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

ClassificationThey 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 and corneal arcus are

common in affected individualscommon in affected individuals

Tendon xanthomas

Corneal arcusCorneal 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 be

associated also with high chylomicrons

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 The condition is exagerated by

environmental factors such as obesity, environmental factors such as obesity,

alcohol intake, use of thiazide diuretics, use alcohol intake, use of thiazide diuretics, use

of the oral contraceptive pill and of the oral contraceptive pill and

glucocorticoids 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, β-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 Al-Nozha 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 is diagnosed by

measuring serum lipids. Routine

measurements (lipid profile) include

total cholesterol (TC), TGs, HDL-

cholesterol, and LDL-cholesterol.

Lipid profile measurement: TC, TGs, and HDL-

cholesterol 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 (LDL-cholesterol) < 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