disorders of lipid metabolism lecture
TRANSCRIPT
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