterol absorption by almost 60%, resulting in a reduction
in delivery of dietary sterols in the liver and an increase in hepatic LDL
receptor expression.
The mean reduction in plasma LDL-C on ezetimibe (10 mg) is 18%,
Eﬀects on TG and HDL-C levels are negligible.
The only roles for ezetimibe in monotherapy are in patients who do not
tolerate statins

bile acid sequestrants
bind bile acids in the intestine and promote their excretion rather than
reabsorption in the ileum.
T
o maintain the bile acid pool size, the liver diverts cholesterol to bile
acid synthesis. The decreased hepatic intracellular cholesterol content
results in upregulation of the LDL receptor and enhanced LDL clearance
from the plasma.
Can cause an increase in plasma TGs.
Most side eﬀects of resins are limited to the gastrointestinal tract and
include bloating and constipation.
Not systemically absorbed, they are very safe and the cholesterol-
lowering drug of choice in children and in women of childbearing age
who are lactating, pregnant, or could become pregnant. T

Lomitapide -small-molecule inhibitor of MTP
,
These drugs reduce VLDL production and LDL-C levels in homozygous FH
Causes an increase in hepatic fat, the long-term consequences of which are
SPECIALIZE
D
orphan drugs
DRUGS FOR HOMOZYGOUS FH -
antisense oligonucleotide against apoB
Lomitapide
Mipomersen -
These drugs r
patients.
Causes an
unknown.

LDL APHERESIS
Patients who remain severely hypercholesterolemic despite optimally
tolerated drug therapy are candidates for LDL apheresis. In this
process, the patient’s plasma is passed over a column that
selectively removes the LDL, and the LDL-depleted plasma is
returned to the patient.
Patients on maximally tolerated combination drug therapy who have
CHD and a plasma LDL-C level >200 mg/dL or no CHD and a
plasma LDL-C level >300 mg/ dL are candidates for every-other-
week LDL apheresis

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