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A 46 year old man was diagnosed with hyperlipidaemia when he was 15 years old, his father and grandfather died when they were in the fifth decade. The man is active and has no signs of CVD, his medication is Lovastatin. His laboratory results: TG 95 mg/dl (N:< 150) TC 269 mg/dl (N:< 200) HDL 47 mg/dl (N: 40-60) LDL 205 mg/dl (N:< 130)
INTRODUCTION
Chylomicrons transport dietary TGs and cholesterol from the intestine into the circulation. In the capillaries of adipose and muscle tissue, (apo C-II) on the chylomicron activates endothelial (LPL) to convert most of chylomicron TG to fatty acids and glycerol.
Cholesterol-rich chylomicron remnants are taken by the liver in a process mediated by apoprotein E (apo E).
VLDL contain apoprotein B-100 (apo B), are synthesized in the liver, and transport TGs and cholesterol to peripheral tissues. VLDL synthesis increases with increases in intrahepatic FFA, such as occur with high-fat diets and when excess adipose tissue releases FFAs directly into the circulation (eg, in obesity, uncontrolled diabetes mellitus).
Apo C-II on the VLDL surface activates endothelial LPL to break down TGs into FFAs and glycerol, which are taken up by cells
IDL
are
cholesterol-rich
VLDL
and
LDL,
the
products
of
VLDL
and
IDL
metabolism, are the most cholesterol-rich of all lipoproteins. About 40 to 60% of all LDL
Nonhepatic
scavenger
receptors,
most
hepatic receptors.
the
subendothelial
space
and
become
macrophages; these macrophages then take up more oxidized LDL and form foam cells within atherosclerotic plaques
High-density lipoproteins (HDL) are initially cholesterol-free lipoproteins that are synthesized in both enterocytes and the liver.
The overall role is to obtain cholesterol from peripheral tissues and other lipoproteins and transport it to where it is needed (to other tisuues e.g. liver) Its overall effect is antiatherogenic. Free cholesterol in nascent HDL is esterified by the enzyme lecithin-cholesterol acyl transferase (LCAT), producing mature HDL.
HYPERLIPOPROTEINAEMIAS
Classification
They
are either: A) Primary: group of genetically determined disorders B) Secondary: due to other acquired diseases such as obesity, diabetes, metabolic syndrome, hypothyroidism Hyperlipidiaemias was classified by the WHO according to the work of Fredrickson who classified the disorders according to the type of lipid that increased in blood
This classification does not take in its account HDL-cholesterol abnormalities and also one genetic abnormalities may be reflected with different phenotype changes In general increased plasma lipid concentration is multifactor and may be due to: Genetic factors Environmental factors A combination of the above
Or secondary to other diseases
Primary hyperlipoproteinaemias
In the majority of the patients, the abnormality is due combination of undetermined genetic factors and dietary factors In about of 5 % only, there is specific genetic defects mainly in one of the following: A) the production or nature of the tissues receptors for apoB100 B) the structure of the apoB100 itself
Heterozygotes have about 50 % of the receptors activity and about half of them will develop symptoms of CVD by the fourth or fifth decade
Homozygotes have no receptors activity and develop heart diseases in the second decades Cholesterol levels may reach 8-15 mmol/L (300-580 mg/dl) or much higher especially in homozygotes
Tendon xanthomas
Corneal arcus
It is associated with defects in the production or catabolism of VLDL , HDL-cholesterol is often reduced with normal total cholesterol. In diabetic patients high VLDL may associated also with high chylomicrons be
Also, they are in increased risk of CVD due to decreased HDL levels
It is difficult to classify with unclear picture of inheritance and it is autosomal dominant with population prevalence of 1:200
The patient may have increased VLDL only, LDL only or both of them
Mainly it is due to defect in the conversion of VLDL into LDL, it is associated with apoE2/2 genotype.
Lp(a) Elevation
It is variant of LDL with extra apolipoprotein, called apo (a), it is elevated in blood of patients with CVD more than normal subjects
Unfortunately all cholesterol lowering drugs have no effect on Lp(a) elevation even if the total cholesterol has been significantly
reduced
Secondary causes contribute to 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 fats. Trans fats are polyunsaturated or monounsaturated fatty acids to which hydrogen atoms have been added they are commonly used in many processed foods and are as atherogenic as saturated fat.
Other common secondary causes include: 1- Diabetes mellitus 2- Obesity 3- Nephrotic syndrome 4-Alcohol overuse 5-Chronic kidney disease 6-Hypothyroidism 7-Cholestatic liver diseases 8-Drugs, such as thiazides, -blockers, retinoids, antiretroviral agents, estrogen and progestins, ACE inhibitors and glucocorticoids
Let us take an idea about the prevalence of causes of secondary hyperlipidaemias in KSA
Diabetes mellitus in Saudi Arabia, a survey by AlNozha et al., (2004) Diabetes mellitus in Saudi Arabia. SAUDI MEDICAL JOURNAL , 25.
According
42.2
Prevalence
35.5-40.1
Prevalence of peripheral arterial diseases (PAD): in a survey done by Sultan O. Al-Sheikh, et al., 2007
11.7
Diabetes is the major cause of secondary hyperlipidaemia because patients tend to have an atherogenic combination of high TGs; high small, dense LDL fractions; and low HDL Patients with type 2 diabetes are especially at risk. Obesity and poor control of diabetes increase circulating FFAs (FFA synthesis is increased due to increase in the rate of HMP pathway), 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 type 2 diabetes.
The hyperlipidemia in nephrotic syndrome is characterized by elevated triglycerides and cholesterol and is possibly secondary to two factors: A) Hypoproteinemia is thought to stimulate protein synthesis in the liver, including the overproduction of lipoproteins.
B) Decreased lipid catabolism due to lower levels of lipoprotein lipase, the main enzyme involved in lipoprotein breakdown
Investigation
Dyslipidemia is suspected in patients with characteristic physical findings or complications of dyslipidemia (e.g., atherosclerotic disease).
C) Family history of atherosclerotic disease Serum cholesterol > 240 mg/dL (> 6.2
mmol/L).
Dyslipidemia measuring
is serum
diagnosed lipids.
by
Routine
total
cholesterol
(TC),
TGs,
HDL-
Lipid profile measurement: TC, TGs, and HDLcholesterol are measured directly; TC and TG values reflect cholesterol and TGs in all circulating lipoproteins, including chylomicrons, VLDL, IDL, LDL, and HDL.
TC values vary by 10% and TGs by up to 25% day-to-day even in the absence of a disorder.
Lipid profiles can vary for about 30 days after an acute MI; however, results obtained within 24 h after MI are usually reliable enough to guide initial lipid-lowering therapy
Other tests:
Patients with (a) premature atherosclerotic cardiovascular disease, (b) cardiovascular disease with normal or near-normal lipid levels, (c) high LDL levels refractory to drug therapy or (d) patients with borderline high LDL-cholesterol levels should probably have Lp(a) levels measured. C-reactive protein and homocysteine measurement may be indicated in the same patients.
Creatinine
TSH Urinary protein Screening: A fasting lipid profile should be obtained in all adults >20 yr and should be repeated every 5 yr. Other risk factors should be considered (diabetes, hypertension, sedentary life, obesity, and smoking)
Hypolipidemia
It
is
usually
asymptomatic
and
Hypolipidemia is defined as a total cholesterol (TC) < 120 mg/dL (< 3.1 mmol/L) or low density lipoprotein cholesterol (LDLcholesterol) < 50 mg/dL (< 0.13 mmol/L).
Undernutrition
Malabsorption
Genetic causes
Abeta lipoproteinaemia:
Complete absence of apoB (chylomicron,
VLDL, IDL and LDL)
These lipoproteins are absent in plasma There is severe vitamin E deficiency with neurological manifestation
Tangier
disease:
It is due to increased rate of apo A-I catabolism HDL-cholesterol is markedly decreased LDL-cholesterol is slightly affected
Cholesterol esters accumulate in the reticuloendothelial system may be due to excessive phagocytosis of abnormal chylomicron and VLDL remnant containing less amount of apoA-I