Transcript LDL-C

Dyslipidemia
DISORDERS OF LIPIDS AND LIPOPROTEINS
For Fourth- year Medical students
Dr: Hussein Mohammed Jumaah
CABM
Mosul Medical College
9/3/2014
Lipid Metabolism
Cholesterol and triglyceride(TG) are
insoluble
Plasma lipoproteins : large complexes
composed of hydrophobic core of TG and
cholesterol ester(CE), enveloped by
hydrophilic surface coat of phospholipid (PL),
unesterified ("free") cholesterol, and
apolipoproteins (with detergent-like
properties),
play an essential role in the absorption of
hydrophobic lipids: dietary cholesterol, fatsoluble vitamins; TG, and their transport from
the liver to peripheral tissues; and vice versa.
"lipoprotein" combination of
"lipid and protein."
Transport of Dietary Lipids
Exogenous Pathway
Dietary triglycerides emulsified by bile
(( Bile salts attach to TG to emulsify them, which aids access by pancreatic lipase))
and hydrolyzed by lipases
((monoglycerides and fatty acids are liberated))
within the intestinal lumen and form micelles.
Enterocytes extract monoglyceride and free fatty acids from micelles and
re-esterify them into TG. TG is combined with (Apoprotein B48) ,CE, PL and
cholesterol to produce chylomicrons, secreted into the intestinal lymph ,delivered
via the thoracic duct to the systemic circulation.
Intestinal cholesterol (dietary and biliary sources) ,fatty
acids, and fat-soluble vitamins are absorbed in the
proximal small intestine .
(a specific transport protein (Niemann-Pick C1-Like 1 NPC1L1) has been identified that
ferries cholesterol from the intestinal lumen into the enterocyte). A bulk of the cholesterol is
esterified, incorporated into chylomicrons .
Lacteals(lymphatic capillary)
Figure 16.13 Structure of lipoproteins
Chylomicrons pass into the lacteals, forming a milky substance
known as chyle. The lacteals merge to form larger lymphatic
vessels that transport the chyle to the thoracic duct where it is
emptied into the subclavian vein
Chylomicron is hydrolysed by lipoprotein lipase.
(Released free fatty acids are taken up by adjacent myocytes or adipocytes and either
oxidized to generate energy or reesterified and stored as triglyceride).
The residual 'remnant' chylomicron particle cleared
by (LDL)-receptors in the liver.
Complete absorption of dietary lipids takes about
6-10 hours, so chylomicrons are undetectable in
the plasma after a 12-hour fast.
Chylomicrons and VLDL are TG rich, carrying
dietary and liver produced TG respectively.
Most plasma cholesterol is carried as cholesteryl
esters in LDLs and HDLs.
The density of a lipoprotein
Is determined by the amount
of lipid per particle. HDL is
the smallest and most dense
because they contain the
highest proportion of protein
to cholesterol.
Chylomicrons and VLDLs are
the largest and least dense
lipoprotein particles.
HDL High-density lipoprotein
LDL Low-density lipoprotein
IDL Intermediate-density lipoprotein
VLDL Very low-density lipoprotein
CETP Cholesteryl ester transfer protein enzyme
LCAT Lecithin:cholesterol acyltransferase enzyme
HMGCoAR = hydroxy-methyl-glutaryl-coenzyme A reductase
Endogenous lipid
In the fasting state, the liver is the major source of
plasma lipids, Lipoprotein lipase converts VLDL to
remnant particles called IDL.
(The released free fatty acids are taken up by adjacent myocytes or adipocytes and either
oxidized to generate energy or reesterified and stored as triglyceride, Most IDL cleared by
LDL receptors in the liver, some are processed by hepatic lipase to an LDL).
Also VLDL transfer phospholipids and TGs to HDL in
exchange for CE via CETPenzyme and eventually VLDL are
converted to cholesterol-rich LDL molecules.
70% of circulating LDL is cleared by liver LDL receptor . Delivery of cholesterol via this
pathway down-regulates further expression of the LDL receptor gene and reduces the
synthesis and activity of the rate-limiting enzyme for cholesterol synthesis, HMGCoA
reductase. These negative feedback pathways, control the intracellular free cholesterol
level within a narrow range.
Cholesterol derived from LDL regulates several processes and can be used for the synthesis
of bile acids, steroid hormones, and cell membranes.
Reverse cholesterol transport
HDL particles are synthesized and catabolized in
the liver and intestines.
Peripheral tissues are guarded against excessive
cholesterol accumulation by HDL . Nascent HDL
obtains free cholesterol from peripheral tissues.
Acirculating enzyme, LCAT promotes the uptake of
free cholesterol by HDL (esterification).
HDL release their cholesterol to the liver via the
scavenger receptor B1 (SRB1).
CETP mediates the transfer of CE from the HDL or
LDL to VLDL or chylomicrons in exchange for TG.
The proteins associated with lipoproteins, called
apolipoproteins, are required for the assembly,
structure, and function of lipoproteins.
ApoA-I, which is synthesized in the liver and
intestine, is found on virtually all HDL particles.
ApoA-II is on approximately two-thirds of all HDL
particles.
ApoB is the major structural protein of
chylomicrons, VLDLs, IDLs, and LDLs; one
molecule of apoB, either apoB-48 (chylomicron) or
apoB-100 (VLDL, IDL or LDL), is present on each
lipoprotein particle.
Lipids and cardiovascular disease
Plasma lipoprotein levels are major modifiable
risk factors for cardiovascular disease.
Increased levels of atherogenic lipoproteins
((especially LDL, IDL, lipoprotein (a) and
possibly chylomicron remnants)) contribute to
the development of atherosclerosis.
Increased plasma concentration and reduced
diameter favour subendothelial accumulation of
these lipoproteins. Following oxidation, Apo Bcontaining lipoproteins are no longer cleared
by normal mechanisms.
Lipids and cardiovascular disease
They trigger a self-perpetuating inflammatory
response during which they are taken up by
macrophages to form foam cells, a hallmark of
atherosclerotic lesions.
Conversely, HDL removes cholesterol from the
tissues to the liver, where it is metabolised and
excreted in bile. HDL may also counteract some
components of the inflammatory response.
Consequently, low HDL cholesterol levels, which
are often associated with triglyceride elevation,
also predispose to atherosclerosis.
Primary lipid abnormalities
The Fredrickson classification (types I-V) adds little to clinical decision-making.
Alternatively, primary lipid abnormalities can
be classified according to the
predominant lipid problem:
1. Hypercholesterolaemia,
2. Hypertriglyceridaemia
3. Mixed hyperlipidaemia
Classification of primary hyperlipidaemia
1.Predominant hypercholesterolaemia
Polygenic (majority)
Familial hypercholesterolaemia
Hyperalphalipoproteinaemia
2.Predominant hypertriglyceridaemia
Polygenic (majority)
Familial hypertriglyceridaemia
Lipoprotein lipase deficiency
3.Mixed hyperlipidaemia
Polygenic (majority)
Familial combined hyperlipidaemia
Dysbetalipoproteinaemia
Predominant hypercholesterolaemia
Polygenic hypercholesterolaemia
The most common cause increase in LDL-C. Physical signs,
such as corneal arcus and xanthelasma, The risk of
cardiovascular disease(CVD) is proportional to the
degree of LDL-C (or Apo B) elevation, but is modified by
other major risk factors, particularly low HDL-C.
Familial hypercholesterolaemia (FH)
Autosomal dominant , premature CVD. Xanthomas of
the Achilles or extensor digitorum tendons. Corneal arcus
before age 40 .
Hyperalphalipoproteinaemia
Increased levels of HDL-C. does not cause CVD.
Predominant hypertriglyceridaemia
Polygenic the most common cause. if level exceed
10 mmol/L (880 mg/dL), may pose a risk of acute
pancreatitis, may contribute to cardiovascular risk.
Lipoprotein lipase deficiency autosomal recessive,
massive hypertriglyceridaemia that is not
amenable to treatment. It may commence in
childhood and is associated with pancreatitis.
hepatosplenomegaly, lipaemia retinalis and
eruptive xanthomas
Familial hypertriglyceridaemia dominant
inheritance. also pose a risk of pancreatitis.
Primary mixed hyperlipidaemia
Hypertriglyceridaemia , increase in LDL or IDL, is usually polygenic,
often in association with type 2 diabetes, central obesity, increase
risk of CVD.
Familial combined hyperlipidaemia
Is a dominantly inherited. The overproduction of atherogenic Apo Bcontaining lipoproteins.It results in elevation of cholesterol, TG or
both in different family members at different times. It is associated
with an increased risk of CVD but it does not produce any
pathognomonic physical signs.
Dysbetalipoproteinaemia
(type 3, broad-beta or remnant hyperlipidaemia). Accumulation of
roughly equimolar levels of cholesterol and TG. Premature
cardiovascular disease is common and it may also result
in the formation of palmar xanthomas, tuberous xanthomas
or tendon xanthomas.
Causes of secondary hyperlipidaemia
Secondary
hypercholesterolaemia
Moderately common
1. Hypothyroidism
2. Pregnancy
3. Cholestatic liver disease
4. Drugs (diuretics, ciclosporin,
corticosteroids, androgens,
antiretroviral agents)
Less common
Nephrotic syndrome
Anorexia nervosa
Porphyria
Hyperparathyroidism
Secondary hypertriglyceridaemia
1.
2.
3.
4.
5.
6.
Diabetes mellitus (type 2)
Chronic renal disease
Abdominal obesity
Excess alcohol
Hepatocellular disease
Drugs (β-blockers, retinoids,
corticosteroids, antiretroviral agents)
Clinical manifestations
of hyperlipidaemia.
Note that xanthelasma
and corneal arcus may be
non-specific, especially in
later life.
What are xanthomas?
Skin lesions caused by the
accumulation of fat in
macrophage in the skin
and more rarely in the
layer of fat under the skin.
Tuberous and Tuberoeruptive Xanthomas
Firm , nontender cutaneous and subcutaneous
nodules,on extensor surfaces of the joints,in areas
of prior trauma.
Eruptive Xanthomas
Crops of small, red-yellow painless papules, on
an erythematous base on the torso, elbows
,chest, and buttock regions. may be tender and
itchy
Plane xanthomas
Flat papules anywhere on the body,on the creases
of the palms ( palmar xanthoma ) are indicative
of a type III dysbetalipoproteinaemia
Tendinous xanthoma papules and
nodules associated with Type II
hyperlipidaemia , found in the tendons
of the hands, feet, and Achilles tendon
Lipid measurement
performed for
1. Screening for primary or secondary prevention of CVD
disease .
2. Investigation of patients with clinical features of lipid
disorders.
3. Testing relatives of patients with dyslipidaemia.
Levels of (TC), (TG) and (HDL-C) need to be obtained after
12-hour fast to permit accurate calculation of (LDL-C)
according to the
Friedewald formula (LDL-C = TC - HDL-C - (TG/2.2)
mmol/L). (mg/dL can be converted to mmol/L by dividing by
38 for cholesterol and 88 for triglycerides.) .
The formula unreliable when TG levels exceed 4 mmol/L (350 mg/dL). (requires
ultracentrifugation techniques or direct assays for LDL-C).
Hypertriglyceridaemia interferes with the serum
amylase assay ,produce a falsely low result.
Urine amylase to creatinine ratio measured to
diagnose acute pancreatitis, the result less likely
affected by hypertriglyceridaemia.
Alternatives :removal of lipids before serum
amylase measurement by using ultracentrifugation..
Non-fasting samples are often used to guide therapeutic decisions since they are
unaffected in terms of TC and measured LDL-C, albeit that they differ from fasting
samples in terms of TG, HDL-C and, to some extent, calculated LDL-C.
Direct measurement of VLDL and LDL is also possible; however, due to high cost and
technical complexity, these are performed primarily in reference lab.
‫اليكم بعض التمرينات الخاصه بمنطقه البطن لتقوية عضالتها‬
‫والمداومه عليها تساعد على اختفاء ما يسمى بالكرش‬
Management of dyslipidaemia
Lipid-lowering therapies have a key role in the
secondary and primary prevention of CVD.
Assessment of absolute risk, treatment of all
modifiable risk factors and optimisation of lifestyle,
especially diet and exercise, are central to
management in all cases.
The benefit of lipid lowering is proportional to the
risk of coronary heart disease (CHD) in the
individual patient.
The greatest benefit is obtained in patients with established CHD.
In general, patients who already have CHD, diabetes mellitus, chronic renal impairment or
an absolute risk of cardiovascular disease of greater than 20% in the ensuing 10 years are
arbitrarily regarded as having sufficient risk to justify drug treatment.
Management of dyslipidaemia
Target levels for patients receiving drug treatment.
High-risk patients should aim for HDL-C > 1
mmol/L (38 mg/dL) and fasting TG < 2 mmol/L
(approximately 180 mg/dL), whilst target levels for
LDL-C have been reduced from 2.5 to 2.0 mmol/L
(76 mg/dL) or less.
In general, total cholesterol should be < 5 mmol/L
(190 mg/dL), and < 4 mmol/L (approximately
150 mg/dL) in high-risk patients and in
secondary prevention of CVD.
Non-pharmacological management
Therapeutic Lifestyle Changes (TLC)
Dietary counselling to reduce intake of saturated and
trans-unsaturated fat to less than 7-10% of total energy ,
cholesterol to < 250 mg/day.
Replace sources of saturated fat and cholesterol with
alternative foods ,lean meat, low-fat dairy products, low
glycaemic index carbohydrates.
Increase consumption of cardioprotective , fruit,
vegetables, fish, pulses, nuts, legumes.
Reduce energy-dense foods such as fats, soft drinks, whilst
increasing activity and exercise to maintain or lose weight.
Non-pharmacological management
Therapeutic Lifestyle Changes (TLC)
Even minor weight loss can substantially reduce
cardiovascular risk, especially in centrally obese
patients, adjust alcohol consumption.
Additional benefits with intake of foods
containing lipid-lowering nutrients such as n-3 fatty
acids, dietary fibre and plant sterols.
If possible, drug that adversely affect the lipid
profile should be replaced.
Dietary fats and their food sources
Fatty meats (beef, pork) Poultry skin
Butterfat (in whole milk, cream, ice
cream, cheese) Tropical oils (coconut,
palm) Chocolate
Raises LDL ("bad" cholesterol)
Little effect on HDL ("good"
cholesterol) or triglycerides
Monounsaturated
fat
Olive oil
Peanut oil
Canola oil
Lowers LDL if substituted for
saturated fat
Keeps HDL up
Polyunsaturated fat
Sunflower oil
Sesame oil
Corn oil
Soybean oil
Linoleic acid in moderation can
lower LDL
Omega-3 fats
All fish, especially fatty fish, such
as salmon and mackerel
Plant sources, such as walnuts,
canola, and flaxseed oils
Lowers triglycerides
"Thins" the blood
Trans fatty acids
Hydrogenated fats, margarine,
vegetable shortening, nondairy creamer
and whipped toppings Snack foods
(potato chips, cookies, cakes) Peanut
butter that contains hydrogenated fat
Raises LDL
Little effect on HDL but at high
levels can lower HDL
Saturated fat
Very low-fat diets
Although may indeed lower cholesterol levels,
they are not recommended.
A diet with less than 25% of its calories from fat
can increase triglycerides and decrease HDL.
Such a diet may deplete your body of other
important nutrients and vitamins.
In comparison, a cholesterol-reducing diet
allows 25% to 35% of calories to come from
total fat, with 7% from saturated fat.
Pharmacological management
Predominant hypercholesterolaemia
HMGCoA reductase inhibitors (statins)
Statins inhibit cholesterol synthesis, up-regulating activity
of the LDL receptor. This increases clearance of LDL and
its precursor, IDL, resulting in a secondary reduction in
LDL synthesis.
Reduce LDL-C by up to 60%, TG by up to 40% and
increase HDL-C by up to 10%. There is clear evidence
of protection against total and coronary mortality,
stroke and cardiovascular events in high-risk patients .
'Meta-analysis of major RCTs involving over 90 000 subjects receiving statins for an average of 5
years showed reduced mortality from coronary artery disease, 19%, stroke, 17%) per 1 mmol/L
reduction in LDL-C
Statins are generally well tolerated and
serious side-effects are rare (below 2%).
Liver function test abnormalities , myalgia,
asymptomatic increase in CK, myositis and,
infrequently, rhabdomyolysis.
Side-effects are more likely in
1. Patients who are elderly,
2. Debilitated or
3. Receiving other drugs that interfere with statin
degradation, which usually involves
cytochrome P450 3A4 or glucuronidation.
Cholesterol absorption inhibitors
Ezetimibe inhibit the intestinal mucosal
transporter NPC1L1 that absorbs dietary and
biliary cholesterol. This action is synergistic with
the effect of statins. 10 mg/day dose reduces
LDL-C by 15-20%.
well tolerated, but its effect on cardiovascular
disease endpoints is yet to be determined.
Plant sterol-also reduce cholesterol absorption,
lower LDL-C by 7-15%.
Bile acid sequestering resins, such as
colestyramine, colestipol and colesevalam
Prevent the reabsorption of bile acids, thereby
increasing de novo bile acid synthesis from hepatic
cholesterol, the resultant depletion of hepatic
cholesterol up-regulates LDL receptor activity and
reduces LDL-C in a manner that is synergistic with the
action of statins. High doses can achieve substantial
reductions in LDL-C and modest increases in HDL-C,
but TG may rise. Resins are safe, but they may
interfere with bioavailability of other drugs.
Colesevalam may cause fewer gastrointestinal effects
than older preparations.
Plant sterols and stanols have a structure very
similar to that of cholesterol.
Sterols are found naturally in small quantities in
many fruits, vegetables, nuts, seeds, legumes
Stanols are found in trace levels in similar
foodstuffs but are produced by hydrogenation
of plant sterols for commercial use.
Foods enriched with stanols or sterols lower
serum cholesterol levels by reducing intestinal
absorption of cholesterol.
Predominant hypertriglyceridaemia
Fibrates
Stimulate peroxisome proliferator activated receptor
(PPAR) alpha, which controls the expression of gene
products that mediate the metabolism of TG and HDL. Act
upon lipoprotein lipase by increasing its activity, resulting
in a reduction in TG by up to 50% and increase HDL-C by
up to 20%, but LDL-C changes are variable. well tolerated,
share a similar side-effect profile to statins, myalgia,
abnormal liver function tests,may increase the risk of
cholelithiasis and prolong the action of anticoagulants.
If target levels are not achieved, the fibrates or nicotinic acid and fish oil can be combined.
Insulin deficiency should be corrected for optimal activity of lipoprotein lipase.
Nicotinic acid (vitamin B3)
In pharmacological doses, this
reduces peripheral fatty acid
release with the result that
cholesterol and TG decline whilst
HDL increases.
Side-effects : flushing, gastric
irritation, liver function disturbances,
exacerbation of gout and
At higher doses decrease
hyperglycaemia.
lipolysis in the peripheral tissues,
Slow-release formulations and low- also inhibit synthesis and
dose aspirin may reduce flushing.
esterification of fatty acids in
Combination therapy with the
liver. and therefore it decreases
prostaglandin D2 receptor inhibitor lipid level in blood.
laropiprant to further reduce flushing at lower doses it used as vitamin
is being evaluated.
and in the treatment of Pellagra
Highly polyunsaturated long-chain n-3 fatty acids
Eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA) comprise approximately 30% of the fatty
acids in fish oil.
EPA and DHA are potent inhibitors of VLDL TG
formation. Intakes of greater than 2 g n-3 fatty acid
(equivalent to 6 g of most forms of fish oil) per day
lower TG in a dose-dependent fashion. Up to 50%
reduction in TG may be achieved with 15 g fish oil
per day.
Changes in LDL-C and HDL-C are variable. Fish oil fatty acids have also been shown
to inhibit platelet aggregation and improve cardiac arrhythmia in animal models.
Dietary and pharmacological trials indicate that n-3 fatty acids reduce mortality
from coronary heart disease.
Mixed hyperlipidaemia
Can be difficult to treat. Statins alone are less effective
first-line therapy once fasting TG exceeds around 4 mmol/L
(350 mg/dL). Fibrates alone are first-line therapy for
dysbetalipoproteinaemia, but they may not control the
cholesterol component.
Combination therapy is often required.
Effective combinations include: statin plus fish oil; fibrate
plus ezetimibe; statin plus nicotinic acid; or statin plus
fibrate.
Fibrates are effective in combination with statins but the risk
of myopathy is increased.
There is some evidence that fenofibrate is safer than
gemfibrozil in this regard.
Monitoring of therapy
The effect of drug therapy can be assessed
after 6 weeks (12 weeks for fibrates), and it is
prudent to review side-effects, lipid response,
CK and liver function tests at this stage.
Follow-up should encourage continued
compliance (especially diet and exercise), and
include monitoring for side-effects and
cardiovascular symptoms or signs, and
measurement of weight, blood pressure and
lipids, as well as review of absolute
cardiovascular disease risk status.
If myalgia or weakness is associated with CK
elevation > 5-10 times the upper limit of
normal, or if sustained alanine aminotransferase
(ALT) elevation > 2-3 times the upper limit of
normal is detected, treatment should be
interrupted and alternative therapy sought.
In combined therapy, fibrates should be given
in the morning and
statins at night so that the peak dosages do
not overlap.
Dyslipidaemia in pregnancy
Cardiovascular disease is very unlikely amongst women of childbearing age, but is possible in women with severe risk factor
profiles or familial hypercholesterolaemia.
Lipid metabolism:
lipid and lipoprotein levels increase during pregnancy. Increase in
LDL-C which resolves post-partum. hypertriglyceridaemia may be
exacerbated.
Treatment:
Dyslipidaemia is rarely thought to warrant treatment.
Teratogenicity has been reported with systemically absorbed
agents, and non-absorbed agents may interfere with nutrient
bioavailability.
Management of hyperlipidaemia in the elderly
Benefit of statin therapy: maintained up to the age of 80.
Myocardial infarction
Maximal postinfarction reductions in total cholesterol
occur at days 4 to 5 with levels 47% below baseline;
L &HDL decrease to their nadir on day 7 to 48% and 32%
below baseline, respectively.
Triglyceride increase 58% above baseline on day 7.
These alterations generally stabilize by 2 months after
the event. cholesterol levels are no longer valid after 24 h
from presentation. Nevertheless, several studies have shown
that the total /HDL and the LDL /HDL ratio are also strong
predictors of coronary events, ratios remained unchanged.
Therefore, most experts recommend measuring the serum cholesterol levels within the first
24 h after the onset of MI or measure the ratios.
The ratios of total to HDL cholesterol and LDL to HDL cholesterol that correlate with the
development of coronary events are 4.5 (Ideally, one should strive for ratios of 2 or 3
and 2.5, respectively.