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DISORDERS OF LIPID METABOLISM

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

Intermediate-density lipoproteins (IDL) are


the product of LPL processing of VLDL and chylomicrons.

IDL

are

cholesterol-rich

VLDL

and

chylomicron remnants that are either cleared

by the liver or metabolized by hepatic lipase


into LDL, which retains apo B.

LDL,

the

products

of

VLDL

and

IDL

metabolism, are the most cholesterol-rich of all lipoproteins. About 40 to 60% of all LDL

are cleared by the liver in a process mediated


by apo B and hepatic LDL receptors.

Hepatic LDL receptors are down-regulated by


delivery of cholesterol to the liver by chylomicrons and by increased dietary saturated fat; they can be up-regulated by decreased dietary fat and cholesterol.

Nonhepatic

scavenger

receptors,

most

notably on macrophages, take up excess oxidized circulating LDL not processed by

hepatic receptors.

Monocytes rich in oxidized LDL migrate into

the

subendothelial

space

and

become

macrophages; these macrophages then take up more oxidized LDL and form foam cells within atherosclerotic plaques

There are 2 forms of LDL: large and small, dense LDL.


Small, dense LDL is very rich in cholesterol esters, and increased in condition as hypertriglyceridemia and insulin resistance, and they are highly atherogenic. This atherogenicity of small, dense LDL is due to decrease in hepatic LDL receptor binding, leading to prolonged circulation and exposure to endothelium and increased oxidation.

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.

FATE OF DIFFERENT LIPOPROTEINS

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

1- Familial hypercholesterolaemia (TYPE IIA)

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

Heterozygote patients can benefit from drugs


that inhibit cholesterol synthesis (Statins), as inhibition of cellular cholesterol synthesis will stimulate receptor synthesis

Homozygote can not benefit from this drugs

and treated mainly by a method known as


LDL pheresis

Tendon xanthomas and corneal arcus are


common in affected individuals

Tendon xanthomas

Corneal arcus

2- Familial hypertriglyceridaemia (Type IV)

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

The patient are in increased risk of attacks of acute pancreatitis

Also, they are in increased risk of CVD due to decreased HDL levels

Often overweight and diabetic


More than 30 years old hyperuricaemia The condition is exagerated by environmental factors such as obesity, alcohol intake, use of thiazide diuretics, use of the oral contraceptive pill and glucocorticoids Autosomal dominant inheritance

3- Familial combined hyperlipidaemia (Type 2B)

It is difficult to classify with unclear picture of inheritance and it is autosomal dominant with population prevalence of 1:200

Often is due to hepatic overproduction of

apoB leading to increased in VLDL and


eventually LDL

The patient may have increased VLDL only, LDL only or both of them

4- Remnant hyperlipoproteinaemia (Type III)

It is rare compared to the other primary hyperprteinaemias

Clinically, the patients are in increased risk of premature CVD

In plasma there is increased in VLDL-like particles very rich in cholesterol

Both plasma cholesterol and triglycerides


are elevated often with normal or even decreased LDL

Mainly it is due to defect in the conversion of VLDL into LDL, it is associated with apoE2/2 genotype.

5- Lipoprotein lipase defeciency (Type 5)

It is rare autosomal recessive disorders, it

is due to deficiency of lipoprotein lipase


enzyme or its activators apoC-II

Acute pancreatitis and CVD are common

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

It is highly similar to the coagulation factor, plasminogen

It is considered that due to this similarity,

there is competition between them for


binding to fibrin

If apo (a) binds fibrin it will lead to clot


formation along the arterial wall that will not be dissolved

Unfortunately all cholesterol lowering drugs have no effect on Lp(a) elevation even if the total cholesterol has been significantly

reduced

Secondary hyperlipoproteinaemias & Risk factors

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.

Prevalence of diabetes ranges from 19.5-25.5 %

According

to the WHO data the prevalence of obesity in KSA, Year: 2000 :

42.2

Prevalence

of metabolic syndrome in KSA, in a survey done by Alnozha et al., 2005:

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 and Hyperlipidaemia

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.

Nephrotic syndrome and hperlipidemia

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).

Primary lipid disorders are suspected when


patients have:

A) Physical signs of dyslipidemia B)Onset of premature atherosclerotic

disease (at < 60 yr)


C) Family history of atherosclerotic disease Serum cholesterol > 240 mg/dL (> 6.2

mmol/L).

Dyslipidemia measuring

is serum

diagnosed lipids.

by

Routine

measurements (lipid profile) include

total

cholesterol

(TC),

TGs,

HDL-

cholesterol, and LDL-cholesterol.

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.

It is recommended to postpone lipid profile


test until after resolution of acute illness, because TG increases and cholesterol levels decrease in inflammatory states.

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.

Investigation for secondary causes:


Measurements of fasting glucose Liver enzymes

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

Hypolipidemia is a decrease in plasma lipoprotein caused by primary (genetic) or secondary factors.

It

is

usually

asymptomatic

and

diagnosed incidentally on routine lipid screening.

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).

Secondary causes include:


Hyperthyroidism

Chronic infections and other inflammatory states


Cancers

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

It appears early in life

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

NCEP AND ATP III GUIDELINES

ATP III Classification of Total Cholesterol and LDL Cholesterol

Classification of serum triglycerides

Classification of HDL cholesterol