4. Dyslipidemia
• Disorders of lipoprotein metabolism are collectively referred
to as dyslipidemias.
• This includes lipoprotein overproduction or deficiency.
• Dyslipidemias are generally characterised clinically by
increased plasma levels of cholesterol, triglycerides or both
and variably accompanied by reduced level of HDL cholesterol.
Modern correlations
5.
6. Lipoproteins
• Lipoproteins are complexes of Lipids (core) and proteins (cover).
• The Lipids (core) part consists of cholesterol esters (CE) and triglycerides (TG).
• The outer cover consists of proteins (apolipoprotein).
• Lipoproteins transport triglycerides and cholesterol from the liver and gut,
delivers to the periphery muscles and adipocytes for energy, cellular
maintenance and steroid creation.
• TAG-rich lipoproteins
Chylomicrons
VLDL
• Cholesterol-rich lipoproteins
LDL
HDL
7. Major Lipoproteins classes
• Based on the density, there are five classes of lipoproteins (from high to low);
they are:
High-density lipoprotein (HDL),
Low-density lipoprotein (LDL),
Intermediate density lipoprotein (IDL),
Very-low-density lipoprotein (VLDL), and
Chylomicron.
• There are two important classes of apolipoproteins; they are:
• Apolipoprotein A-I (apoA1) is an alpha mobility; be in high-density
lipoproteins (HDL). There are more than one apoA1 per HDL particle.
• Apolipoprotein B (apoB) is a beta mobility; mostly be in low-density
lipoprotein (LDL). There is only one apoB per LDL particle.
8.
9. Lipoprotein classifications (cont…)
Lipoproteins of large size have low density (contain more fat and less protein).
Whereas, lipoproteins of small size are high density with less fat and more protein.
• Chylomicron transport triglyceride (fat) from intestines to liver, skeletal muscle, and
adipose tissue. 99% of its total weight contains lipid. (exogenous)
• VLDL - Very low-density lipoproteins transport triglycerides from the liver to adipose
tissue. 91% of its total weight contains lipid.
• IDL - Intermediate density lipoproteins are not usually detectable in the blood. Its size
is between VLDL and LDL. 91% of its total weight contain lipid.
• LDL – Low-density lipoproteins transports cholesterol from the liver to cells. 80% of its
total weight contain lipid.
• HDL – High-density lipoproteins brings back cholesterol from the body tissues to the
liver. 44% of its total weight contains lipid.
Each lipoprotein has a varying proportion of triglycerides (TG) and cholesterol ester (CE).
Once cells consume lipids in the lipoprotein; the triglyceride level drops and protein raises.
10. Lipoprotein metabolism pathways
• Assembly and secretion of TG-rich VLDLs by the liver
• Lipolysis of TG-rich lipoproteins by ILP
• Receptor mediated uptake of apoB-containing lipoproteins by the liver.
• Cellular cholesterol metabolism in the hepatocyte and the enterocyte
• Neutral lipid transfer and phospholipid hydrolysis in the plasma.
PATHOGENESIS IN DYSLIPIDEMIAS
Hundreds of proteins influence lipoprotein metabolism and may
interact to produce dyslipidemia.
11. Classifications of
DYSLIPIDEMIAS
Hyperlipoproteinemia
Primary or Familial
hyperlipoproteinaemia
(FH)
Six phenotypes I , IIa , IIb, III, IV, and V
Secondary
hyperlipoproteinaemia
Hypolipoproteinemia
Secondary
Primary
• Primary / Familial caused by specific genetic abnormalities
• secondary / Acquired resulting from another underlying disorder that leads to alterations in
plasma lipid and lipoprotein metabolism
12. Phenotype Elevated Particles Major Lipid Increased
I Chylomicron TG
IIA LDL LDL-C
IIB LDL and VLDL LDL-C, TG
III IDL and remnants TC, TG
IV VLDL TG
V Chylomicron and VLDL TG
IDL = intermediate-density lipoprotein; LDL-C = low-density lipoprotein cholesterol;
TC = total cholesterol; TG = triglycerides; VLDL = very low-density lipoprotein.
Frederickson Classification of Dyslipidemias
Familial hyperlipidemias are classified according to the Fredrickson classification,
which is based on the pattern of lipoproteins on electrophoresis or ultracentrifugation. It was
later adopted by the World Health Organization (WHO).
14. (Cont….)
HYPERCHOLESTEROLEMIA
Genetic disorder Lipoproteins elevated Clinical findings
Familial Hypercholesterolemia LDL Tendon xanthomas, CHD
Familial defective apoB-100 LDL Tendon xanthomas, CHD
Autosomal dominant Hypercholesterolemia, Type 3 LDL Tendon xanthomas, CHD
Autosomal recessive Hypercholesterolemia LDL Tendon xanthomas, CHD
Sitosterolemia LDL Tendon xanthomas, CHD
• Lipoprotein lipase (LPL) – It hydrolyses the circulating triglyceride-rich lipoproteins releasing fatty acids that can be
taken up by tissues.
• CHD – Coronary Heart disease, PVD – Peripheral vascular disease
• Xanthomas are small skin blemishes that happen due to a buildup of fats under the surface of the skin. Most
common locations are Tuberous xanthoma (mostly at knees and elbows joints), Tendon xanthoma (mostly on
tendons of hands, feet and heel), Palmar xanthoma (palms and flexural surfaces of the fingers), Xanthelasma
(eyelids )
• Eruptive xanthoma – Xanthomas with Erythematous halo that appear suddenly all over the body, especially the
hands, buttocks, and the extensor surfaces of the extremities.
18. • Hypoalphalipoproteinemia (Apolipoprotein A-1 deficiency) - Low HDL
• Hypobetalipoproteinemia and Abetalipoproteinemia - Low LDL and VLDL, but not low HDL
• Chylomicron retention disease
• Cholesteryl ester transfer protein (CETP) elevation
• Familial combined hypolipidemia (does not increase risk of atherosclerosis)
• LCAT deficiency (Lecithin-Cholesterol Acyltransferase)
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) loss of function or deficiency
• Adenosine triphosphate (ATP)-binding cassette transporter (ABCA1) gene mutations
Familial HDL deficiency. This is the most common cause of low HDL and coronary artery disease.
Tangier disease
(Rare)
20. • History – H/O Eruptive xanthomas, Abdominal pain (relation between
severe hypertriglyceridemia and acute pancreatitis), Wt. gain, D.M., Estrogens,
Alcohol, Family H/o of CHD
LIPIDS IN BLOOD
TOTAL CHOLESTEROL
GOOD CHOLESTEROL
(HDL 1 and HDL 2)
BAD CHOLESTEROL
{LDL, VLDL, Lp(a)}
TRIGLYCERIDES (TG)
• Investigations
Lipid profile (Fasting)
OGTT, TSH, LFT, KFT
CHD and other risk factor
assessment by ECG, TMT,
Angiography
21. TC – (TG/5) – HDL
LDL + HDL + (TG/5)
Plasma lipid levels should be measured preferably after a 12 hrs over night fast.
LDL level
• Ideal - Less than 100 mg/dL
• Near optimal/slightly elevated - 100 to 129 mg/dL
• Borderline high - 130 to 159 mg/dL
• High - 160 to 189 mg/dL
• Severely high - Higher than 190 mg/dL
TRIGLYCERIDE level
• Ideal - Less than 150 mg/dL
• Elevated - 150 to 199 mg/dL
• High - 200 to 499 mg/dL
• Extremely high - Higher than 500 mg/dL
VLDL = (TG/5)
22. • TG to HDL-C ratio
A higher TG/HDL ratio indicates increases chance for small dense LDL phenotype
B, risk of CHD (harmful), Whereas lower TG/HDL ratio indicates larger LDL particle
(harmless).
Increases chance for small dense LDL phenotype B, risk of CHD
Normal: Less than 3.5 (in Men), < 3.0 (in Women)
Moderate: 3.5 to 5.0 (in Men), 3.0 to 4.4 (in Women)
High: More than 5.0 (in Men), > 4.4 (in Women)
• Non-HDL Cholesterol
Contains all the "bad" types of cholesterol, so is a better predictor of future CVD
risk than LDL-C
Non-HDL-C is equal to total cholesterol minus HDL-C i.e. Non-HDL-C = TC – HDL
Normal: Less than 130 mg/dL (< 3.3 mmol/l)
Borderline: 130 to 159 mg/dL (3.3 to 4.1 mmol/l)
High: More than 159 mg/dL (> 4.1 mmol.l)
23. • TC/HDL ratio (Total cholesterol/HDL cholesterol ratio)
TC/HDL-C ratio helps to predict the atherosclerosis risk, High ratio increased risk
of heart attack whereas a low ratio indicates lower risk
Calculate TC/HDL ratio by dividing the total cholesterol by high-density
lipoprotein cholesterol.
Women have higher HDL-C levels than men. Thus, the women’s ratio is lower
compared to men.
Ideal: Less than 3.5 (in Men) < 3.0 (in Women)
Moderate: 3.5 to 5.0 (in Men) 3.0 to 4.4 (in Women)
High: More than 5.0 (in Men) > 4.4 (in Women)
The Framingham Heart Study suggest a TC/HDL-C ratio of 9.6 (men) & 7 (women)
doubled the average risk.
24. • LDL/HDL cholesterol ratio
The LDL/HDL ratio calculated by dividing the LDL cholesterol by HDL cholesterol.
Ideal: Less than 2.5
Moderate: 2.5 to 3.3
High: More than 3.3
• HDL/LDL ratio
Ideal: More than 0.4
Moderate: 0.4 to 0.3
High: Less than 0.3
• VLDL
VLDL contains the highest amount of triglycerides.
VLDL is calculated by dividing the TG by 5 (TG/5).
Normal VLDL cholesterol level is between 2 and 30 mg/dL.
• During an emergency (fight or flight), the adrenal
gland needs HDL cholesterol to produce cortisone.
Critical infection (sepsis) and severe inflammation
(rheumatoid arthritis) consume a lot of HDL
cholesterol. Thus, people with these condition has low
HDL-C levels.
• Any minor liver problem, inflammation, infection, or
slow metabolism (hypothyroidism) may raise LDL level.
25. • Advanced Lipid Testing
LDL particle size – is grouping LDL particles based on size.
LDL particle number (LDL-P or Apo-B) – is measuring number of LDL particles
Lipoprotein (a) – measures the number of lipoproteins (a) particle attached with LDL.
Reference range for LDL-P
• Optimal: less than 1000 nmol/L
• Low/No risk: 1000 to 1299 nmol/L
• High risk: more than equal to 1300 nmol/L
Reference range for apoB
• Optimal: less than 60 mg/dL (<0.6 g/l)
• Moderate risk: 60 to 80 mg/dL (0.6 to 0.8 g/l)
• High risk: more than 80 mg/dL (>0.8 g/l)
Reference range for Lp(a)
• Optimal: less than 20 mg/dL (<50 nmol/l)
• Moderate risk: 20 to 30 mg/dL (50 to 75 nmol/l)
• High risk: more than 30 mg/dL (>75 nmol/l)
26.
27. Treatment Principle
Lifestyle - Dietary modification {fat restriction (Oil, Meats, Butter), no simple
carbohydrate}, Increased physical activity, Quit Smoking, Eliminate alcohol.
Elimination of associated risk factors
• Prevention of acute pancreatitis in patients with severe
hypertriglyceridemia.
• Prevention of CVD and related cardiovascular events
• Weight reduction
Antihyperlipidemic factors
• Hypertriglyceridemia – Fibrates, Omega-3 fatty acids (Fish oil), Statins
(CVD)
• Hypercholesterolemia – Statins, Cholesterol absorption inhibitors, Bile
acid sequestrants (Resins) , PCSK9 inhibitors
Simple carbohydrate – Insulin drive TG production in liver.
29. • Mechanism – HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) involved
in the synthesis of MEVALONATE, a naturally occurring substance that is then used by
the body to make sterols, including cholesterol. HMG-CoA reductage inhibitors
(Statins) block the enzyme HMG-CoA reductase.
↓ Cholesterol synthesis, ↓ VLDL production
↑ Hepatic LDL receptors (enhances the uptake and breakdown of LDL-cholesterol)
• Grapefruit juice increases levels of atorvastatin, lovastatin, and simvastatin, which
may increase the risk of side effects. So Grapefruit juice should be avoided with these
statins.
• ↑ LDL With kidney disease – Preferred Atorvastatin and fluvastatin
• Side effect – Myalgia, Myopathy, ↑ transaminases, ↑ diabetes risk
30. Cholesterol absorption inhibitor
Drugs Starting dose Maximum dose
Major
indications
Method of
Administration
Ezetimibe 10 mg daily 10 mg daily
• Elevated
LDL-C
ORAL
• Mechanism – Cholesterol absorption inhibitors reduce the absorption of dietary and
biliary cholesterol through the intestines. Therefore it deceases the amount of
intestinal cholesterol that is delivered to the liver. Reduced levels of cholesterol
delivered to the liver results in increased hepatic LDL (low density lipoprotein)
receptor activity, which leads to increased clearance of LDL cholesterol.
↓ Cholesterol absorption, ↑ LDL receptors
• Adverse effect – Elevated transaminases
↓ LDL-C
31. Bile acid sequestrants
Drugs Starting dose Maximum dose
Major
indications
Method of
Admiistation
Cholestyramine 4 g daily 32 g daily
• Elevated
LDL-C
ORAL
Colestipol 5 g daily 40 g daily
Colesevelam 3750 mg daily 4357 mg daily
• Mechanism – Bile acid sequestrants bind to bile acids (which contains cholesterol) in
the intestine and prevent their reabsorption into the body. The bound complex is
insoluble and is excreted in the faeces. Liver then needs the cholesterol from blood
to make more bile acid. This reduces cholesterol level.
↑ Bile acid excretion, ↑ LDL receptors
• Adverse effect – bloating, constipation, elevated triglycerides
↓ LDL-C
32. PCSK9 inhibitors
(Proprotein convertase subtilisin/kexin type 9 inhibitors)
Drugs Starting dose Maximum dose
Major
indications
Method of
Admiistation
Evolocumab
140 mg SQ q 2
weeks
420 mg SQ q 1
month (hoFH) • Elevated
LDL-C
Subcutaneous
injections
Alirocumab
75 mg SQ q 2
weeks
150 mg SQ q 2
weeks
• Mechanism – PCSK9 is an enzyme that binds to low-density lipoprotein receptors
(LDL receptors), which stops LDL being removed from the blood, leading to an
increase in blood levels of LDL. The PCSK9 inhibitor blocks the PCSK9 enzyme,
resulting in more LDL receptors available to remove LDL from the blood, which
produces in a decrease in LDL blood levels.
↓ PCSK9 activity, ↑ LDL receptors
• Adverse effect – Injection site reactions
↓ LDL-C
33. MTP inhibitors
(Microsomal triglyceride transfer protein inhibitors)
Drugs Starting dose Maximum dose
Major
indications
Method of
Admiistation
Lomitapide 5 mg daily 60 mg daily • HoFH Oral
• Mechanism – MTP is an endosomal protein present in hepatocytes and intestinal
enterocytes. MTP mediates triglyceride absorption and chylomicron secretion from
the intestine and VLDL secretion from the liver by linking lipid molecules with ApoB.
Inhibition of MTP reduces the level of all ApoB-containing lipoproteins,
including LDL.
↓ VLDL production
• Adverse effect – Nausea, diarrhoea, increased hepatic fat
(HoFH - Homozygous Familial Hypercholesterolemia)
↓ HoFH
34. ApoB inhibitors
(Apolipoprotein B Synthesis Inhibitor)
Drugs Starting dose Maximum dose
Major
indications
Method of
Admiistation
Mipomersen
200 mg SC
weekly
200 mg SC
weekly
• HoFH
Subcutaneous
injections
• Mechanism – Apolipoprotein B-100 (ApoB-100) allows LDLs to attach to specific
receptors on the surface of cells, particularly in the liver. Once attached, the
receptors transport LDLs into the cell, where they are broken down to release
cholesterol. ApoB inhibitors reduce the production of ApoB-100 in the liver cells.
↓ VLDL production
• Adverse effect – Injection site reactions, Flu-like symptoms, increased hepatic fat
↓ HoFH
(HoFH - Homozygous Familial Hypercholesterolemia)
35. Fibric acid derivatives
Drugs Starting dose Maximum dose
Major
indications
Method of
Admiistation
Gemfibrozil 600 mg BID 600 mg BID • Elevated
TG
Oral
Fenofibrate 145 mg OD 145 mg OD
• Mechanism – Fibrates activate the protein called PPAR-alpha (peroxisome proliferator-
activated receptor alpha) which in turn activates the enzyme LPL (lipoprotein lipase).
This increases lipolysis and the elimination of triglycerides from the plasma.
↑ LPL, ↓ VLDL synthesis
• Adverse effect – Dyspepsia, myalgia, Gall stones, Elevated transaminases
↓ TG
36. Omega-3 fatty acids
Drugs Starting dose Maximum dose
Major
indications
Method of
Admiistation
Omega-3 fatty
acid ethyl
esters
4 g daily 4 g daily • Elevated
TG
Oral
Icosapent ethyl 4 g daily 4 g daily
• Mechanism – Omega-3 fatty acids slow the rate at which the liver makes
triglycerides. Omega-3 fatty acids also have an anti-inflammatory effect in the body,
decrease the growth of plaque in the arteries and aid in thinning blood.
↑ TG catabolism
• Adverse effect – Dyspepsia, fishy odor to breath
↓ TG